Abstract
Ubiquitination is a critical type of post-translational modifications, of which K63-linked ubiquitination regulates interaction, translocation, and activation of proteins. In recent years, emerging evidence suggest involvement of K63-linked ubiquitination in multiple signaling pathways and various human diseases including cancer. Increasing number of studies indicated that K63-linked ubiquitination controls initiation, development, invasion, metastasis, and therapy of diverse cancers. Here, we summarized molecular mechanisms of K63-linked ubiquitination dictating different biological activities of tumor and highlighted novel opportunities for future therapy targeting certain regulation of K63-linked ubiquitination in tumor.
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Facts
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Ubiquitination is a critical type of post-translational modifications.
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K63-linked ubiquitination regulates interaction, translocation, and activation of proteins.
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K63-linked ubiquitination controls initiation, development, invasion, metastasis, and therapy of diverse cancers.
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Increasing technologies and comprehensive understanding of ubiquitination signal suggest promising therapeutic strategies to improve tumor therapy.
Open questions
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The role of K63-linked ubiquitination in the initiation, development, and metastasis of cancer was not clearly clarified.
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What are the molecular mechanisms of K63-linked ubiquitination dictating different biological activities of tumor?
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Is it a promising strategy in clinical cancer treatment targeting ubiquitinated proteins and sites?
Introduction
As one of the most essential regulation of proteins, post-translational modifications (PTMs) represent the residue modifications of certain amino acid, which determine functions of proteins in various aspects [1]. PTMs mainly involve ubiquitination, phosphorylation, acetylation, methylation, glycosylation, and SUMOylation, which regulate multiple biological progresses including proliferation, death, differentiation, and cell cycle [2]. Ubiquitination is the connection of ubiquitin, a molecule consisted with 76-amino acid, with the substrate protein or itself in covalent form via its C-terminus [3]. According to the number of connected ubiquitin molecules, ubiquitination can be classified into mono-ubiquitination (modified by a single ubiquitin molecule) and poly-ubiquitination (modified by a ubiquitin chain) [4]. From a functional perspective, mono-ubiquitination often alters the interaction, localization, and transport of protein substrates, while poly-ubiquitination is mainly related with proteasome-dependent degradation, activity and translocation of the substrates [5]. As for poly-ubiquitination, ubiquitin molecule can be linked each other through seven different receptor sites, since ubiquitin molecules contain seven sites of lysine (K6, K11, K27, K29, K33, K48, and K63) [6]. K48-linked polyubiquitin chains are usually related with the proteolysis of certain substrates through the ubiquitin-proteasome system [7]. K63-linked polyubiquitin chains, however, modulate the activity, interaction or intracellular trafficking of tagged proteins, participating in diverse biological procedures [3].
A number of properties of protein could be affected by K63-linked ubiquitination such as protein-protein interaction, translocation, and activation. For example, the K63-linked ubiquitination of β-catenin is regulated by RNF8, which promotes its nuclear translocation and further oncogenic activity [8]. In addition, K63-linked polyubiquitination of ERK controlled by TRIM15 and CYLD determines its interaction with and activation by MEK [9]. Various physiological and pathological processes could be influenced by K63-linked ubiquitination. For instance, K63-linked ubiquitination of TBK1, regulated by E3 ubiquitin ligase RNF128, facilitates innate immunity [10]. K63-linked ubiquitination of YAP induced by IL-1b-TRAF6 signaling in macrophages leads to increased YAP stability and nuclear entry, resulting in pro-inflammatory gene expression and subsequently atherosclerosis [11]. Integrin α3β1 controls Akt K63-linked polyubiquitination in a TRAF6-dependent manner, thus modulating the development of kidney collecting duct [12]. Importantly, K63-linked ubiquitination influence different processes of cancer, including tumorigenesis, development, metastasis and therapy. In this review, we summarized different aspects of tumor biological activities in relation to K63-linked ubiquitination as well as their molecular mechanisms and potential future applications.
K63-linked ubiquitination and tumorigenesis
Tumorigenesis is a gradual process by which normal cells develop into tumors, which involves multistage reactions and the accumulation of key mutations. A number of signaling pathways are often altered including PI3K/AKT signaling, Wnt/β-Catenin signaling, SAPK/JNK signaling, Hippo Signaling in the tumor initiation [13].
PI3K/Akt signaling
PI3K/AKT signaling pathway participates in the regulation of multiple biological processes of proliferation, metabolism, growth, transcription, and protein synthesis [14]. Akt regulates proliferation of cells by mTOR signaling and phosphorylating CDK inhibitors p21 and p27. As a serine/threonine kinase, AKT is activated by PI3K or phosphoinositide-dependent kinases (PDK), which is frequently dysregulated in multiple diseases of diabetes, cardiovascular diseases, and cancer [15].
The K63-linked polyubiquitination of Akt was found to regulate tumorigenesis. The K63-linked ubiquitination Akt and its activation is affected by E3 ligase activity of Skp2 SCF complex, which is responsible for subsequent oncogenesis [16]. Furthermore, SETDB1 methylates Akt and facilitates the K63-linked ubiquitination as well as activation of Akt, resulting in tumor initiation [17]. In addition, E3 ubiquitin ligase TRAF2 and deubiquitinating enzyme OTUD7B control a K63-linked polyubiquitination switch of GβL that modulates homeostasis and activation of mTORC2/AKT signaling [18].
Wnt/β-catenin
The Wnt/β-catenin pathway modulates the pluripotency of stem cell and affects how cells differentiate during development [19]. The on or off state of Wnt receptor complex controls β-catenin degradation or enter into nuclear, thus altering the expression of target genes. Wnt/β-catenin pathway contributes to different types of cancers especially colon cancer [20].
Previous studies revealed that K63-linked ubiquitination of Wnt/β-catenin promote carcinogenesis. Trabid could bind to and deubiquitinate APC, a tumor suppressor protein of Wnt signaling, which regulates β-catenin destruction complex and promotes cancers [21, 22]. In addition, the oncogenic potential of Usp14 has been reported for deubiquitination of Dvl at K444, K451 sties and reinforcement of Wnt signaling of colorectal cancer [23]. It was suggested that E3 ligase Pellino-1 facilitates lung cancer through stabilizing Snail and Slug by K63-linked ubiquitination [24]. Besides, Rad6B mediates K63-linked ubiquitination of β-catenin at K394 site, which regulates the stability and activity of β-catenin in breast cancer [25].
c-Myc
Highly regulated by various transcriptional regulatory mechanisms, the proto-oncogene c-Myc, participates in multiple growth promoting signaling pathways. Aberrant Myc status impedes genomic stability in relation to tumorigenesis [26].
Several studies suggested that the oncogenic effect of c-Myc is mediated by K63-linked ubiquitination. For example, ZCCHC2 has been reported to suppress RB tumorigenesis via inhibiting HectH9-mediated K63-linked ubiquitination and activation of c-Myc [27]. FBXL6 promotes K63-dependent ubiquitination of HSP90AA1 and its stabilization, which leads to c-Myc activation to promote hepatocellular carcinogenesis [28]. In addition, TRAF6 facilitates hepatocarcinogenesis through interaction with and regulation of HDAC3 K63-linked ubiquitination at K422 to increase c-Myc gene expression and stabilization [29].
JNK
JNK pathway are responsible for numerous biological processes of protein expression, inflammatory responses, growth, differentiation, survival, and death of cells [30]. JNK functions together with NF-κB, JAK/STAT or other regulatory factors to sustain cell survival. In tumor development, JNK regulates cell apoptosis, cell survival and immune response of cancer [31].
CYLD removes K63-linked ubiquitination c-Fos and c-Jun, and blocks JNK/AP1 signaling, thereby inhibiting tumorigenesis and metastasis of epidermal malignancy [32]. Besides, BLM enhances Fbw7a-mediated c-Jun K63-linked ubiquitylation and suppresses cancer by preventing its oncogenic activity [33].
YAP/TAZ
As transcriptional coactivators encoded by paralogous genes, YAP and TAZ proteins translocate cytoplasm/nucleus upon different stimulus, including the Hippo pathway [34]. It has been reported that YAP/TAZ remodel cancer cells into cancer stem cells and promote occurrence, growth, and metastasis of cancer [35].
TAK1 has been reported to inhibit YAP/TAZ proteasomal degradation through a complex with E3 ligase TRAF6, thereby promoting their K63-ubiquitination in contrast to K48-ubiquitination [36]. In addition, non-proteolytic K63-linked ubiquitination of YAP controls nuclear translocation and its activity, which is regulated by the E3 ligase complex SKP2 and the deubiquitinase OTUD1 at K321, K497 sites [37].
Carcinogen
Carcinogen generally includes an agent, mixture, or exposure that lead to carcinogenesis. Carcinogenic chemicals often induce DNA damage to facilitate tumor formation [38].
Carcinogen Cadmium leads to protein aggregates as well as inactivates CYLD to deubiquitinate K63-ubiquitinated proteins and selective autophagy to degrade them [39]. In addition, K63-linked polyubiquitination chains decrease mutagenicity of human lung cells against benzo[a]pyrene-diol-epoxide and contribute to genomic stability [40].
Others
The K63-linked ubiquitination of other substrates also participate in the regulation of carcinogenesis. For instance, IL-17B/IL-17RB signaling pathway leads to malignant transformation of cancer stem cells via promoting binding of TRAF6 to Beclin-1 and its K63-mediated ubiquitination [41]. Ubiquitination of CALML5 in the nucleus contribute to carcinogenesis of breast cancer, and K63-linked ubiquitination of CALML5 was found in breast cancer tissue, but not in healthy tissue [42]. The E3 ligase HectH9 mediated K63-polyubiquitination of DDX17 upon hypoxia to modulate stem-like and tumor-initiating abilities [43]. Tankyrases bind to and ribosylate LKB1, inducing its K63-linked ubiquitination through RNF146 and inhibiting LKB1 activation. Tankyrase inhibitors activates LKB1, thus promoting AMPK and suppressing tumor [44]. SKP2 regulates Bcr-Abl by inducing its K63-linked ubiquitination and subsequent activation, promoting the initiation and development of chronic myeloid leukemia (CML) [45]. In addition, SKP2 reduces the K63-linked ubiquitination of JARID1B through affecting TRAF6. Inactivating SKP2 inhibits the initiation of prostate cancer via ubiquitination of JARID1B [46]. PLK1 phosphorylates KLF4 and recruits TRAF6, which leads to K63-linked ubiquitination of KLF4 at K32 site and promotes nasopharyngeal cancer [47]. In addition, K95 acetylation of SHMT2 induces SHMT2 degradation by TRIM21-mediated K63 ubiquitination dependent of glucose concentration. Deacetylation of SHMT2 by SIRT3 promotes colorectal carcinogenesis [48].
K63-linked ubiquitination and tumor growth
One of the most distinct characteristic of cancer cells is unlimited proliferation [49]. Normal cells finely regulate the generation of pro-proliferative signaling pathways, thus keeping stable cell amount as well as maintaining structure and function in tissue. Under the stimulation of multiple carcinogenic factors, the cells escape from normal regulatory mechanism of their growth, and then lead to aberrant cell proliferation [50].
PI3K/Akt signaling
The activation of Akt is promoted by its K63 ubiquitination, which leads to tumorigenesis. As an E3 ligase, RNF8 activates Akt by K63-linked ubiquitination, which facilitates proliferation of lung cancer cells [51]. In addition, F-box protein FBXL18, the subunit of SCF E3 ligase complex, contributes to glioma growth by facilitating Akt K63-linked ubiquitination [52]. Besides, Skp2-mediated K63-ubiquitination and activation of Akt, which promotes mitochondrial localization of EGF-induced Akt and tumor growth [53]. Stimulation of growth factor promotes dissociation between CYLD and Akt, thus permitting E3 ligases for Akt ubiquitination and activation [54]. BDMC promotes the CYLD expression, mediating Akt K63 deubiquitination and inactivation, which inhibits hepatocellular carcinoma proliferation [55].
RNF
As a subfamily of ubiquitin ligases, RING finger (RNF) proteins have 49 protein members sharing transmembrane regions. The RING E3 ligases, the major member of RNFs, induce translocation of ubiquitin molecules from E2-ubiquitin intermediates to the substrate [56].
It has been found that RNF8 promotes Twist activation by inducing its K63-linked ubiquitination, which facilitates progression of tumor [57]. Also, RNF8 facilitates c-Myc expression and colon cancer proliferation by mediating β-catenin K63 ubiquitination as well as nuclear translocation [8]. RNF6, another member of RNF family, contributes to proliferation of myeloma cell by inducing K63-linked ubiquitination of glucocorticoid receptor [58]. In addition, RNF181 mediates K63-linked ubiquitination and stabilization of ERα, thus regulating progression of breast cancer [59].
TRAF
TNFR-associated factors (TRAFs) play crucial role in regulation of IL-17 signaling and proper immune response [60]. TRAFs have been found to function as mediators of multiple stimulation and regulate the downstream activity of many cytokine receptors [61]. TRAFs participate in various biological processes of growth, differentiation, and death of cells [62].
HTLV-1 tax protein regulates MCL-1 stability through TRAF6-mediated K63-linked ubiquitination to promote cell survival [63]. SKP2 knockdown inhibits EZH2 expression prostate cancer cells by promoting TRAF6-induced K63-linked ubiquitination of EZH2 for degradation [64]. Epigallocatechin-3-gallate has been reported to inhibit growth of melanoma cell through suppressing TRAF6 activity [65]. In addition, the link between TRAF6 and autophagy also results in cancer progression. For example, NPM1-mA promotes TRAF6-mediated K63 ubiquitination and stability of ULK1, thus modulating autophagy progress and facilitating proliferation of leukemic cell [66]. TRAF6 interacts with p62 and activates mTORC1 by catalyzing its K63 ubiquitination, which regulate autophagy and cancer cell growth [67]. Autophagy induced by TLR4 or TLR3 activation stimulates multiple cytokine productions via TRAF6 K63-linked ubiquitination and thus facilitates progression of lung cancer cells [68]. Besides, TRAF2 induces K63-linked ubiquitination of DYRK1A, which results in its translocation to vesicles and interaction with SPRY2. Phosphorylated SPRY2 suppresses the endocytosis and recycling of EGFR, which facilitates glioma cell proliferation [69].
CYLD
As a deubiquitination enzyme (DUB), CYLD could remove the K63-linked polyubiquitin chains from substrates and affect various cellular functions. Decreased CYLD expression is involved in diverse kinds of tumor, CYLD has been regarded as a tumor suppressor gene [70].
CYLD has been reported to interact with and modulate K63-linked ubiquitination of Dvl. Loss of CYLD stimulates tumor growth in human cylindromatosis by hyperubiquitination of Dvl and enhanced Wnt signal [71]. In addition, CYLD phosphorylation impairs its deubiquitinating function, leading to enhanced RIPK1 K63-linked ubiquitination and survival signal of Adult T-cell leukemia/lymphoma cells [72]. Moreover, cancer-related mutations alter CYLD structure and which disturb its binding capacity to K63 ubiquitin molecule. The absence of CYLD DUB activity enhances cancer-promoting function and increases survival of cells [73].
P53
As a tumor suppressor gene, p53 closely modulates cell proliferation via inducing apoptosis and DNA repair response under stressful conditions [74]. The tumor suppressor p53 exerts multiple functions in the cell by regulating different regulatory signals that ensure accurate cellular responses to stress. p53 status is usually inactive due to ubiquitination by various E3 ubiquitin ligases which target p53 for proteasomal degradation [75].
The K63-linked ubiquitination of p53 has been reported to regulate cancer progression. TRIM31 interacts with p53 and mediates its K63-linked ubiquitination to inhibit breast cancer development [76]. TRIM45 suppresses tumor progression in the brain by stabilizing p53 through K63-linked ubiquitination [77]. TRAF6 restricts amount of p53 in mitochondria by inducing K63-linked ubiquitination of p53 at K24 site in cytoplasm. In addition, TRAF6 facilitates the K63-linked ubiquitination of nuclear p53, which therefore influence apoptosis and tumor inhibition [78].
Cell cycle
Cell cycle is a complicated process that involves numerous regulatory proteins that dictates the cell through a series of events culminating in mitosis and the generation of two new cells [79]. Cell cycle process is orchestrated by sequential activation of cyclin-dependent kinases (CDKs) by their corresponding cyclin partner. The cell cycle represents an irreversible process that sustains multiple sequenced events controlled by three key checkpoints [80].
DZIP3 interacts with and promotes K63-linked ubiquitination and stabilization of Cyclin D1, which drives cell cycle and cancer progression [81]. In addition, ERLIN2 induces K63-linked ubiquitination of Cyclin B1 to stabilize it for modulating cell cycle progression of breast cancer [82]. Besides, FBW7 suppresses cell growth and G2/M cell cycle transition by inducing K63-linked ubiquitination of γ-catenin [83].
TRIM
Tripartite motif (TRIM) family proteins, most of which possess E3 ubiquitin ligase activities because they contain a RING-finger domain, play various roles in cellular processes including intracellular signaling, autophagy, apoptosis, protein quality regulation, innate immunity, development, and carcinogenesis [84].
TRIM9s induces the K63-linked ubiquitination of MKK6 at K82, thus suppressing the K48-linked ubiquitination of MKK6 at this site responsible for degradation. In turn, MKK6 increases stability of TRIM9s by inducing its phosphorylation by p38, thus inhibiting its ubiquitin-proteasome degradation. The interaction and stabilization of TRIM9s with MKK6 enhance p38 pathway to suppress progression of glioblastoma [85]. Besides, TRIM56 keeps stability of ER alpha protein by targeting its K63-linked ubiquitination to enhance estrogen signaling and growth of breast cancer [86].
Metabolism
Metabolism refers to various kinds of reactions in organisms that can maintain the process of life. Metabolic processes involve multiple interrelated cellular pathways that ultimately provide cells with the energy they need to perform their functions [87]. It has long been known that cancers have remodeled metabolism pattern to help meet the needs of cells that have the potential for uncontrolled proliferation.
The ubiquitin ligase HectH9 hijacks Hexokinase 2 (HK2) to mitochondria K63-linked ubiquitination for promoting its dual functions in glycolysis and apoptosis suppression, which in turn contribute to tumor development [88]. Furthermore, PSMD14 suppresses K63-linked ubiquitination of PKM2 and pyruvate kinase activity, which promotes its nuclear translocation and leads to aerobic glycolysis and progression of ovarian cancer [89].
Others
Some other regulation of K63-linked ubiquitination also participates in the growth of tumor. As an E2 enzyme specific for K63-linked ubiquitin, UBE2N has been found to potentiate melanoma proliferation through MEK-FRA1-SOX10 pathway [90]. USP10 removes TRIM25-induced K63 polyubiquitination of PTEN and activate it, thus inhibiting growth of lung cancer [91]. Ubiquitin E3 Ligase Pellino-1 suppresses IL-10-mediated polarization of macrophage by IRAK1 K63 ubiquitination and STAT1 activation, which leads to decreased tumor proliferation rate [92]. Skp2-SCF induces K63-linked ubiquitination of LKB1, which regulates its activation and liver cancer growth [93]. USP1 has been found to deubiquinate K63-linked ubiquitination of ULK1, which modulates autophagy and tumor growth [94]. GASC1 transcriptionally represses ubiquitin ligase FBXO42, thus reducing degradation of ROCK2 via K63 ubiquitination and promoting growth of hepatocellular carcinoma [95]. NEDD4 ubiquitin E3 ligase catalyzes K63-linked ubiquitination of IGPR-1, resulting in its lysosomal-dependent degradation to suppress angiogenesis and tumor growth [96]. Skp2 induces K63-linked ubiquitination of MTH1, which promotes its stability and growth of melanoma cells upon oxidative stress [97]. Moreover, hypoxia induces K63 ubiquitination of HAUSP and subsequent HIF-1α deubiquitination, which induces H3K56 acetylation by CBP on promoters of HIF-1α target genes [98].
K63-linked ubiquitination and tumor invasion
The invasive behavior of cells is a unique sign of cancer, which is characterized by the invasion of cells to change the original cellular environment. The steps of cell invasion include cell adhesion, degradation of extracellular matrix proteins and final cell migration [99]. Cancer development is characterized by the capacity of cancer cells to exploit an innate migratory ability to invade peri-tumor tissues [100].
Breast cancer
Breast cancer, the most frequently occurred cancer and the leading cause of cancer-related death of women, is affected by multiple genetic and epigenetic factors. Breast cancer is classified as hormone receptor positive, HER2 positive and triple-negative breast cancer on the basis of certain characteristics [101].
Several studies unraveled the critical of K63-linked ubiquitination in regulating breast cancer invasion. For example, Ubc13-Uev1A complex activates AKT pathway via K63-linked ubiquitination and increases CT45A expression, resulting in cell migration and EMT of breast cancer cells [102]. TRIM59 suppresses K63 ubiquitination by RNFT1 and PDCD10 degradation by p62-mediated selective autophagy, which promotes migration of breast cancer cells [103]. Besides, K63-linked ubiquitination was suggested as a regulator of arachidonic acid-induced adhesion and migration of cells [104].
Lung cancer
Lung cancer is a malignant tumor with the high incidence rate and mortality in the world. Emerging epidemic studies reveal that smoking, air pollution, harmful occupational exposure, genetic susceptibility, radiation exposure are responsible for high incidence of lung cancer [105]. Lung cancer are divided into small cell carcinoma and non-small cell carcinoma, which are useful for prognosis evaluation and therapy decisions [106].
TRAF6 upregulation and K63-linked ubiquitination is found in lung cancer cells, while TRAF6 knockdown suppresses the invasion of lung cancer cells [107]. TRIM37 promotes K63-linked ubiquitination of TRAF2, activating the NF-κB pathway and enhancing the aggressive behaviors of NSCLC cells [108]. In addition, K63-linked ubiquitination of TRAF4 promotes aggressiveness of lung cancer by remodeling tumor microenvironment of certain fibroblasts [109].
Nervous system cancer
Gliomas are tumors of central nervous system that originate from oligodendrocytes or astrocytes [110]. As a common and malignant brain cancer, the morphological characteristics of glioblastoma are excessive cell structures and mitotic behavior, necrosis and vascular proliferation [111]. Neuroblastoma is an embryonic tumor that occurs in the tissues of the sympathetic nervous system [112].
E3 ubiquitin ligase Nedd4-1 induces K63 ubiquitination of Rap2a and promotes the migration as well as invasion of glioma cells [113]. In addition, CaMKII phosphorylates Beclin 1 to promote its K63 ubiquitination and subsequent activation of autophagy, which contributing to the differentiation of neuroblastoma cells [114]. Moreover, Nrdp1 binds to the Vangl1 and Vangl2 proteins to mediate K63 ubiquitination of the wnt pathway protein Dishevelled (Dvl), regulating the invasiveness and malignancy of glioblastoma [115].
Gastric cancer
Gastric cancer is a common digestive tract tumor with high incidence rate and mortality [116]. Carcinogenesis of gastric cancer is a multifactorial process regulated by microbial, environmental, and genetic factors, although Helicobacter pylori infection is regarded as the primary cause [117].
CPT1A succinylates LDHA at K222 and impairs the interaction of K63-ubiquitinated LDHA with p62, which inhibiting LDHA degradation and potentiating invasion of gastric cancer cells [118].
K63-linked ubiquitination and tumor metastasis
Migration represents the cellular movement across the tissue, which includes migration of single cell and grouped cells [99]. Metastatic behavior is the final outcome of the multi-step cell process of invasion and metastasis, which means that cancer cells spread far away and adapt to the tissue microenvironment of different locations [119].
Breast cancer
TRAF6/USP17 regulates the K63-linked ubiquitination of AEP, and cooperates with HSP90α to facilitate metastasis of breast cancer cells [120]. Ubiquitin-conjugating enzyme Ubc13, an E2 enzyme responsible for K63-linked protein ubiquitination, promotes metastasis of breast cancer through a TAK1-p38 MAP pathway [121]. Suppression of TRIM59, a highly expressed E3 ligase in breast cancer with metastasis, inhibits metastasis by inducing RNFT1-induced K63 ubiquitination of PDCD10 [122]. Besides, OTUD7B deubiquitinates LSD1 at K226/277 sites, leading to dynamic binding regulation of LSD1 and further metastasis of breast cancer cells [123].
Digestive cancer
Digestive system cancers are the most common malignancies, which mainly include gastric cancer, esophageal cancer, colorectal cancer, liver cancer, and pancreatic cancer [124]. Colorectal cancer is one of the most frequent neoplasms, most of which are localized with or without lymph node metastases [125]. Hepatocellular carcinoma is a common malignancy with an increasing worldwide prevalence, which usually develop on the basis of chronic liver disease [126].
Uev1A-Ubc13 promotes K63-linked ubiquitination of CXCL1 expression and NF-кB activation, thus regulating metastasis of colorectal cancer [127]. TRAF6 binds to MAP1LC3B/LC3B and induces LC3B K63-linked ubiquitination, which inhibiting colorectal cancer metastasis via regulating degradation of β-catenin by selective autophagy [128]. In addition, Trabid cooperates with Twist1 to specifically removes RNF8-mediated K63 ubiquitin chains from Twist1, thus suppressing hepatocellular carcinoma metastasis [129].
Others
RNF8 mediates K63-linked polyubiquitin and stabilization of Slug, promoting Epithelial-Mesenchymal Transition of lung cancer cells [130]. In addition, TRAF6 modulates invasion as well as metastasis of melanoma via Basigin ubiquitination and BSG-dependent MMP9 induction [131].
K63-linked ubiquitination and apoptosis
Known as a highly conserved programmed cell death, apoptosis is a rational and active decision made to sacrifice certain cells for the better benefits of the organism [132]. Apoptosis plays key roles in various cellular processes, including homeostasis, development, immunity cell survival and fate [133].
TNF/TNFR
Tumor necrosis factor is an essential cytokine responsible for signaling pathway of immune response [134]. TNF-alpha, TNF-beta represent the most important TNF members. TNF receptors induce two distinct pathways: TNFR1 participates in apoptosis pathway. In contrary, TNFR2 is involved in cell survival pathways [135].
USP4 potentiates TNF-α-mediated apoptosis by deubiquitinating RIP1 in head and neck squamous cell carcinoma [136]. RACK1 recruits the E3 ligase TRAF2 to MOAP-1 to facilitate K63 ubiquitination, which interacts with Bax for apoptosis [137]. ASK1-induced phosphorylation of Daxx promotes K63-linked ubiquitination of Daxx at Lys122, which further increases ASK1 activity by a positive feedback loop and regulate apoptosis [138]. Moreover, knockdown of miR-182 upregulates CYLD and RIP1 deubiquitination, which activates caspase-8 and apoptosis in triple-negative breast cancer cells [139].
EBV
As one of the most widespread human virus, Epstein-Barr virus (EBV) infection causes life-long latent infection, which leads to various tumorigenic diseases [140]. The interaction of EBV latent genes with oncogenes contribute to aberrant cell cycle, thereby promoting the development of EBV-associated neoplasms [141].
Upon proteasomal block, K63-linked ubiquitination of EBNA3C is induced for co-localization with certain autophagy-lysosomal components of the cytoplasm, which induces cell death in B-lymphocytes through apoptosis [142]. In addition, LMP1 promotes K63 ubiquitination of p53 via TRAF2, thereby contributing to p53 accumulation and disrupting p53-induced apoptosis [143].
Mitochondria
Mitochondria are well known for its function of ATP production by oxidative phosphorylation [144]. In addition, production of lipids and amino acids, degradation of fatty acids, the urea cycle also occur within mitochondria [145]. Mitochondria supports cell function and determinates cell death pathways, which is involved in aberrant metabolism and tumorigenesis [146].
Vorinostat and quinacrine increase intracellular ROS and promote the accumulation of K63-linked ubiquitination of the mitochondria, leading to mitochondrial dysfunction and apoptosis in T-cell acute lymphoblastic leukemia [147]. Besides, K63-linked ubiquitination of Hexokinase 2 induced by HectH9 modulates its mitochondrial localization and function, which controls tumor metabolism and apoptosis [148].
Others
TRIM25 induces K63-linked ubiquitination of PTEN at K266, which activates the AKT/mTOR pathway and regulates NSCLC growth and apoptosis under stimulation [149]. USP9X interacts with FLT3-ITD and induces its K63-linked ubiquitination while FLT3-ITD promotes degradation of USP9X via the ubiquitin-proteasome pattern, the cooperation of which controls apoptosis in AML cells [150]. Small-molecule WP1130 selectively blocks DUB activity of USP14, USP5, UCH37 and USP9x, decreasing antiapoptotic and increasing proapoptotic proteins, such as MCL-1 and p53 [151]. Selenite increases CYLD by downregulating LEF1 and cIAP, both of which lead to deubiquitination of RIP1 and apoptosis of colorectal cancer cells [152]. WP1130 blocks kinase signaling by inhibiting Usp9x deubiquitinase activity and Bcr-Abl ubiquitination, thus inducing apoptosis CML cell [153]. In addition, E3 ubiquitin ligase HECTD3 was suggested to interact with and induce K63-linked ubiquitination of caspase-8 which impair its activation [154].
K63-linked ubiquitination and immune
Immunity is a physiological function that destroy and reject antigenic substances that enter the body, or damage cells and tumor cells produced by the body itself, in order to maintain the health of the human body [155]. The immune system consists of intrinsic immunity and adaptive immunity, which is further divided into humoral and cellular immunity, the disregulation of which contribute to caicinogenesis [156].
T cell
T cells regulate all aspects of adaptive immunity throughout life, including responses to pathogens, allergens, and tumors. T cells are indispensable for the establishment and maintenance of immune response, homeostasis, and memory [157]. Receptors expressed by T cells are responsible for recognizing a variety of antigens from pathogens, tumors, and the environment, and maintaining immune memory and tolerance [158].
Regulatory T cells (Tregs) are key regulators of immune control, the suppression of which largely rely on FOXP3 transcriptional activity. E3 ligase TRAF6 mediates K63-linked ubiquitination of FOXP3 at K262, which ensures its proper localization and subsequent functions of Tregs [159]. In addition, CD137 promotes NF-κB activation in a K63-linked ubiquitination-dependent manner mediated by TRAF2, and CD137 antibodies potentiate CD8-related anti-tumor immune response [160].
Th9
Th9 cells, a specific helper T cell subset that specifically secretes cytokine IL-9, might be involved in host reaction towards pathogen, immune response to tumor, and immune-related disorders, such as allergic and autoimmune diseases [161, 162].
BFAR induces K63-linked ubiquitination on TGFβR1 at K268 site, which mediates TGFβ signaling activation and Th9-mediated cancer immunotherapy [163]. In addition, transcription factor PU.1 selective degradation via K63 ubiquitination in autophagy inhibits the differentiation and anti-tumor ability of Th9 cells [164].
MDSC
Myelogenous suppressor cells (MDSC) are a special subgroup of immunosuppressive myeloid cells. Their accumulation under chronic inflammatory conditions is one of the important characteristics of cancer [165]. MDSC significantly limits the antitumor activity of T and NK cells, and mediates the aggregation along with initiation of immunosuppressive cells such as Treg and M2 macrophages, thereby promoting tumor progression [166].
TRAF6 promotes the immunosuppression of MDSCs via inducing K63-linked ubiquitination and phosphorylation of STAT3, which might become a potential target for antitumor immunotherapy [167]. Besides, silencing p66a leads to phosphorylation as well as K63 ubiquitination of STAT3, thus promoting accumulation, differentiation, and activation of MDSC [168].
Others
Helicobacter pylori virulent factor CagA interacts with SHP-1 and target TRAF6 for K63-Linked ubiquitination, thereby inhibiting the expression of proinflammatory cytokines and subsequent immune response [169]. DAPK3 phosphorylates the E3 ligase LMO7 at S863, resulting in LMO7-STING interaction, K63-linked polyubiquitination of STING, and tumor-intrinsic immunity [170]. USP22 removed K63-linked ubiquitination of PD-L1 as well as CSN5, which regulating PD-L1 abundance via USP22/CSN5/PD-L1 signal. USP22 knockout suppresses tumorigenesis and increases the cytotoxicity of T cell [171]. Furthermore, HER2 recruits AKT1 to directly phosphorylate TBK1, which impairs the TBK1-STING association and K63-linked ubiquitination of TBK1, thus disrupting STING signaling and inhibiting antitumor immunity [172].
K63-linked ubiquitination and NF-κB Signaling
The nuclear factor kappa B (NF-κB) transcription factors family mainly regulate inflammation response, immunity, and tumor [173]. Aberrant NF-κB signaling has been reported to participate in multiple diseases of inflammatory or immune disorders and cancer [174].
TRAF2/5
The tumor necrosis factor receptor-associated factor (TRAF) family members are adaptor proteins regulating inflammation, adhesion, growth, differentiation, and apoptosis [175]. TRAF2 is a prototypical TRAF member, which associates with canonical as well as non-canonical NF-κB signal [176]. Another important member TRAF5 could interact with LTβR to activate NF-κB [175].
Several studies indicated the involvement of TRAF2 in regulating NF-κB activation. Siva-1 suppresses NF-κB activation by K63-ubiquitination of TRAF2, thus regulating homeostasis and memory of T-cell [177]. TRIM31 increases nuclear p65 by mediating K63-linked ubiquitination of TRAF2 and NF-κB activation of pancreatic cancer [178]. E3 ligase complex cIAP1/cIAP2/TRAF2 triggers IKKε K63-linked polyubiquitination, which is critical for NF-κB activation and malignant transformation breast cancer cells [179]. In addition, GOLPH3 promotes K63-linked ubiquitination of RIP, NEMO and TRAF2, which causes NF-κB activation and aggressiveness of hepatocellular carcinoma cells [180]. Besides, E2 regulatory protein of α, β and µ-HPV genotypes promotes TNF-induced NF-κB activation via K63-linked ubiquitination mediated TRAF5 activation [181].
IKKβ/IKK
Blocking nuclear factor-κB (IκB) kinase (IKK) complex mainly regulate the NF-κB signaling pathway [182]. IKKalpha and IKKbeta mediate IkappaB phosphorylation, of which IKKbeta are responsible for rapid NF-κB activation by proinflammatory signaling pathways while IKKalpha activates a certain forms of NF-κB in reaction to a portion of TNFs [183].
The pVHL-mediated K63-ubiquitination of IKKβ, a key modulator of NF-κB, impairs TAK1 binding, which inhibits IKKβ phosphorylation and activation of NF-κB [184]. cIAP1/2 mediates K63-linked ubiquitination of themselves as well as BCL10, recruiting and activating IKK [185]. Inhibiting UBC13-UEV1A complex controlling K63-linked ubiquitination suggests K147 as the main site of K63 ubiquitination and necessary for activation of STAT3 [186]. Furthermore, K63-linked ubiquitination occurs in K578 in BRAF V600E other homologous to IKKβ K147, which drives melanoma and other cancers [187].
RIP1
The receptor-interacting protein (RIP1) is widely expressed and belongs to a kinase family which induces responses to stress or inflammation of cells, thus determining cell survival or death [188]. RIP1 is closely implicated in apoptosis-related cellular death induced by TNFα stimulation as well as in necrotic pattern of cell death induced when caspase is inactivated [189].
Silencing miR-138 induces K63-linked ubiquitination of RIP1 and sustains activation of NF-κB as well as esophageal squamous cell carcinoma progression [190]. MicroRNAs miR-125a and miR-125b target TNFAIP3, which altering K63 ubiquitination of RIP1 and transcription of NF-κB target genes [191]. EGFRvIII mediates RIP1 K63 ubiquitination while RIP1 interacts with NEMO and TAK1 to activate NF-κB, which modulates tumorigenesis and efficacy of targeted treatment in GBM [192]. FLOT1 promotes tumor necrosis factor-α receptor signaling via mediating its K63-linked ubiquitination and activates NF-κB in ESCC cells [193]. In addition, p62 has been reported as an oncotarget regulates cisplatin sensitivity of human ovarian cancer cells via activating RIP1-NF-κB pathway in a K63-linked ubiquitination manner [194].
CYLD
The HPV-encoded E6 protein mediates activation of NF-κB under hypoxia by targeting CYLD K63 deubiquitinase which negatively regulate NF-κB pathway [195]. In addition, CYLD protein with D681G mutation could not cleave K63-linked polyubiquitin chains, significantly impairing its capacity to inhibit TRAF2- and TRAF6-induced NF-κB activation and to deubiquitinate TRAF2 [196].
Others
TRIM14 decreases K63 ubiquitination of p100/p52 by recruiting deubiquitinase USP14, thus inhibiting selective autophagic degradation of p100/p52 induced by p62 and promoting noncanonical activation of NF-κB [197]. Triggering of MSR1 mediated through K63 polyubiquitylation in macrophages with activated IL-4 promotes JNK signal, thus changing from anti-inflammation into pro-inflammation [198]. TRIM22 contributes to NF-κB activation by binding with IKKγ and facilitating its K63-linked ubiquitination, which results in phosphorylation of IKKα/β and IκBα in glioblastoma [199]. Moreover, RNF138 promotes K63 ubiquitination of MYD88L265P, thus recruiting of kinases in relation with interleukin-1 receptor and activating NF-κB in lymphomas [200].
K63-linked ubiquitination and DNA damage repair
DNA repair system protect cells from the endogenous and exogenous insults, which prevents tumorigenesis [201]. DNA repair systems maintain genetic integrity and stability, including base excision repair (BER), mismatch repair (MMR), nucleotide excision repair (NER) and double-strand break repair (DSBR) [202].
DSBR
DNA double-strand breaks (DSBs) are harmful lesions that lead to genetic insults. To avoid genome instability, several DSBR pathways exist in organisms including non-homologous end-joining (NHEJ) and homologous recombination (HR) as the two most commonly adopted systems [203].
NHEJ
NHEJ is known as an error-prone pattern and independent of homologous DNA for end joining [204].
USP38 decreases the K63-linked ubiquitination of HDAC1 and promote its deacetylase activity, thus deacetylating H3K56. USP38 deletion reduces NHEJ efficiency and increases genome instability, which potentiates sensitivity of cancer cells to genotoxic insults [205]. Moreover, FBXW7 has been found to facilitate NHEJ via K63-Linked ubiquitylation of XRCC4 at lysine 296, thus interacting with the Ku70/80 complex to promote NHEJ repair [206].
HR
HR is largely error free which needs extensive homology for repairing DNA DSBs [207].
K63-linked ubiquitination of RYBP keep it away from DNA damage sites, which impairs BRCA1 recruitment and Rad51 to DNA double-strand breaks, thus suppressing HR repair. As a result, cancer cells with high RYBP expression are more sensitive to DNA damage therapy [208]. Skp2 E3 ligase interacts with NBS1 and promotes its K63-linked ubiquitination in response to DSBs, which is important for NBS1-ATM interaction, thus recruiting ATM to the DNA foci for further activation [209]. In addition, FANCG K63 ubiquitination mediates its interaction with the Rap80-BRCA1 complex for the regulation of HR repair [210].
Other DSBR
E3 ubiquitin ligase ITCH could trigger K63-linked ubiquitination of WWOX at K274 site and regulate the nuclear accumulation of WWOX, which is critical for ATM activation and DNA repair [211]. SOCS1 leads to nuclear redistribution and K63 ubiquitination of VHL under DSBs, while VHL loss impairs the DDR [212]. Tax promotes RNF8 for nuclear K63-linked ubiquitination which sequester DDR factors of Tax speckles, inhibiting DDR as well as DSB repair in Adult T-Cell Leukemia cells [213]. USP19 cleaves K63-linked ubiquitin of HDAC1/2, which modulates HDAC1/2 activity upon DNA damage repair [214]. Moreover, it has been found that the interaction of K63-linked ubiquitin molecules with DNA recruits repair effector via their interaction with an Ile patch in ubiquitin to promote DNA repair upon DNA damage [215].
Others
Deubiquitinase CYLD promotes DNA damage-induced p53 activation by removing K48-ubiquitin chains from p53 and cleaving K63-ubiquitin, which regulates p53 responses to genotoxic stress in cancer cells [216]. Furthermore, UBC13 mediates K63-linked PCNA ubiquitination, which regulates DNA damage-induced replication fork slowing and reversal during eukaryotic replication [217].
K63-linked ubiquitination and cancer therapy
Tumor therapy mainly includes surgery, chemotherapy, radiotherapy, biotherapy and molecular targeted therapy. Generally, surgery is the main treatment for most tumors, but some patients need chemotherapy, radiotherapy and other treatments [218].
Chemotherapeutic drug
Chemotherapy refers to the treatment that uses chemical agents to kill cancer cells, inhibit the growth of tumor cells or promote their differentiation. According to the specific mechanism, commonly used chemotherapeutic agents can be classified into different classes [219].
Nuclear XIAP increases NFκB expression and K63-ubiquitination, which influences drug resistance and confers poor prognosis in breast cancer [220]. IRAK1/4 signaling promotes activation of the E3 ubiquitin ligase TRAF6, which triggers K63-linked ubiquitination and stabilization of antiapoptotic protein MCL1, thus decreasing sensitivity of T-ALL to combined therapy [221]. SMO stabilizes TRAF6 via recruiting USP8 to remove its K48 ubiquitination, which is associated with enhancement of TRAF6 K63 ubiquitination, thereby regulating AKT activation and cause doxorubicin resistance in diffuse large B cell lymphoma [222]. Moreover, SphK2 promotes the RXRα degradation dependent of K63-linked ubiquitination in autophagy, resulting all-trans retinoic acid (ATRA) therapy insensitivity of colon cancer [223].
Targeted drug
The classic commonly used chemotherapy drugs generally act directly on the DNA of cells, while new anticancer drugs include molecular targeted therapy, such as targeting the abnormally expressed indicators in cancer cells [224]. Targeting drugs usually function in several ways including enzyme mediation, pH-dependent delivery, special vehicles transport and receptor targeting [225].
Ubiquitin ligase TRIM15 and deubiquitinase CYLD regulate K63-linked ubiquitination of ERK and its interaction with MEK and subsequent activation. Decrease of TRIM15 suppresses proliferation of melanomas, which might become potential target for cancer therapy [9]. RBX1 activates POLR2A which encodes RNAP2 catalytic subunit through K63 ubiquitination and increases the RNAP2-induced biosynthesis of mRNA. Synergistic suppression of RBX1 and RNAP2 inhibits prostate cancer development, which promotes the therapeutic sensitivity of the RNAP2 inhibitor [226]. ErbB2/HER2 receptor tyrosine kinase is a validated clinical target for increasing number of anti-ErbB2 therapeutics. E3 ubiquitin ligase c-Cbl and deubiquitinase USP9x regulate ErbB2 trafficking as well as degradation in relation to K48 or K63 ubiquitination [227]. Recombinant monoclonal antibody Trastuzumab targets ErbB family members against cancer. ATG9A loss has been found to confer resistance to trastuzumab through c-Cbl induced Her2 K63 ubiquitination [228]. In addition, TRIM32 is responsible for K63-linked ubiquitination and activation of TBK1 upon EGFR suppression, which exerts efficacy in treating non-small cell lung cancer [229].
Summary and future directions
As a specific pattern of post-translational modifications, K63-linked ubiquitination controls various properties of protein including protein-protein interaction, translocation, and activation. Emerging evidence indicates that K63-linked ubiquitination participates in the initiation, development, and therapy of cancer. However, there was previously a lack of an overview of the contribution of K63-linked ubiquitination in different aspects of tumor. Therefore, our review summarized recent advances of studies focusing on the critical implication of K63-linked ubiquitination in cancer (Fig. 1) (Supplementary Table 1).
Tumorigenesis, tumor growth, invasion, and metastasis are complicated processes regulated by multiple pathways such as PI3K/Akt signaling, c-myc, JNK, YAP, p53 and Wnt/β-catenin. Previous studies suggested that various factors of these pathways are regulated by K63-linked ubiquitination. As for different cancer types, K63-linked ubiquitination participate in the regulation of numerous cancers including breast cancer, gastric cancer, colorectal cancer, hepatocellular carcinoma, which indicates most cancers are modulated by this specific ubiquitination pattern. In addition, diverse cellular processes including cell cycle, DNA damage repair, NF-κB signaling, autophagy and mitochondria function require proper K63-linked ubiquitination of certain members. Furthermore, exciting discoveries are anticipated to unravel switches of different Ub chains (such as between K48 and K63) in cancer.
Chemotherapy refers to the treatment that uses chemical agents to kill cancer cells, while targeting drugs usually function by special vehicles transport and receptor targeting. In addition, anti-tumor immune turn out to be a promising approach to kill tumor cells. Extensive studies reported that K63-linked ubiquitination regulate multiple cancer therapies of chemotherapy, target drug, and anti-tumor immune, which offer a novel way for cancer treatment by targeting distinct aspects of the ubiquitin system (Supplementary Table 2). Multiple E3 ligases of TRAFs, RNFs, TRIMs, and DUBs of USPs, CYLD, OTUDs participate in the modulation of K63-linked ubiquitination of different substrates. Development of novel therapeutic approaches could be promising that selectively target interaction of proteins, thus altering the binding of various Ub to conjugation enzymes or Ub receptors. Small molecules targeting certain E3 ligase or DUBs might exert favorable effect to suppress tumor development and metastasis. Along with increasing technologies and comprehensive understanding of ubiquitination signal, it is anticipated that novel therapeutic strategies improve tumor therapy.
Data availability
All the data used in the manuscript are freely available online.
References
Han ZJ, Feng YH, Gu BH, Li YM, Chen H. The post-translational modification, SUMOylation, and cancer (Review). Int J Oncol. 2018;52:1081–94.
Wang R, Wang G. Protein modification and autophagy activation. Adv Exp Med Biol. 2019;1206:237–59.
Swatek KN, Komander D. Ubiquitin modifications. Cell Res. 2016;26:399–422.
Buneeva OA, Medvedev AE. Atypical ubiquitination of proteins. Biomeditsinskaia khimiia. 2016;62:496–509.
Torres MP, Lee MJ, Ding F, Purbeck C, Kuhlman B, Dokholyan NV, et al. G protein mono-ubiquitination by the Rsp5 ubiquitin ligase. J Biol Chem. 2009;284:8940–50.
Kwon YT, Ciechanover A. The ubiquitin code in the ubiquitin-proteasome system and autophagy. Trends Biochem. Sci. 2017;42:873–86.
Hjerpe R, RodrÃguez MS. Alternative UPS drug targets upstream the 26S proteasome. Int J Biochem Cell Biol. 2008;40:1126–40.
Ren L, Zhou T, Wang Y, Wu Y, Xu H, Liu J, et al. RNF8 induces β-catenin-mediated c-Myc expression and promotes colon cancer proliferation. Int J Biol Sci. 2020;16:2051–62.
Zhu G, Herlyn M, Yang X. TRIM15 and CYLD regulate ERK activation via lysine-63-linked polyubiquitination. Nat Cell Biol. 2021;23:978–91.
Song G, Liu B, Li Z, Wu H, Wang P, Zhao K, et al. E3 ubiquitin ligase RNF128 promotes innate antiviral immunity through K63-linked ubiquitination of TBK1. Nat Immunol. 2016;17:1342–51.
Liu M, Yan M, Lv H, Wang B, Lv X, Zhang H, et al. Macrophage K63-linked ubiquitination of YAP promotes its nuclear localization and exacerbates atherosclerosis. Cell Rep. 2020;32:107990.
Yazlovitskaya EM, Tseng HY, Viquez O, Tu T, Mernaugh G, McKee KK, et al. Integrin α3β1 regulates kidney collecting duct development via TRAF6-dependent K63-linked polyubiquitination of Akt. Mol Biol Cell. 2015;26:1857–74.
Patterson AD, Gonzalez FJ, Perdew GH, Peters JM. Molecular regulation of carcinogenesis: friend and foe. Toxicological Sci. 2018;165:277–83.
Noorolyai S, Shajari N, Baghbani E, Sadreddini S, Baradaran B. The relation between PI3K/AKT signalling pathway and cancer. Gene. 2019;698:120–8.
Yu JS, Cui W. Proliferation, survival and metabolism: the role of PI3K/AKT/mTOR signalling in pluripotency and cell fate determination. Development. 2016;143:3050–60.
Han F, Li CF, Cai Z, Zhang X, Jin G, Zhang WN, et al. The critical role of AMPK in driving Akt activation under stress, tumorigenesis and drug resistance. Nat Commun. 2018;9:4728.
Wang G, Long J, Gao Y, Zhang W, Han F, Xu C, et al. SETDB1-mediated methylation of Akt promotes its K63-linked ubiquitination and activation leading to tumorigenesis. Nat Cell Biol. 2019;21:214–25.
Wang B, Jie Z, Joo D, Ordureau A, Liu P, Gan W, et al. TRAF2 and OTUD7B govern a ubiquitin-dependent switch that regulates mTORC2 signalling. Nature. 2017;545:365–9.
Zhang Y, Wang X. Targeting the Wnt/β-catenin signaling pathway in cancer. J Hematol Oncol. 2020;13:165.
Bian J, Dannappel M, Wan C, Firestein R. Transcriptional regulation of Wnt/β-catenin pathway in colorectal cancer. Cells. 2020;9:2125.
Tran H, Hamada F, Schwarz-Romond T, Bienz M. Trabid, a new positive regulator of Wnt-induced transcription with preference for binding and cleaving K63-linked ubiquitin chains. Genes Dev. 2008;22:528–42.
Tran H, Polakis P. Reversible modification of adenomatous polyposis coli (APC) with K63-linked polyubiquitin regulates the assembly and activity of the β-catenin destruction complex. J Biol Chem. 2012;287:28552–63.
Jung H, Kim BG, Han WH, Lee JH, Cho JY, Park WS, et al. Deubiquitination of dishevelled by Usp14 is required for Wnt signaling. Oncogenesis. 2013;2:e64.
Jeon YK, Kim CK, Hwang KR, Park HY, Koh J, Chung DH, et al. Pellino-1 promotes lung carcinogenesis via the stabilization of Slug and Snail through K63-mediated polyubiquitination. Cell Death Differ. 2017;24:469–80.
Gerard B, Sanders MA, Visscher DW, Tait L, Shekhar MP. Lysine 394 is a novel Rad6B-induced ubiquitination site on beta-catenin. Biochimica Biophysica Acta. 2012;1823:1686–96.
Mai S, Mushinski JF. c-Myc-induced genomic instability. J Environ Pathol, Toxicol Oncol. 2003;22:179–99.
Dai H, Yan M, Li Y. The zinc-finger protein ZCCHC2 suppresses retinoblastoma tumorigenesis by inhibiting HectH9-mediated K63-linked polyubiquitination and activation of c-Myc. Biochem. Biophys. Res. Commun. 2020;521:533–8.
Shi W, Feng L, Dong S, Ning Z, Hua Y, Liu L, et al. FBXL6 governs c-MYC to promote hepatocellular carcinoma through ubiquitination and stabilization of HSP90AA1. Cell Commun Signal. 2020;18:100.
Wu H, Yang TY, Li Y, Ye WL, Liu F, He XS, et al. Tumor necrosis factor receptor-associated factor 6 promotes hepatocarcinogenesis by interacting with histone deacetylase 3 to enhance c-Myc gene expression and protein stability. Hepatology. 2020;71:148–63.
Kumar A, Singh UK, Kini SG, Garg V, Agrawal S, Tomar PK, et al. JNK pathway signaling: a novel and smarter therapeutic targets for various biological diseases. Future Med Chem. 2015;7:2065–86.
Wu Q, Wu W, Fu B, Shi L, Wang X, Kuca K. JNK signaling in cancer cell survival. Med Res Rev. 2019;39:2082–104.
Miliani de Marval P, Lutfeali S, Jin JY, Leshin B, Selim MA, Zhang JY. CYLD inhibits tumorigenesis and metastasis by blocking JNK/AP1 signaling at multiple levels. Cancer Prev Res. 2011;4:851–9.
Priyadarshini R, Hussain M, Attri P, Kaur E, Tripathi V, Priya S, et al. BLM potentiates c-Jun degradation and alters its function as an oncogenic transcription factor. Cell Rep. 2018;24:947–961.e947.
Piccolo S, Dupont S, Cordenonsi M. The biology of YAP/TAZ: hippo signaling and beyond. Physiol Rev. 2014;94:1287–312.
Thompson BJ. YAP/TAZ: drivers of tumor growth, metastasis, and resistance to therapy. BioEssays: N Rev Mol, Cell Dev Biol. 2020;42:e1900162.
Santoro R, Zanotto M, Simionato F, Zecchetto C, Merz V, Cavallini C, et al. Modulating TAK1 expression inhibits YAP and TAZ oncogenic functions in pancreatic cancer. Mol Cancer Therapeutics. 2020;19:247–57.
Yao F, Zhou Z, Kim J, Hang Q, Xiao Z, Ton BN, et al. SKP2- and OTUD1-regulated non-proteolytic ubiquitination of YAP promotes YAP nuclear localization and activity. Nat Commun. 2018;9:2269.
Poirier MC. Chemical-induced DNA damage and human cancer risk. Discov Med. 2012;14:283–8.
Chargui A, Belaid A, Ndiaye PD, Imbert V, Samson M, Guigonis JM, et al. The carcinogen cadmium activates lysine 63 (K63)-linked ubiquitin-dependent signaling and inhibits selective autophagy. Cancers. 2021;13:2490.
Langie SA, Knaapen AM, Ramaekers CH, Theys J, Brun J, Godschalk RW, et al. Formation of lysine 63-linked poly-ubiquitin chains protects human lung cells against benzo[a]pyrene-diol-epoxide-induced mutagenicity. DNA Repair. 2007;6:852–62.
Bie Q, Song H, Chen X, Yang X, Shi S, Zhang L, et al. IL-17B/IL-17RB signaling cascade contributes to self-renewal and tumorigenesis of cancer stem cells by regulating Beclin-1 ubiquitination. Oncogene. 2021;40:2200–16.
Debald M, Schildberg FA, Linke A, Walgenbach K, Kuhn W, Hartmann G, et al. Specific expression of k63-linked ubiquitination of calmodulin-like protein 5 in breast cancer of premenopausal patients. J Cancer Res Clin Oncol. 2013;139:2125–32.
Kao SH, Cheng WC, Wang YT, Wu HT, Yeh HY, Chen YJ, et al. Regulation of miRNA biogenesis and histone modification by K63-polyubiquitinated DDX17 controls cancer stem-like features. Cancer Res. 2019;79:2549–63.
Li N, Wang Y, Neri S, Zhen Y, Fong LWR, Qiao Y, et al. Tankyrase disrupts metabolic homeostasis and promotes tumorigenesis by inhibiting LKB1-AMPK signalling. Nat Commun. 2019;10:4363.
Liao Y, Liu N, Xia X, Guo Z, Li Y, Jiang L, et al. USP10 modulates the SKP2/Bcr-Abl axis via stabilizing SKP2 in chronic myeloid leukemia. Cell Discov. 2019;5:24.
Lu W, Liu S, Li B, Xie Y, Adhiambo C, Yang Q, et al. SKP2 inactivation suppresses prostate tumorigenesis by mediating JARID1B ubiquitination. Oncotarget. 2015;6:771–88.
Mai J, Zhong ZY, Guo GF, Chen XX, Xiang YQ, Li X, et al. Polo-Like Kinase 1 phosphorylates and stabilizes KLF4 to promote tumorigenesis in nasopharyngeal carcinoma. Theranostics. 2019;9:3541–54.
Wei Z, Song J, Wang G, Cui X, Zheng J, Tang Y, et al. Deacetylation of serine hydroxymethyl-transferase 2 by SIRT3 promotes colorectal carcinogenesis. Nat Commun. 2018;9:4468.
Macheret M, Halazonetis TD. DNA replication stress as a hallmark of cancer. Annu Rev Pathol. 2015;10:425–48.
Kroemer G, Pouyssegur J. Tumor cell metabolism: cancer’s Achilles’ heel. Cancer Cell. 2008;13:472–82.
Xu Y, Hu Y, Xu T, Yan K, Zhang T, Li Q, et al. RNF8-mediated regulation of Akt promotes lung cancer cell survival and resistance to DNA damage. Cell Rep. 2021;37:109854.
Zhang J, Yang Z, Ou J, Xia X, Zhi F, Cui J. The F-box protein FBXL18 promotes glioma progression by promoting K63-linked ubiquitination of Akt. FEBS Lett. 2017;591:145–54.
Yu X, Wang R, Zhang Y, Zhou L, Wang W, Liu H, et al. Skp2-mediated ubiquitination and mitochondrial localization of Akt drive tumor growth and chemoresistance to cisplatin. Oncogene. 2019;38:7457–72.
Yang WL, Jin G, Li CF, Jeong YS, Moten A, Xu D, et al. Cycles of ubiquitination and deubiquitination critically regulate growth factor-mediated activation of Akt signaling. Sci Signal. 2013;6:ra3.
Qiu C, Liu K, Zhang S, Gao S, Chen W, Li D, et al. Bisdemethoxycurcumin inhibits hepatocellular carcinoma proliferation through Akt inactivation via CYLD-mediated deubiquitination. Drug Des, Dev Ther. 2020;14:993–1001.
Okamoto T, Imaizumi K, Kaneko M. The role of tissue-specific ubiquitin ligases, RNF183, RNF186, RNF182 and RNF152, in disease and biological function. Int J Mol Sci. 2020;21:3921.
Lee HJ, Li CF, Ruan D, Powers S, Thompson PA, Frohman MA, et al. The DNA damage transducer RNF8 facilitates cancer chemoresistance and progression through twist activation. Mol Cell. 2016;63:1021–33.
Ren Y, Xu X, Mao CY, Han KK, Xu YJ, Cao BY, et al. RNF6 promotes myeloma cell proliferation and survival by inducing glucocorticoid receptor polyubiquitination. Acta Pharmacol Sin. 2020;41:394–403.
Zhu J, Li X, Su P, Xue M, Zang Y, Ding Y. The ubiquitin ligase RNF181 stabilizes ERα and modulates breast cancer progression. Oncogene. 2020;39:6776–88.
Arkee T, Bishop GA. TRAF family molecules in T cells: multiple receptors and functions. J Leukoc Biol. 2020;107:907–15.
Swaidani S, Liu C, Zhao J, Bulek K, Li X. TRAF regulation of IL-17 cytokine signaling. Front Immunol. 2019;10:1293.
Zhu S, Jin J, Gokhale S, Lu AM, Shan H, Feng J, et al. Genetic alterations of TRAF proteins in human cancers. Front Immunol. 2018;9:2111.
Choi YB, Harhaj EW. HTLV-1 tax stabilizes MCL-1 via TRAF6-dependent K63-linked polyubiquitination to promote cell survival and transformation. PLoS Pathog. 2014;10:e1004458.
Lu W, Liu S, Li B, Xie Y, Izban MG, Ballard BR, et al. SKP2 loss destabilizes EZH2 by promoting TRAF6-mediated ubiquitination to suppress prostate cancer. Oncogene. 2017;36:1364–73.
Zhang J, Lei Z, Huang Z, Zhang X, Zhou Y, Luo Z, et al. Epigallocatechin-3-gallate(EGCG) suppresses melanoma cell growth and metastasis by targeting TRAF6 activity. Oncotarget. 2016;7:79557–71.
Tang Y, Tao Y, Wang L, Yang L, Jing Y, Jiang X, et al. NPM1 mutant maintains ULK1 protein stability via TRAF6-dependent ubiquitination to promote autophagic cell survival in leukemia. FASEB J. 2021;35:e21192.
Linares JF, Duran A, Yajima T, Pasparakis M, Moscat J, Diaz-Meco MT. K63 polyubiquitination and activation of mTOR by the p62-TRAF6 complex in nutrient-activated cells. Mol Cell. 2013;51:283–96.
Zhan Z, Xie X, Cao H, Zhou X, Zhang XD, Fan H, et al. Autophagy facilitates TLR4- and TLR3-triggered migration and invasion of lung cancer cells through the promotion of TRAF6 ubiquitination. Autophagy. 2014;10:257–68.
Zhang P, Zhang Z, Fu Y, Zhang Y, Washburn MP, Florens L, et al. K63-linked ubiquitination of DYRK1A by TRAF2 alleviates Sprouty 2-mediated degradation of EGFR. Cell Death Dis. 2021;12:608.
Massoumi R. CYLD: a deubiquitination enzyme with multiple roles in cancer. Future Oncol. 2011;7:285–97.
Tauriello DV, Haegebarth A, Kuper I, Edelmann MJ, Henraat M, Canninga-van Dijk MR, et al. Loss of the tumor suppressor CYLD enhances Wnt/beta-catenin signaling through K63-linked ubiquitination of Dvl. Mol Cell. 2010;37:607–19.
Xu X, Kalac M, Markson M, Chan M, Brody JD, Bhagat G, et al. Reversal of CYLD phosphorylation as a novel therapeutic approach for adult T-cell leukemia/lymphoma (ATLL). Cell Death Dis. 2020;11:94.
Johari T, Maiti TK. Catalytic domain mutation in CYLD inactivates its enzyme function by structural perturbation and induces cell migration and proliferation. Biochimica Biophysica Acta Gen Subj. 2018;1862:2081–9.
Vieler M, Sanyal S. p53 Isoforms and their implications in cancer. Cancers. 2018;10:288.
Chao CC. Mechanisms of p53 degradation. Clin Chim Acta; Int J Clin Chem. 2015;438:139–47.
Guo Y, Li Q, Zhao G, Zhang J, Yuan H, Feng T, et al. Loss of TRIM31 promotes breast cancer progression through regulating K48- and K63-linked ubiquitination of p53. Cell Death Dis. 2021;12:945.
Zhang J, Zhang C, Cui J, Ou J, Han J, Qin Y, et al. TRIM45 functions as a tumor suppressor in the brain via its E3 ligase activity by stabilizing p53 through K63-linked ubiquitination. Cell Death Dis. 2017;8:e2831.
Zhang X, Li CF, Zhang L, Wu CY, Han L, Jin G, et al. TRAF6 restricts p53 mitochondrial translocation, apoptosis, and tumor suppression. Mol Cell. 2016;64:803–14.
Schafer KA. The cell cycle: a review. Vet Pathol. 1998;35:461–78.
Icard P, Fournel L, Wu Z, Alifano M, Lincet H. Interconnection between metabolism and cell cycle in cancer. Trends Biochem. Sci. 2019;44:490–501.
Kolapalli SP, Sahu R, Chauhan NR, Jena KK, Mehto S, Das SK, et al. RNA-binding RING E3-ligase DZIP3/hRUL138 stabilizes cyclin D1 to drive cell-cycle and cancer progression. Cancer Res. 2021;81:315–31.
Zhang X, Cai J, Zheng Z, Polin L, Lin Z, Dandekar A, et al. A novel ER-microtubule-binding protein, ERLIN2, stabilizes Cyclin B1 and regulates cell cycle progression. Cell Discov. 2015;1:15024.
Li Y, Hu K, Xiao X, Wu W, Yan H, Chen H, et al. FBW7 suppresses cell proliferation and G2/M cell cycle transition via promoting γ-catenin K63-linked ubiquitylation. Biochem Biophys Res Commun. 2018;497:473–9.
Hatakeyama S. TRIM family proteins: roles in autophagy, immunity, and carcinogenesis. Trends Biochem Sci. 2017;42:297–311.
Liu K, Zhang C, Li B, Xie W, Zhang J, Nie X, et al. Mutual stabilization between TRIM9 short isoform and MKK6 potentiates p38 signaling to synergistically suppress glioblastoma progression. Cell Rep. 2018;23:838–51.
Xue M, Zhang K, Mu K, Xu J, Yang H, Liu Y, et al. Regulation of estrogen signaling and breast cancer proliferation by an ubiquitin ligase TRIM56. Oncogenesis. 2019;8:30.
Judge A, Dodd MS. Metabolism. Essays Biochem. 2020;64:607–47.
Lee HJ, He J, Chan CH. HectH9 hijacks glucose metabolism to fuel tumor growth. Mol Cell Oncol. 2019;6:e1644599.
Sun T, Liu Z, Bi F, Yang Q. Deubiquitinase PSMD14 promotes ovarian cancer progression by decreasing enzymatic activity of PKM2. Mol Oncol. 2021;15:3639–58.
Dikshit A, Jin YJ, Degan S, Hwang J, Foster MW, Li CY, et al. UBE2N Promotes melanoma growth via MEK/FRA1/SOX10 signaling. Cancer Res. 2018;78:6462–72.
He Y, Jiang S, Mao C, Zheng H, Cao B, Zhang Z, et al. The deubiquitinase USP10 restores PTEN activity and inhibits non-small cell lung cancer cell proliferation. J Biol Chem. 2021;297:101088.
Kim D, Koh J, Ko JS, Kim HY, Lee H, Chung DH. Ubiquitin E3 ligase pellino-1 inhibits IL-10-mediated M2c polarization of macrophages, thereby suppressing tumor growth. Immune Netw. 2019;19:e32.
Lee SW, Li CF, Jin G, Cai Z, Han F, Chan CH, et al. Skp2-dependent ubiquitination and activation of LKB1 is essential for cancer cell survival under energy stress. Mol Cell. 2015;57:1022–33.
Raimondi M, Cesselli D, Di Loreto C, La Marra F, Schneider C, Demarchi F. USP1 (ubiquitin specific peptidase 1) targets ULK1 and regulates its cellular compartmentalization and autophagy. Autophagy. 2019;15:613–30.
Shao N, Cheng J, Huang H, Gong X, Lu Y, Idris M, et al. GASC1 promotes hepatocellular carcinoma progression by inhibiting the degradation of ROCK2. Cell Death Dis. 2021;12:253.
Sun L, Amraei R, Rahimi N. NEDD4 regulates ubiquitination and stability of the cell adhesion molecule IGPR-1 via lysosomal pathway. J Biomed Sci. 2021;28:35.
Wang JY, Liu GZ, Wilmott JS, La T, Feng YC, Yari H, et al. Skp2-mediated stabilization of MTH1 promotes survival of melanoma cells upon oxidative stress. Cancer Res. 2017;77:6226–39.
Wu HT, Kuo YC, Hung JJ, Huang CH, Chen WY, Chou TY, et al. K63-polyubiquitinated HAUSP deubiquitinates HIF-1α and dictates H3K56 acetylation promoting hypoxia-induced tumour progression. Nat Commun. 2016;7:13644.
van de Merbel AF, van der Horst G, Buijs JT, van der Pluijm G. Protocols for migration and invasion studies in prostate cancer. Methods Mol Biol. 1786;2018:67–79.
Dart AE, Gordon-Weeks PR. The role of drebrin in cancer cell invasion. Adv Exp Med Biol. 2017;1006:375–89.
Nagini S. Breast cancer: current molecular therapeutic targets and new players. Anti-cancer Agents Med Chem. 2017;17:152–63.
Niu T, Wu Z, Xiao W. Uev1A promotes breast cancer cell migration by up-regulating CT45A expression via the AKT pathway. BMC Cancer. 2021;21:1012.
Tan P, Ye Y, He L, Xie J, Jing J, Ma G, et al. TRIM59 promotes breast cancer motility by suppressing p62-selective autophagic degradation of PDCD10. PLoS Biol. 2018;16:e3000051.
Ray DM, Rogers BA, Sunman JA, Akiyama SK, Olden K, Roberts JD. Lysine 63-linked ubiquitination is important for arachidonic acid-induced cellular adhesion and migration. Biochem cell Biol = Biochim et biologie cellulaire. 2010;88:947–56.
Mao Y, Yang D, He J, Krasna MJ. Epidemiology of lung cancer. Surgical Oncol Clin North Am. 2016;25:439–45.
Collins LG, Haines C, Perkel R, Enck RE. Lung cancer: diagnosis and management. Am Fam Physician. 2007;75:56–63.
He Z, Huang C, Lin G, Ye Y. siRNA-induced TRAF6 knockdown promotes the apoptosis and inhibits the invasion of human lung cancer SPC-A1 cells. Oncol Rep. 2016;35:1933–40.
Li Y, Deng L, Zhao X, Li B, Ren D, Yu L, et al. Tripartite motif-containing 37 (TRIM37) promotes the aggressiveness of non-small-cell lung cancer cells by activating the NF-κB pathway. J Pathol. 2018;246:366–78.
Kim E, Kim W, Lee S, Chun J, Kang J, Park G, et al. TRAF4 promotes lung cancer aggressiveness by modulating tumor microenvironment in normal fibroblasts. Sci Rep. 2017;7:8923.
Stylli SS, Luwor RB, Ware TM, Tan F, Kaye AH. Mouse models of glioma. J Clin Neurosci. 2015;22:619–26.
Omuro A, DeAngelis LM. Glioblastoma and other malignant gliomas: a clinical review. JAMA. 2013;310:1842–50.
Maris JM. Recent advances in neuroblastoma. N Engl J Med. 2010;362:2202–11.
Wang L, Zhu B, Wang S, Wu Y, Zhan W, Xie S, et al. Regulation of glioma migration and invasion via modification of Rap2a activity by the ubiquitin ligase Nedd4-1. Oncol Rep. 2017;37:2565–74.
Li X, Wu XQ, Deng R, Li DD, Tang J, Chen WD, et al. CaMKII-mediated Beclin 1 phosphorylation regulates autophagy that promotes degradation of Id and neuroblastoma cell differentiation. Nat Commun. 2017;8:1159.
Wald JH, Hatakeyama J, Printsev I, Cuevas A, Fry WHD, Saldana MJ, et al. Suppression of planar cell polarity signaling and migration in glioblastoma by Nrdp1-mediated Dvl polyubiquitination. Oncogene. 2017;36:5158–67.
Johnston FM, Beckman M. Updates on management of gastric cancer. Curr Oncol Rep. 2019;21:67.
Correa P. Gastric cancer: overview. Gastroenterol Clin North Am. 2013;42:211–7.
Li X, Zhang C, Zhao T, Su Z, Li M, Hu J, et al. Lysine-222 succinylation reduces lysosomal degradation of lactate dehydrogenase a and is increased in gastric cancer. J Exp Clin Cancer Res. 2020;39:172.
Valastyan S, Weinberg RA. Tumor metastasis: molecular insights and evolving paradigms. Cell. 2011;147:275–92.
Lin Y, Qiu Y, Xu C, Liu Q, Peng B, Kaufmann GF, et al. Functional role of asparaginyl endopeptidase ubiquitination by TRAF6 in tumor invasion and metastasis. J Natl Cancer Inst. 2014;106:dju012.
Wu X, Zhang W, Font-Burgada J, Palmer T, Hamil AS, Biswas SK, et al. Ubiquitin-conjugating enzyme Ubc13 controls breast cancer metastasis through a TAK1-p38 MAP kinase cascade. Proc Natl Acad Sci USA. 2014;111:13870–5.
Tan P, He L, Zhou Y. TRIM59 deficiency curtails breast cancer metastasis through SQSTM1-selective autophagic degradation of PDCD10. Autophagy. 2019;15:747–9.
Gong Z, Li A, Ding J, Li Q, Zhang L, Li Y, et al. OTUD7B deubiquitinates LSD1 to govern its binding partner specificity, homeostasis, and breast cancer metastasis. Adv Sci. 2021;8:e2004504.
Han J, Zhou Y, Zheng Y, Wang M, Cui J, Chen P, et al. Positive effect of higher adult body mass index on overall survival of digestive system cancers except pancreatic cancer: a systematic review and meta-analysis. BioMed Res Int. 2017;2017:1049602.
Haraldsdottir S, Einarsdottir HM, Smaradottir A, Gunnlaugsson A, Halfdanarson TR. Colorectal cancer - review. Laeknabladid. 2014;100:75–82.
Clark T, Maximin S, Meier J, Pokharel S, Bhargava P. Hepatocellular carcinoma: review of epidemiology, screening, imaging diagnosis, response assessment, and treatment. Curr Probl Diagnostic Radiol. 2015;44:479–86.
Wu Z, Neufeld H, Torlakovic E, Xiao W. Uev1A-Ubc13 promotes colorectal cancer metastasis through regulating CXCL1 expression via NF-кB activation. Oncotarget. 2018;9:15952–67.
Wu H, Lu XX, Wang JR, Yang TY, Li XM, He XS, et al. TRAF6 inhibits colorectal cancer metastasis through regulating selective autophagic CTNNB1/β-catenin degradation and is targeted for GSK3B/GSK3β-mediated phosphorylation and degradation. Autophagy. 2019;15:1506–22.
Zhu Y, Qu C, Hong X, Jia Y, Lin M, Luo Y, et al. Trabid inhibits hepatocellular carcinoma growth and metastasis by cleaving RNF8-induced K63 ubiquitination of Twist1. Cell Death Differ. 2019;26:306–20.
Kuang J, Min L, Liu C, Chen S, Gao C, Ma J, et al. RNF8 promotes epithelial-mesenchymal transition in lung cancer cells via stabilization of slug. Mol Cancer Res. 2020;18:1638–49.
Luo Z, Zhang X, Zeng W, Su J, Yang K, Lu L, et al. TRAF6 regulates melanoma invasion and metastasis through ubiquitination of Basigin. Oncotarget. 2016;7:7179–92.
Xu X, Lai Y, Hua ZC. Apoptosis and apoptotic body: disease message and therapeutic target potentials. Biosci Rep. 2019;39:BSR20180992.
Chen M, Wu W, Liu D, Lv Y, Deng H, Gao S, et al. Evolution and structure of API5 and its roles in anti-apoptosis. Protein Pept Lett. 2021;28:612–22.
Kalliolias GD, Ivashkiv LB. TNF biology, pathogenic mechanisms and emerging therapeutic strategies. Nat Rev Rheumatol. 2016;12:49–62.
Doss GP, Agoramoorthy G, Chakraborty C. TNF/TNFR: drug target for autoimmune diseases and immune-mediated inflammatory diseases. Front Biosci. 2014;19:1028–40.
Hou X, Wang L, Zhang L, Pan X, Zhao W. Ubiquitin-specific protease 4 promotes TNF-α-induced apoptosis by deubiquitination of RIP1 in head and neck squamous cell carcinoma. FEBS Lett. 2013;587:311–6.
Law J, Kwek I, Svystun O, Lim J, Tan CT, Luong L, et al. RACK1/TRAF2 regulation of modulator of apoptosis-1 (MOAP-1). Biochim Biophys Acta Mol Cell Res. 2018;1865:684–94.
Fukuyo Y, Kitamura T, Inoue M, Horikoshi NT, Higashikubo R, Hunt CR, et al. Phosphorylation-dependent Lys63-linked polyubiquitination of Daxx is essential for sustained TNF-{alpha}-induced ASK1 activation. Cancer Res. 2009;69:7512–7.
Wo L, Lu D, Gu X. Knockdown of miR-182 promotes apoptosis via regulating RIP1 deubiquitination in TNF-α-treated triple-negative breast cancer cells. Tumour Biol. 2016;37:13733–42.
Kanda T. EBV-encoded latent genes. Adv Exp Med Biol. 2018;1045:377–94.
Yin H, Qu J, Peng Q, Gan R. Molecular mechanisms of EBV-driven cell cycle progression and oncogenesis. Med Microbiol Immunol. 2019;208:573–83.
Gain C, Malik S, Bhattacharjee S, Ghosh A, Robertson ES, Das BB, et al. Proteasomal inhibition triggers viral oncoprotein degradation via autophagy-lysosomal pathway. PLoS Pathog. 2020;16:e1008105.
Li L, Li W, Xiao L, Xu J, Chen X, Tang M, et al. Viral oncoprotein LMP1 disrupts p53-induced cell cycle arrest and apoptosis through modulating K63-linked ubiquitination of p53. Cell Cycle. 2012;11:2327–36.
Koch RE, Josefson CC, Hill GE. Mitochondrial function, ornamentation, and immunocompetence. Biol Rev Camb Philos Soc. 2017;92:1459–74.
Priesnitz C, Becker T. Pathways to balance mitochondrial translation and protein import. Genes Dev. 2018;32:1285–96.
Bock FJ, Tait SWG. Mitochondria as multifaceted regulators of cell death. Nat Rev Mol Cell Biol. 2020;21:85–100.
Jing B, Jin J, Xiang R, Liu M, Yang L, Tong Y, et al. Vorinostat and quinacrine have synergistic effects in T-cell acute lymphoblastic leukemia through reactive oxygen species increase and mitophagy inhibition. Cell Death Dis. 2018;9:589.
Lee HJ, Li CF, Ruan D, He J, Montal ED, Lorenz S, et al. Non-proteolytic ubiquitination of Hexokinase 2 by HectH9 controls tumor metabolism and cancer stem cell expansion. Nat Commun. 2019;10:2625.
He YM, Zhou XM, Jiang SY, Zhang ZB, Cao BY, Liu JB, et al. TRIM25 activates AKT/mTOR by inhibiting PTEN via K63-linked polyubiquitination in non-small cell lung cancer. Acta Pharmacol Sinica. 2021;43:681–91.
Akiyama H, Umezawa Y, Ishida S, Okada K, Nogami A, Miura O. Inhibition of USP9X induces apoptosis in FLT3-ITD-positive AML cells cooperatively by inhibiting the mutant kinase through aggresomal translocation and inducing oxidative stress. Cancer Lett. 2019;453:84–94.
Kapuria V, Peterson LF, Fang D, Bornmann WG, Talpaz M, Donato NJ. Deubiquitinase inhibition by small-molecule WP1130 triggers aggresome formation and tumor cell apoptosis. Cancer Res. 2010;70:9265–76.
Wu P, Shi KJ, An JJ, Ci YL, Li F, Hui KY, et al. The LEF1/CYLD axis and cIAPs regulate RIP1 deubiquitination and trigger apoptosis in selenite-treated colorectal cancer cells. Cell Death Dis. 2014;5:e1085.
Sun H, Kapuria V, Peterson LF, Fang D, Bornmann WG, Bartholomeusz G, et al. Bcr-Abl ubiquitination and Usp9x inhibition block kinase signaling and promote CML cell apoptosis. Blood. 2011;117:3151–62.
Li Y, Kong Y, Zhou Z, Chen H, Wang Z, Hsieh YC, et al. The HECTD3 E3 ubiquitin ligase facilitates cancer cell survival by promoting K63-linked polyubiquitination of caspase-8. Cell Death Dis. 2013;4:e935.
Parkin J, Cohen B. An overview of the immune system. Lancet. 2001;357:1777–89.
Xia L, Oyang L, Lin J, Tan S, Han Y, Wu N, et al. The cancer metabolic reprogramming and immune response. Mol Cancer. 2021;20:28.
Laidlaw BJ, Craft JE, Kaech SM. The multifaceted role of CD4(+) T cells in CD8(+) T cell memory. Nat Rev Immunol. 2016;16:102–11.
Kumar BV, Connors TJ, Farber DL. Human T cell development, localization, and function throughout life. Immunity. 2018;48:202–13.
Ni X, Kou W, Gu J, Wei P, Wu X, Peng H, et al. TRAF6 directs FOXP3 localization and facilitates regulatory T-cell function through K63-linked ubiquitination. EMBO J. 2019;38:e99766.
Martinez-Forero I, Azpilikueta A, Bolaños-Mateo E, Nistal-Villan E, Palazon A, Teijeira A, et al. T cell costimulation with anti-CD137 monoclonal antibodies is mediated by K63-polyubiquitin-dependent signals from endosomes. J Immunol. 2013;190:6694–706.
Wang W, Sung N, Gilman-Sachs A, Kwak-Kim JT. Helper (Th) cell profiles in pregnancy and recurrent pregnancy losses: Th1/Th2/Th9/Th17/Th22/Tfh cells. Front Immunol. 2020;11:2025.
Badolati I, Sverremark-Ekström E, van der Heiden M. Th9 cells in allergic diseases: a role for the microbiota? Scand J Immunol. 2020;91:e12857.
Pei S, Huang M, Huang J, Zhu X, Wang H, Romano S, et al. BFAR coordinates TGFβ signaling to modulate Th9-mediated cancer immunotherapy. J Exp Med. 2021;218:e20202144.
Rivera Vargas T, Cai Z, Shen Y, Dosset M, Benoit-Lizon I, Martin T, et al. Selective degradation of PU.1 during autophagy represses the differentiation and antitumour activity of T(H)9 cells. Nat Commun. 2017;8:559.
Hegde S, Leader AM, Merad M. MDSC: Markers, development, states, and unaddressed complexity. Immunity. 2021;54:875–84.
Weber R, Groth C, Lasser S, Arkhypov I, Petrova V, Altevogt P, et al. IL-6 as a major regulator of MDSC activity and possible target for cancer immunotherapy. Cell Immunol. 2021;359:104254.
Song G, Zhang Y, Tian J, Ma J, Yin K, Xu H, et al. TRAF6 regulates the immunosuppressive effects of myeloid-derived suppressor cells in tumor-bearing host. Front Immunol. 2021;12:649020.
Xin J, Zhang Z, Su X, Wang L, Zhang Y, Yang R. Epigenetic component p66a modulates myeloid-derived suppressor cells by modifying STAT3. J Immunol. 2017;198:2712–20.
He H, Liu J, Li L, Qian G, Hao D, Li M, et al. Helicobacter pylori CagA interacts with SHP-1 to suppress the immune response by targeting TRAF6 for K63-linked ubiquitination. J Immunol. 2021;206:1161–70.
Takahashi M, Lio CJ, Campeau A, Steger M, Ay F, Mann M, et al. The tumor suppressor kinase DAPK3 drives tumor-intrinsic immunity through the STING-IFN-β pathway. Nat Immunol. 2021;22:485–96.
Wang Y, Sun Q, Mu N, Sun X, Wang Y, Fan S, et al. The deubiquitinase USP22 regulates PD-L1 degradation in human cancer cells. Cell Commun Signal. 2020;18:112.
Wu S, Zhang Q, Zhang F, Meng F, Liu S, Zhou R, et al. HER2 recruits AKT1 to disrupt STING signalling and suppress antiviral defence and antitumour immunity. Nat Cell Biol. 2019;21:1027–40.
Mitchell JP, Carmody RJ. NF-κB and the transcriptional control of inflammation. Int Rev cell Mol Biol. 2018;335:41–84.
Mitchell S, Vargas J, Hoffmann A. Signaling via the NFκB system. Wiley Interdiscip Rev Syst Biol Med. 2016;8:227–41.
Xu W, Zhang L, Ma S, Zhang Y, Cai Z, Zhang K, et al. TRAF5 protects against myocardial ischemia reperfusion injury via AKT signaling. Eur J Pharmacol. 2020;878:173092.
Zhang L, Blackwell K, Shi Z, Habelhah H. The RING domain of TRAF2 plays an essential role in the inhibition of TNFalpha-induced cell death but not in the activation of NF-kappaB. J Mol Biol. 2010;396:528–39.
Gudi R, Barkinge J, Hawkins S, Prabhakar B, Kanteti P. Siva-1 promotes K-48 polyubiquitination of TRAF2 and inhibits TCR-mediated activation of NF-kappaB. J Environ Pathol, Toxicol Oncol. 2009;28:25–38.
Yu C, Chen S, Guo Y, Sun C. Oncogenic TRIM31 confers gemcitabine resistance in pancreatic cancer via activating the NF-κB signaling pathway. Theranostics. 2018;8:3224–36.
Zhou AY, Shen RR, Kim E, Lock YJ, Xu M, Chen ZJ, et al. IKKε-mediated tumorigenesis requires K63-linked polyubiquitination by a cIAP1/cIAP2/TRAF2 E3 ubiquitin ligase complex. Cell Rep. 2013;3:724–33.
Dai T, Zhang D, Cai M, Wang C, Wu Z, Ying Z, et al. Golgi phosphoprotein 3 (GOLPH3) promotes hepatocellular carcinoma cell aggressiveness by activating the NF-κB pathway. J Pathol. 2015;235:490–501.
Boulabiar M, Boubaker S, Favre M, Demeret C. Keratinocyte sensitization to tumour necrosis factor-induced nuclear factor kappa B activation by the E2 regulatory protein of human papillomaviruses. J Gen Virol. 2011;92:2422–7.
Liu F, Xia Y, Parker AS, Verma IM. IKK biology. Immunol Rev. 2012;246:239–53.
Häcker H, Karin M. Regulation and function of IKK and IKK-related kinases. Science’s STKE: Signal Transduct Knowl Environ. 2006;2006:re13.
Wang Y, Zhao W, Gao Q, Fan L, Qin Y, Zhou H, et al. pVHL mediates K63-linked ubiquitination of IKKβ, leading to IKKβ inactivation. Cancer Lett. 2016;383:1–8.
Yang Y, Kelly P, Shaffer AL 3rd, Schmitz R, Yoo HM, Liu X, et al. Targeting non-proteolytic protein ubiquitination for the treatment of diffuse large B cell lymphoma. Cancer Cell. 2016;29:494–507.
Gallo LH, Meyer AN, Motamedchaboki K, Nelson KN, Haas M, Donoghue DJ. Novel Lys63-linked ubiquitination of IKKβ induces STAT3 signaling. Cell Cycle. 2014;13:3964–76.
Meyer AN, Gallo LH, Ko J, Cardenas G, Nelson KN, Siari A, et al. Oncogenic mutations in IKKβ function through global changes induced by K63-linked ubiquitination and result in autocrine stimulation. PLoS ONE. 2018;13:e0206014.
Festjens N, Vanden Berghe T, Cornelis S, Vandenabeele P. RIP1, a kinase on the crossroads of a cell’s decision to live or die. Cell Death Differ. 2007;14:400–10.
Liu Y, Liu T, Lei T, Zhang D, Du S, Girani L, et al. RIP1/RIP3-regulated necroptosis as a target for multifaceted disease therapy (Review). Int J Mol Med. 2019;44:771–86.
Gong H, Song L, Lin C, Liu A, Lin X, Wu J, et al. Downregulation of miR-138 sustains NF-κB activation and promotes lipid raft formation in esophageal squamous cell carcinoma. Clin Cancer Res. 2013;19:1083–93.
Kim SW, Ramasamy K, Bouamar H, Lin AP, Jiang D, Aguiar RC. MicroRNAs miR-125a and miR-125b constitutively activate the NF-κB pathway by targeting the tumor necrosis factor alpha-induced protein 3 (TNFAIP3, A20). Proc Natl Acad Sci USA. 2012;109:7865–70.
Puliyappadamba VT, Chakraborty S, Chauncey SS, Li L, Hatanpaa KJ, Mickey B, et al. Opposing effect of EGFRWT on EGFRvIII-mediated NF-κB activation with RIP1 as a cell death switch. Cell Rep. 2013;4:764–75.
Song L, Gong H, Lin C, Wang C, Liu L, Wu J, et al. Flotillin-1 promotes tumor necrosis factor-α receptor signaling and activation of NF-κB in esophageal squamous cell carcinoma cells. Gastroenterology. 2012;143:995–1005.e1012.
Yan XY, Zhang Y, Zhang JJ, Zhang LC, Liu YN, Wu Y, et al. p62/SQSTM1 as an oncotarget mediates cisplatin resistance through activating RIP1-NF-κB pathway in human ovarian cancer cells. Cancer Sci. 2017;108:1405–13.
An J, Mo D, Liu H, Veena MS, Srivatsan ES, Massoumi R, et al. Inactivation of the CYLD deubiquitinase by HPV E6 mediates hypoxia-induced NF-kappaB activation. Cancer Cell. 2008;14:394–407.
Almeida S, Maillard C, Itin P, Hohl D, Huber M. Five new CYLD mutations in skin appendage tumors and evidence that aspartic acid 681 in CYLD is essential for deubiquitinase activity. J investigative Dermatol. 2008;128:587–93.
Chen M, Zhao Z, Meng Q, Liang P, Su Z, Wu Y, et al. TRIM14 Promotes noncanonical NF-κB activation by modulating p100/p52 stability via selective autophagy. Adv Sci. 2020;7:1901261.
Guo M, Härtlova A, Gierliński M, Prescott A, Castellvi J, Losa JH, et al. Triggering MSR1 promotes JNK-mediated inflammation in IL-4-activated macrophages. EMBO J. 2019;38.
Ji J, Ding K, Luo T, Zhang X, Chen A, Zhang D, et al. TRIM22 activates NF-κB signaling in glioblastoma by accelerating the degradation of IκBα. Cell Death Differ. 2021;28:367–81.
Yu X, Li W, Deng Q, Liu H, Wang X, Hu H, et al. MYD88 L265P elicits mutation-specific ubiquitination to drive NF-κB activation and lymphomagenesis. Blood. 2021;137:1615–27.
Jackson SP, Bartek J. The DNA-damage response in human biology and disease. Nature. 2009;461:1071–8.
Liu J, Zheng B, Li Y, Yuan Y, Xing C. Genetic polymorphisms of DNA repair pathways in sporadic colorectal carcinogenesis. J Cancer. 2019;10:1417–33.
Ray U, Raghavan SC. Understanding the DNA double-strand break repair and its therapeutic implications. DNA Repair. 2021;106:103177.
Chang HHY, Pannunzio NR, Adachi N, Lieber MR. Non-homologous DNA end joining and alternative pathways to double-strand break repair. Nat Rev Mol Cell Biol. 2017;18:495–506.
Yang Y, Yang C, Li T, Yu S, Gan T, Hu J, et al. The deubiquitinase USP38 promotes NHEJ repair through regulation of HDAC1 activity and regulates cancer cell response to genotoxic insults. Cancer Res. 2020;80:719–31.
Zhang Q, Karnak D, Tan M, Lawrence TS, Morgan MA, Sun Y. FBXW7 facilitates nonhomologous end-joining via K63-linked polyubiquitylation of XRCC4. Mol Cell. 2016;61:419–33.
Wright WD, Shah SS, Heyer WD. Homologous recombination and the repair of DNA double-strand breaks. J Biol Chem. 2018;293:10524–35.
Ali MAM, Strickfaden H, Lee BL, Spyracopoulos L, Hendzel MJ. RYBP Is a K63-ubiquitin-chain-binding protein that inhibits homologous recombination repair. Cell Rep. 2018;22:383–95.
Wu J, Zhang X, Zhang L, Wu CY, Rezaeian AH, Chan CH, et al. Skp2 E3 ligase integrates ATM activation and homologous recombination repair by ubiquitinating NBS1. Mol Cell. 2012;46:351–61.
Zhu B, Yan K, Li L, Lin M, Zhang S, He Q, et al. K63-linked ubiquitination of FANCG is required for its association with the Rap80-BRCA1 complex to modulate homologous recombination repair of DNA interstand crosslinks. Oncogene. 2015;34:2867–78.
Abu-Odeh M, Salah Z, Herbel C, Hofmann TG, Aqeilan RI. WWOX, the common fragile site FRA16D gene product, regulates ATM activation and the DNA damage response. Proc Natl Acad Sci USA. 2014;111:E4716–25.
Metcalf JL, Bradshaw PS, Komosa M, Greer SN, Stephen Meyn M, Ohh M. K63-ubiquitylation of VHL by SOCS1 mediates DNA double-strand break repair. Oncogene. 2014;33:1055–65.
Zhi H, Guo X, Ho YK, Pasupala N, Engstrom HAA, Semmes OJ, et al. RNF8 dysregulation and down-regulation during HTLV-1 infection promote genomic instability in adult T-cell leukemia. PLoS Pathog. 2020;16:e1008618.
Wu M, Tu HQ, Chang Y, Tan B, Wang G, Zhou J, et al. USP19 deubiquitinates HDAC1/2 to regulate DNA damage repair and control chromosomal stability. Oncotarget. 2017;8:2197–208.
Liu P, Gan W, Su S, Hauenstein AV, Fu TM, Brasher B, et al. K63-linked polyubiquitin chains bind to DNA to facilitate DNA damage repair. Sci Signal. 2018;11:eaar8133.
Fernández-Majada V, Welz PS, Ermolaeva MA, Schell M, Adam A, Dietlein F, et al. The tumour suppressor CYLD regulates the p53 DNA damage response. Nat Commun. 2016;7:12508.
Vujanovic M, Krietsch J, Raso MC, Terraneo N, Zellweger R, Schmid JA. et al. Replication fork slowing and reversal upon DNA Damage require PCNA polyubiquitination and ZRANB3 DNA translocase activity. Mol Cell. 2017;67:882–90.e885.
Moo TA, Sanford R, Dang C, Morrow M. Overview of breast cancer therapy. PET Clin. 2018;13:339–54.
Bukowski K, Kciuk M, Kontek R. Mechanisms of multidrug resistance in cancer chemotherapy. Int J Mol Sci. 2020;21:3233.
Delbue D, Mendonça BS, Robaina MC, Lemos LGT, Lucena PI, Viola JPB, et al. Expression of nuclear XIAP associates with cell growth and drug resistance and confers poor prognosis in breast cancer. Biochim Biophys Acta Mol Cell Res. 2020;1867:118761.
Li Z, Younger K, Gartenhaus R, Joseph AM, Hu F, Baer MR, et al. Inhibition of IRAK1/4 sensitizes T cell acute lymphoblastic leukemia to chemotherapies. J Clin Investig. 2015;125:1081–97.
Qu C, Kunkalla K, Vaghefi A, Frederiksen JK, Liu Y, Chapman JR, et al. Smoothened stabilizes and protects TRAF6 from degradation: a novel non-canonical role of smoothened with implications in lymphoma biology. Cancer Lett. 2018;436:149–58.
Shi WN, Cui SX, Song ZY, Wang SQ, Sun SY, Yu XF, et al. Overexpression of SphK2 contributes to ATRA resistance in colon cancer through rapid degradation of cytoplasmic RXRα by K48/K63-linked polyubiquitination. Oncotarget. 2017;8:39605–17.
Kumar B, Singh S, Skvortsova I, Kumar V. Promising targets in anti-cancer drug development: recent updates. Curr Med Chem. 2017;24:4729–52.
Ashique S, Sandhu NK, Chawla V, Chawla PA. Targeted drug delivery: trends and perspectives. Curr Drug Deliv. 2021;18:1435–55.
Li Y, Liu Y, Xu H, Jiang G, Van der Jeught K, Fang Y, et al. Heterozygous deletion of chromosome 17p renders prostate cancer vulnerable to inhibition of RNA polymerase II. Nat Commun. 2018;9:4394.
Marx C, Held JM, Gibson BW, Benz CC. ErbB2 trafficking and degradation associated with K48 and K63 polyubiquitination. Cancer Res. 2010;70:3709–17.
Nunes J, Zhang H, Angelopoulos N, Chhetri J, Osipo C, Grothey A, et al. ATG9A loss confers resistance to trastuzumab via c-Cbl mediated Her2 degradation. Oncotarget. 2016;7:27599–612.
Gong K, Guo G, Panchani N, Bender ME, Gerber DE, Minna JD, et al. EGFR inhibition triggers an adaptive response by co-opting antiviral signaling pathways in lung cancer. Nat Cancer. 2020;1:394–409.
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This study is supported by the National Natural Science Foundation of China (82102740) and the Natural Science Foundation of Liaoning Province (2019-ZD-0748).
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LC and XL wrote the manuscript. BZ revised the manuscript. CX and JL designed the study.
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Cao, L., Liu, X., Zheng, B. et al. Role of K63-linked ubiquitination in cancer. Cell Death Discov. 8, 410 (2022). https://doi.org/10.1038/s41420-022-01204-0
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DOI: https://doi.org/10.1038/s41420-022-01204-0
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