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KIAA1429 is a potential prognostic marker in colorectal cancer by promoting the proliferation via downregulating WEE1 expression in an m6A-independent manner

Oncogene volume 41, pages 692–703 (2022)Cite this article

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Abstract

N6-methyladenosine (m6A), the most abundant mRNA modification in mammals, is involved in the metabolism of mRNA. KIAA1429 is regarded as the largest m6A methyltransferase and plays an important role in m6A modification. However, the prognostic value and function of KIAA1429 in colorectal cancer (CRC) are unclear. Quantitative real-time PCR and immunohistochemical assays were performed to evaluate the expression of KIAA1429 in CRC tissues. Kaplan–Meier survival curves and log-rank tests were used to assess the association between KIAA1429 expression and the prognosis of patients with CRC. CCK-8 assays, colony formation assays, cell cycle assays, and xenograft experiments were performed to investigate the effect of KIAA1429 on cell proliferation. RNA immunoprecipitation, methylated RNA immunoprecipitation assays, and RNA stability assays were conducted to explore the underlying mechanism. KIAA1429 was significantly upregulated in CRC tissues compared with adjacent normal tissues. Patients with higher expression of KIAA1429 had shorter overall survival than those with lower expression. Functionally, KIAA1429 promoted CRC cell proliferation in vitro and in vivo. Mechanistically, KIAA1429 negatively regulated the expression of WEE1 by decreasing its stability in an m6A-independent manner by binding to the third segment in the 3′-UTR of WEE1 mRNA. Moreover, butyrate decreased the expression of KIAA1429 by downregulating the level of the transcription factor NFκB1. Our findings indicated that KIAA1429 plays an oncogenic role in CRC cells by inhibiting the expression of WEE1 in an m6A-independent manner and is associated with poor survival in CRC patients. These results suggested that KIAA1429 might be a potential prognostic marker for CRC.

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Fig. 1: KIAA1429 was highly expressed and associated with poor survival in patients with CRC.
Fig. 2: KIAA1429 promoted CRC proliferation in vitro and in vivo.
Fig. 3: WEE1 was identified as a downstream target of KIAA1429.
Fig. 4: KIAA1429 promoted CRC tumorigenesis through WEE1-mediated tumor proliferation regulation.
Fig. 5: KIAA1429 regulated the mRNA expression of WEE1 in an m6A-independent manner.
Fig. 6: Butyrate inhibited the expression of KIAA1429 by regulating NF-κB1 in CRC cells.
Fig. 7: A schematic model of the role of the butyrate/KIAA1429/WEE1 pathway in regulating the proliferation of CRC.

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References

  1. Sung H, Ferlay J, Siegel RL, Laversanne M, Soerjomataram I, Jemal A, et al. Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries. CA Cancer J Clin. 2021;71:209–49.

    Google Scholar 

  2. van der Geest LGM, Lam-Boer JT, Koopman M, Verhoef C, Elferink MAG, de Wilt JHW. Nationwide trends in incidence, treatment and survival of colorectal cancer patients with synchronous metastases. Clin Exp Metastasis. 2015;32:457–65.

    Article  Google Scholar 

  3. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2019. CA Cancer J Clin. 2019;69:7–34.

    Article  Google Scholar 

  4. Pan Y, Ma P, Liu Y, Li W, Shu Y. Multiple functions of m(6)A RNA methylation in cancer. J Hematol Oncol. 2018;11:48.

    Article  Google Scholar 

  5. Yue B, Song C, Yang L, Cui R, Cheng X, Zhang Z, et al. METTL3-mediated N6-methyladenosine modification is critical for epithelial-mesenchymal transition and metastasis of gastric cancer. Mol Cancer. 2019;18:142.

    Article  Google Scholar 

  6. Chen Y, Peng C, Chen J, Chen D, Yang B, He B, et al. WTAP facilitates progression of hepatocellular carcinoma via m6A-HuR-dependent epigenetic silencing of ETS1. Mol Cancer. 2019;18:127.

    Article  Google Scholar 

  7. Cai X, Wang X, Cao C, Gao Y, Zhang S, Yang Z, et al. HBXIP-elevated methyltransferase METTL3 promotes the progression of breast cancer via inhibiting tumor suppressor let-7g. Cancer Lett. 2018;415:11–9.

    Article  CAS  Google Scholar 

  8. Peng W, Li J, Chen R, Gu Q, Yang P, Qian W, et al. Upregulated METTL3 promotes metastasis of colorectal Cancer via miR-1246/SPRED2/MAPK signaling pathway. J Exp Clin Cancer Res. 2019;38:393.

    Article  Google Scholar 

  9. Bai Y, Yang C, Wu R, Huang L, Song S, Li W, et al. YTHDF1 Regulates Tumorigenicity and Cancer Stem Cell-Like Activity in Human Colorectal Carcinoma. Int J Cancer. 2019;9:332.

    Google Scholar 

  10. Chen X, Xu M, Xu X, Zeng K, Liu X, Pan B, et al. METTL14-mediated N6-methyladenosine modification of SOX4 mRNA inhibits tumor metastasis in colorectal cancer. Mol Cancer. 2020;19:106.

    Article  CAS  Google Scholar 

  11. Li T, Hu PS, Zuo Z, Lin JF, Li X, Wu QN, et al. METTL3 facilitates tumor progression via m(6)A-IGF2BP2-Depend mechanism colorectal carcinoma. Mol Cancer. 2019;18:112.

  12. Ni W, Yao S, Zhou Y, Liu Y, Huang P, Zhou A, et al. Long noncoding RNA GAS5 inhibits progression of colorectal cancer by interacting with and triggering YAP phosphorylation and degradation and is negatively regulated by the m(6)A reader YTHDF3. Mol Cancer. 2019;18:143.

    Article  Google Scholar 

  13. Nishizawa Y, Konno M, Asai A, Koseki J, Kawamoto K, Miyoshi N, et al. Oncogene c-Myc promotes epitranscriptome m(6)A reader YTHDF1 expression in colorectal cancer. Oncotarget. 2018;9:7476–86.

    Article  Google Scholar 

  14. Wang Y, Lu JH, Wu QN, Jin Y, Wang DS, Chen YX, et al. LncRNA LINRIS stabilizes IGF2BP2 and promotes the aerobic glycolysis in colorectal cancer. Mol Cancer. 2019;18:174.

    Article  CAS  Google Scholar 

  15. Yang P, Wang Q, Liu A, Zhu J, Feng J. ALKBH5 Holds Prognostic Values and Inhibits the Metastasis of Colon Cancer. Pathol Oncol Res. 2020;26:1615–23.

    Article  CAS  Google Scholar 

  16. Chen X, Xu M, Xu X, Zeng K, Liu X, Sun L, et al. METTL14 Suppresses CRC Progression via Regulating N6-Methyladenosine-Dependent Primary miR-375 Processing. Mol Ther. 2020;28:599–612.

    Article  CAS  Google Scholar 

  17. Yue Y, Liu J, Cui X, Cao J, Luo G, Zhang Z, et al. VIRMA mediates preferential m(6)A mRNA methylation in 3’UTR and near stop codon and associates with alternative polyadenylation. Cell Disco. 2018;4:10.

    Article  Google Scholar 

  18. Schwartz S, Mumbach MR, Jovanovic M, Wang T, Maciag K, Bushkin GG, et al. Perturbation of m6A writers reveals two distinct classes of mRNA methylation at internal and 5’ sites. Cell Rep. 2014;8:284–96.

    Article  CAS  Google Scholar 

  19. Cheng X, Li M, Rao X, Zhang W, Li X, Wang L, et al. KIAA1429 regulates the migration and invasion of hepatocellular carcinoma by altering m6A modification of ID2 mRNA. Onco Targets Ther. 2019;12:3421–8.

    Article  CAS  Google Scholar 

  20. Lan T, Li H, Zhang D, Xu L, Liu H, Hao X, et al. KIAA1429 contributes to liver cancer progression through N6-methyladenosine-dependent post-transcriptional modification of GATA3. Mol Cancer. 2019;18:186.

    Article  CAS  Google Scholar 

  21. Barros-Silva D, Lobo J, Guimaraes-Teixeira C, Carneiro I, Oliveira J, Martens-Uzunova ES, et al. VIRMA-Dependent N6-Methyladenosine Modifications Regulate the Expression of Long Non-Coding RNAs CCAT1 and CCAT2 in Prostate Cancer. Cancers (Basel). 2020;12.771.

  22. Qian JY, Gao J, Sun X, Cao MD, Shi L, Xia TS, et al. KIAA1429 acts as an oncogenic factor in breast cancer by regulating CDK1 in an N6-methyladenosine-independent manner. Oncogene. 2019;38:6123–41.

    Article  CAS  Google Scholar 

  23. Miao R, Dai CC, Mei L, Xu J, Sun SW, Xing YL, et al. KIAA1429 regulates cell proliferation by targeting c-Jun messenger RNA directly in gastric cancer. J Cell Physiol. 2020;235:7420–32.

    Article  CAS  Google Scholar 

  24. Zhu W, Wang JZ, Wei JF, Lu C. Role of m6A methyltransferase component VIRMA in multiple human cancers (Review). Cancer Cell Int. 2021;21:172.

    Article  CAS  Google Scholar 

  25. Wang X, Fu X, Zhang J, Xiong C, Zhang S, Lv Y. Identification and validation of m(6)A RNA methylation regulators with clinical prognostic value in Papillary thyroid cancer. Cancer Cell Int. 2020;20:203.

    Article  Google Scholar 

  26. Zhu W, Si Y, Xu J, Lin Y, Wang JZ, Cao M, et al. Methyltransferase like 3 promotes colorectal cancer proliferation by stabilizing CCNE1 mRNA in an m6A-dependent manner. J Cell Mol Med. 2020;24:3521–33.

    Article  CAS  Google Scholar 

  27. Goncalves P, Martel F. Butyrate and colorectal cancer: the role of butyrate transport. Curr Drug Metab. 2013;14:994–1008.

    Article  CAS  Google Scholar 

  28. Liu Y, Upadhyaya B, Fardin-Kia AR, Juenemann RM, Dey M. Dietary resistant starch type 4-derived butyrate attenuates nuclear factor-kappa-B1 through modulation of histone H3 trimethylation at lysine 27. Food Funct. 2016;7:3772–81.

    Article  CAS  Google Scholar 

  29. Li Y, Xiao J, Bai J, Tian Y, Qu Y, Chen X, et al. Molecular characterization and clinical relevance of m(6)A regulators across 33 cancer types. Mol Cancer. 2019;18:137.

    Article  Google Scholar 

  30. Russell P, Nurse P. Negative regulation of mitosis by wee1+, a gene encoding a protein kinase homolog. Cell. 1987;49:559–67.

    Article  CAS  Google Scholar 

  31. Watanabe N, Broome M, Hunter T. Regulation of the human WEE1Hu CDK tyrosine 15-kinase during the cell cycle. Embo J. 1995;14:1878–91.

    Article  CAS  Google Scholar 

  32. Domínguez-Kelly R, Martín Y, Koundrioukoff S, Tanenbaum ME, Smits VA, Medema RH, et al. Wee1 controls genomic stability during replication by regulating the Mus81-Eme1 endonuclease. J Cell Biol. 2011;194:567–79.

    Article  Google Scholar 

  33. Backert S, Gelos M, Kobalz U, Hanski ML, Bohm C, Mann B, et al. Differential gene expression in colon carcinoma cells and tissues detected with a cDNA array. Int J Cancer. 1999;82:868–74.

    Article  CAS  Google Scholar 

  34. Ge XC, Wu F, Li WT, Zhu XJ, Liu JW, Wang BL. Upregulation of WEE1 is a potential prognostic biomarker for patients with colorectal cancer. Oncol Lett. 2017;13:4341–8.

    Article  CAS  Google Scholar 

  35. Wang X, Li Y, Chen W, Shi H, Eren AM, Morozov A, et al. Transcriptome-wide reprogramming of N6-methyladenosine modification by the mouse microbiome. Cell Res. 2018;29:167–70.

    Article  Google Scholar 

  36. Wu X, Wu Y, He L, Wu L, Wang X, Liu Z. Effects of the intestinal microbial metabolite butyrate on the development of colorectal cancer. J Cancer. 2018;9:2510–7.

    Article  Google Scholar 

  37. Encarnacao JC, Abrantes AM, Pires AS, Botelho MF. Revisit dietary fiber on colorectal cancer: butyrate and its role on prevention and treatment. Cancer Metastasis Rev. 2015;34:465–78.

    Article  CAS  Google Scholar 

  38. Wang JJ, Wei ZK, Zhang X, Wang YN, Fu YH, Yang ZT. Butyrate protects against disruption of the blood-milk barrier and moderates inflammatory responses in a model of mastitis induced by lipopolysaccharide. Br J Pharm. 2017;174:3811–22.

    Article  CAS  Google Scholar 

  39. Patel M, Horgan PG, McMillan DC, Edwards J. NF-kappaB pathways in the development and progression of colorectal cancer. Transl Res. 2018;197:43–56.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

This study was supported by grants from Natural Science Foundation of Jiangsu Province (BK20201495), Jiangsu Province’s Key Provincial Talents Program (ZDRCA2016089), and the National Natural Science Foundation of China (No. 82102981).

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Author notes

  1. These authors contributed equally: Ling Ma, Yu Lin, Shan-Wen Sun, Jun Xu.

Authors and Affiliations

  1. Department of Oncology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China

    Ling Ma, Yu Lin, Shan-Wen Sun, Jun Xu, Ting Yu, Liang-Hui Zhang, Yu-Chen Guo & Ling-Jun Zhu

  2. Department of Colorectal Surgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China

    Wen-Long Chen, Yi-Wen Wang & Tao Chen

  3. Research Division of Clinical Pharmacology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China

    Ji-Fu Wei

  4. Department of Pharmacy, Jiangsu Cancer Hospital & Jiangsu Institute of Cancer Research & The Affiliated Cancer Hospital of Nanjing Medical University, 210009, Nanjing, China

    Ji-Fu Wei

  5. Department of Oncology, The Sir Run Run Hospital, Nanjing Medical University, Nanjing, China

    Ling-Jun Zhu

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Contributions

LJZ, JFW, TC and LM conceptualized and supervised the research. LM, YL, SWS and JX designed and performed most experiments. YL, TY and LM performed animal experiments. LM, YL, SWS, JX and JFW were engaged in biostatistics and bioinformatics analysis. WLC, LHZ, YCG, YWW, TC and LJZ were responsible for patient recruitment, biospecimen and clinical data collection. LM, YL and JFW wrote the paper.

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Correspondence to Tao Chen, Ji-Fu Wei or Ling-Jun Zhu.

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Ma, L., Lin, Y., Sun, SW. et al. KIAA1429 is a potential prognostic marker in colorectal cancer by promoting the proliferation via downregulating WEE1 expression in an m6A-independent manner. Oncogene 41, 692–703 (2022). https://doi.org/10.1038/s41388-021-02066-z

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