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TRIM58 downregulation maintains stemness via MYH9-GRK3-YAP axis activation in triple-negative breast cancer stem cells

Cancer Gene Therapy (2024)Cite this article

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Abstract

TRIM58 is a member of the TRIM protein family, which possess with E3 ubiquitin ligase activities. Studies have revealed that low expression of TRIM58 plays key roles, has been implicated in the tumor progression of tumor formation due to its reduced expression. However, its role in regulating the stemness of breast cancer stem cells (CSCs) remains unexplored. Here, we found that TRIM58 was underexpressed in TNBC tissues and cells compared to adjacent mucosa tissue, and its downregulation was significantly associated with shorter survival. Overexpression of TRIM58 reduced the proportion of CD44 + /CD24- cells, upregulated differentiation genes, and inhibited stemness-related gene expression in TNBC CSCs. In vitro and in vivo experiments revealed that TRIM58 overexpression in CSCs suppressed tumor sphere formation and tumorigenic capacity. Co-IP results indicated direct interaction between TRIM58 and MYH9, with TRIM58 inducing MYH9 degradation via ubiquitination in differentiated cells. Label-free quantitative proteomics identified GRK3 and Hippo-YAP as downstream targets and signaling pathways of MYH9. TIMER database analysis, immunohistochemistry, western blotting, DNA-protein pulldown experiments, and dual luciferase reporter assays demonstrated that MYH9 regulated GRK3 transcriptional activation in CSCs. In conclusion, elevated TRIM58 expression in CSCs downregulates MYH9 protein levels by promoting ubiquitin-mediated degradation, thereby inhibiting downstream GRK3 transcription, inactivating the YAP stemness pathway, and ultimately promoting CSC differentiation.

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Fig. 1: TRIM58 exhibits low expression in TNBC and inhibits the proliferation of TNBC cells in vitro.
Fig. 2: TRIM58 regulates the stemness and differentiation of TNBC CSCs.
Fig. 3: TRIM58 promotes MYH9 degradation through ubiquitination.
Fig. 4: TRIM58 affects the stemness of CSCs by regulating MYH9.
Fig. 5: MYH9 may regulate cellular stemness through GRK3 and Hippo signaling pathways.
Fig. 6: MYH9 regulates GRK3 gene transcriptional activation in CSCs.
Fig. 7: TRIM58 activates the GRK3/YAP axis through MYH9.
Fig. 8: The proposed model of TRIM58 downregulation maintains stemness via MYH9-GRK3-YAP axis activation in triple-negative breast cancer stem cells.

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Data availability

The representative data are included in this article. The datasets used and/or analysed during the current study are available from the corresponding author (yangfan@ucas.ac.cn) upon reasonable request.

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Funding

Funding

This work was supported by the Zhejiang Provincial Natural Science Foundation of China under Grant No. LY22H160010; Medical Scientific Research Foundation of Zhejiang Province, Grant No. 2021KY338, 2023KY1086; Ningbo Natural Science Foundation, Project ID: 2021J318, 2021J311, 2023J325; Project of Ningbo Leading Medical & Health Discipline, Project No: 2022-B13.

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Author notes

  1. These authors contributed equally: Xujun Li, Jing Jiang.

Authors and Affiliations

  1. Department of Oncology, Ningbo No.2 Hospital, Ningbo, Zhejiang, PR China

    Xujun Li, Jing Jiang & Fan Yang

  2. Department of Breast Surgery, Ningbo No.2 Hospital, Ningbo, Zhejiang, PR China

    Xujun Li, Jing Jiang, Qian Wu & Fan Yang

  3. Ningbo Institute of Life and Health Industry, University of Chinese Academy of Sciences, Ningbo, Zhejiang, PR China

    Qian Wu & Fan Yang

  4. Traditional Chinese Medicine Hospital of Ninghai County, Ningbo, Zhejiang, PR China

    Tianzi You

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Contributions

YF designed and analyzed the experiments. LXJ and JJ wrote the manuscript. LXJ and YF performed and analyzed the experiments and prepared the figures. LXJ, JJ, WQ, YTZ performed the experiments. YF guided the experiment. LXJ and JJ contributed equally to this work. All authors have read and approved the final manuscript.

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Correspondence to Fan Yang.

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Ethical approval

Animal experiments were approved by the Animal Ethics Committee of Ningbo Institute of Life and Health Industry, Ningbo, Zhejiang, China (Approval number: GK-2023-XM-0076). All surgical procedures were performed under full anesthesia, and all efforts were made to minimize animal suffering. All the animals were handled according to the Ministry of Health guidelines for the care and use of laboratory animals (GB 14925–2001). The human study was approved by the Committee on Ethics of Ningbo No.2 Hospital, Ningbo, Zhejiang, China (Approval number: PJ-NBEY-KY-2020-191-01). The experiments were undertaken with the understanding and written consent of each subject. The study methodologies conformed to the standards set by the Declaration of Helsinki.

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Li, X., Jiang, J., Wu, Q. et al. TRIM58 downregulation maintains stemness via MYH9-GRK3-YAP axis activation in triple-negative breast cancer stem cells. Cancer Gene Ther (2024). https://doi.org/10.1038/s41417-024-00780-w

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