Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

MYBL2 promotes proliferation and metastasis of bladder cancer through transactivation of CDCA3

Oncogene volume 41, pages 4606–4617 (2022)Cite this article

Subjects

Abstract

The transcription factor MYB proto-oncogene like 2 (MYBL2) is critical in regulating gene expression and tumorigenesis. However, the biological function of MYBL2 in bladder cancer (BLCA) remains to be elucidated. Here, we first revealed that MYBL2 was elevated in BLCA tissues and significantly correlated with clinicopathological parameters and cancer-specific survival in BLCA patients. Phenotypic assays showed that MYBL2 deficiency suppressed the proliferation and migration of BLCA cells in vitro and in vivo, whereas MYBL2 overexpression contributed to the opposite phenotype. Mechanistically, MYBL2 could bind to the promoter of its downstream target gene cell division cycle-associated protein 3 (CDCA3) and transactivate it, which in turn promoted the malignant phenotype of BLCA cells. Further investigations revealed that MYBL2 interacted with forkhead box M1 (FOXM1) to co-regulate the transcription of CDCA3. In addition, MYBL2/FOXM1 and CDCA3 might activate Wnt/β-catenin signaling, thereby promoting the malignant phenotype of BLCA cells. In conclusion, the current study identifies MYBL2 as an oncogene in BLCA. MYBL2 can accelerate the proliferation and metastasis of BLCA through the transactivation of CDCA3.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: MYBL2 is up-regulated in BLCA.
Fig. 2: MYBL2 deficiency inhibits the proliferation of BLCA cells.
Fig. 3: MYBL2 depletion triggers cell cycle arrest in BLCA.
Fig. 4: Knockdown of MYBL2 suppresses the metastasis of BLCA cells.
Fig. 5: MYBL2 transactivates CDCA3 by directly binding to its promoter.
Fig. 6: MYBL2 regulates CDCA3 to promote the aggressiveness of BLCA cells.
Fig. 7: MYBL2 interacts with FOXM1 to co-regulate CDCA3.
Fig. 8: MYBL2 and CDCA3 regulate Wnt/β-catenin signaling in BLCA.

Similar content being viewed by others

Data availability

The microarray data could be downloaded from the NCBI Gene Expression Omnibus (GEO) database with accession number GSE13507, GSM1526875, GSM2797580, and GSE119971. Other bioinformatics analyses could be performed using the online databases: UALCAN, GEPIA, and JASPAR. Raw RNA sequencing data generated in this study have been submitted to the GEO database under accession number GSE201875 and GSE201979.

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.

    Article  PubMed  Google Scholar 

  2. Rimar KJ, Tran PT, Matulewicz RS, Hussain M, Meeks JJ. The emerging role of homologous recombination repair and PARP inhibitors in genitourinary malignancies. Cancer. 2017;123:1912–24.

    Article  CAS  PubMed  Google Scholar 

  3. Pan CW, Liu H, Zhao Y, Qian C, Wang L, Qi J. JNK2 downregulation promotes tumorigenesis and chemoresistance by decreasing p53 stability in bladder cancer. Oncotarget. 2016;7:35119–31.

    Article  PubMed  PubMed Central  Google Scholar 

  4. Shen D, Fang Y, Zhou F, Deng Z, Qian K, Wang G, et al. The inhibitory effect of silencing CDCA3 on migration and proliferation in bladder urothelial carcinoma. Cancer Cell Int. 2021;21:257.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Xiong YC, Wang J, Cheng Y, Zhang XY, Ye XQ. Overexpression of MYBL2 promotes proliferation and migration of non-small-cell lung cancer via upregulating NCAPH. Mol Cell Biochem. 2020;468:185–93.

    Article  CAS  PubMed  Google Scholar 

  6. Cicirò Y, Sala A. MYB oncoproteins: emerging players and potential therapeutic targets in human cancer. Oncogenesis. 2021;10:19.

    Article  PubMed  PubMed Central  Google Scholar 

  7. Bayley R, Ward C, Garcia P. MYBL2 amplification in breast cancer: molecular mechanisms and therapeutic potential. Biochim Biophys Acta Rev Cancer. 2020;1874:188407.

    Article  CAS  PubMed  Google Scholar 

  8. Li Q, Wang M, Hu Y, Zhao E, Li J, Ren L, et al. MYBL2 disrupts the Hippo-YAP pathway and confers castration resistance and metastatic potential in prostate cancer. Theranostics. 2021;11:5794–812.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Hou X, Zhang Y, Han S, Hou B. A novel DNA methylation 10-CpG prognostic signature of disease-free survival reveal that MYBL2 is associated with high risk in prostate cancer. Expert Rev Anticancer Ther. 2020;20:1107–19.

    Article  CAS  PubMed  Google Scholar 

  10. Liu Q, Guo L, Qi H, Lou M, Wang R, Hai B, et al. A MYBL2 complex for RRM2 transactivation and the synthetic effect of MYBL2 knockdown with WEE1 inhibition against colorectal cancer. Cell Death Dis. 2021;12:683.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Yu R, Li C, Lin X, Chen Q, Li J, Song L, et al. Clinicopathologic features and prognostic implications of MYBL2 protein expression in pancreatic ductal adenocarcinoma. Pathol Res Pr. 2017;213:964–8.

    Article  CAS  Google Scholar 

  12. Okumura F, Uematsu K, Byrne SD, Hirano M, Joo-Okumura A, Nishikimi A, et al. Parallel regulation of von Hippel-Lindau disease by pVHL-mediated degradation of B-Myb and hypoxia-inducible factor α. Mol Cell Biol. 2016;36:1803–17.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Heinrichs S, Conover LF, Bueso-Ramos CE, Kilpivaara O, Stevenson K, Neuberg D, et al. MYBL2 is a sub-haploinsufficient tumor suppressor gene in myeloid malignancy. Elife. 2013;2:e00825.

    Article  PubMed  PubMed Central  Google Scholar 

  14. Han J, Xie R, Yang Y, Chen D, Liu L, Wu J, et al. CENPA is one of the potential key genes associated with the proliferation and prognosis of ovarian cancer based on integrated bioinformatics analysis and regulated by MYBL2. Transl Cancer Res. 2021;10:4076–86.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Sadasivam S, Duan S, DeCaprio JA. The MuvB complex sequentially recruits B-Myb and FoxM1 to promote mitotic gene expression. Genes Dev. 2012;26:474–89.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Wang Z, Ahmad A, Li Y, Banerjee S, Kong D, Sarkar FH. Forkhead box M1 transcription factor: a novel target for cancer therapy. Cancer Treat Rev. 2010;36:151–6.

    Article  CAS  PubMed  Google Scholar 

  17. Xue YJ, Xiao RH, Long DZ, Zou XF, Wang XN, Zhang GX, et al. Overexpression of FoxM1 is associated with tumor progression in patients with clear cell renal cell carcinoma. J Transl Med. 2012;10:200.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Engeland K. Cell cycle arrest through indirect transcriptional repression by p53: I have a DREAM. Cell Death Differ. 2018;25:114–32.

    Article  CAS  PubMed  Google Scholar 

  19. Fischer M, Grossmann P, Padi M, DeCaprio JA. Integration of TP53, DREAM, MMB-FOXM1 and RB-E2F target gene analyses identifies cell cycle gene regulatory networks. Nucleic Acids Res. 2016;44:6070–86.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Xie H, Miao N, Xu D, Zhou Z, Ni J, Yin F, et al. FoxM1 promotes Wnt/β-catenin pathway activation and renal fibrosis via transcriptionally regulating multi-Wnts expressions. J Cell Mol Med. 2021;25:1958–71.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Gong A, Huang S. FoxM1 and Wnt/β-catenin signaling in glioma stem cells. Cancer Res. 2012;72:5658–62.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Sheng Y, Yu C, Liu Y, Hu C, Ma R, Lu X, et al. FOXM1 regulates leukemia stem cell quiescence and survival in MLL-rearranged AML. Nat Commun. 2020;11:928.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Li M, Liu Y, Liu J, Li W, Li N, Xue D, et al. Circ_0006332 promotes growth and progression of bladder cancer by modulating MYBL2 expression via miR-143. Aging (Albany NY). 2019;11:10626–43.

    Article  CAS  PubMed Central  Google Scholar 

  24. Zhang X, Lv QL, Huang YT, Zhang LH, Zhou HH. Akt/FoxM1 signaling pathway-mediated upregulation of MYBL2 promotes progression of human glioma. J Exp Clin Cancer Res. 2017;36:105.

    Article  PubMed  PubMed Central  Google Scholar 

  25. Ayad NG, Rankin S, Murakami M, Jebanathirajah J, Gygi S, Kirschner MW. Tome-1, a trigger of mitotic entry, is degraded during G1 via the APC. Cell. 2003;113:101–13.

    Article  CAS  PubMed  Google Scholar 

  26. Iness AN, Felthousen J, Ananthapadmanabhan V, Sesay F, Saini S, Guiley KZ, et al. The cell cycle regulatory DREAM complex is disrupted by high expression of oncogenic B-Myb. Oncogene. 2019;38:1080–92.

    Article  CAS  PubMed  Google Scholar 

  27. Guiley KZ, Iness AN, Saini S, Tripathi S, Lipsick JS, Litovchick L, et al. Structural mechanism of Myb-MuvB assembly. Proc Natl Acad Sci USA. 2018;115:10016–21.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Salik B, Yi H, Hassan N, Santiappillai N, Vick B, Connerty P, et al. Targeting RSPO3-LGR4 signaling for leukemia stem cell eradication in acute myeloid leukemia. Cancer Cell. 2020;38:263.

    Article  CAS  PubMed  Google Scholar 

  29. Choi BR, Cave C, Na CH, Sockanathan S. GDE2-dependent activation of canonical Wnt signaling in neurons regulates oligodendrocyte maturation. Cell Rep. 2020;31:107540.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. He S, Tang S. WNT/β-catenin signaling in the development of liver cancers. Biomed Pharmacother. 2020;132:110851.

    Article  CAS  PubMed  Google Scholar 

  31. Bian J, Dannappel M, Wan C, Firestein R. Transcriptional regulation of Wnt/β-catenin pathway in colorectal cancer. Cells. 2020;9:2125.

    Article  CAS  PubMed Central  Google Scholar 

  32. Ge X, Wang X. Role of Wnt canonical pathway in hematological malignancies. J Hematol Oncol. 2010;3:33.

    Article  PubMed  PubMed Central  Google Scholar 

  33. Ramirez JG, Smit DJ, Viol F, Schrader J, Ghadban T, Pantel K, et al. High serum levels of Wnt signaling antagonist dickkopf-related protein 1 are associated with impaired overall survival and recurrence in esophageal cancer patients. Cancers (Basel). 2021;13:4980.

    Article  CAS  Google Scholar 

  34. Cao R, Wang G, Qian K, Chen L, Ju L, Qian G, et al. TM4SF1 regulates apoptosis, cell cycle and ROS metabolism via the PPARγ-SIRT1 feedback loop in human bladder cancer cells. Cancer Lett. 2018;414:278–93.

    Article  CAS  PubMed  Google Scholar 

  35. Chen G, Deng X. Cell synchronization by double thymidine block. Bio Protoc. 2018;8:e2994.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Association WM. World Medical Association Declaration of Helsinki: ethical principles for medical research involving human subjects. JAMA. 2013;310:2191–4.

    Article  Google Scholar 

Download references

Acknowledgements

The excellent technical assistance of Ms. Yayun Fang and Ms. Danni Shan are gratefully acknowledged. Part of the analysis was performed on the High Performance Computing Platform of the Center for Life Science (Peking University). The study was funded by National Natural Science Foundation of China (82172985 and 81772730), Improvement Project for Theranostic Ability on Difficulty Miscellaneous Disease (Tumor) from National Health Commission of China (ZLYNXM202006), Non-profit Central Research Institute Fund of Chinese Academy of Medical Sciences (2020-PT320-004), Research Fund of Zhongnan Hospital of Wuhan University (ZNJC201915, SWYBK00-03, 413100049, and PTXM2020024), Science and Technology Department of Hubei Province Key Project (2022EJD001 and YYXKNL2022001).

Author information

Author notes

  1. These authors contributed equally: Wei Liu, Dexin Shen, Lingao Ju, Renjie Zhang.

Authors and Affiliations

  1. Department of Urology, Zhongnan Hospital of Wuhan University, Wuhan, China

    Wei Liu, Dexin Shen, Renjie Zhang, Wenzhi Du, Kangping Xiong, Kaiyu Qian, Yu Xiao & Xinghuan Wang

  2. Department of Biological Repositories, Zhongnan Hospital of Wuhan University, Wuhan, China

    Lingao Ju, Wan Jin, Gang Wang, Kaiyu Qian, Yu Xiao & Xinghuan Wang

  3. Euler Technology, ZGC Life Sciences Park, Beijing, China

    Wan Jin & Yi Zhang

  4. Center for Quantitative Biology, School of Life Sciences, Peking University, Beijing, China

    Yi Zhang

  5. Wuhan Research Center for Infectious Diseases and Cancer, Chinese Academy of Medical Sciences, Wuhan, China

    Xinghuan Wang

Authors
  1. Wei Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Dexin Shen
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Lingao Ju
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Renjie Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Wenzhi Du
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Wan Jin
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Kangping Xiong
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Gang Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Kaiyu Qian
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Yi Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Yu Xiao
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Xinghuan Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

W.L., X.W., and Y.X. devised the study and wrote the manuscript. W.L., D.S., L.J., and R.Z. performed most experiments. G.W., K.Q., W.D., and W.J. helped with data collection and assembly. K.X. and Y.Z. performed data analysis and interpretation. X.W. and Y.X. corrected the final manuscript.

Corresponding authors

Correspondence to Yi Zhang, Yu Xiao or Xinghuan Wang.

Ethics declarations

Competing interests

The authors declare no competing interests.

Ethics approval

This study was performed in accordance with the Declaration of Helsinki [36] and was approved by the Institutional Ethics Committee of Zhongnan Hospital of Wuhan University (approval number: 2020102) and Experimental Animal Welfare and Ethics of Zhongnan Hospital (approval number: ZN2021065). Bioinformatics data involving humans were collected from publicly available databases with anonymous patient information.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

Rights and permissions

Springer Nature or its licensor holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Liu, W., Shen, D., Ju, L. et al. MYBL2 promotes proliferation and metastasis of bladder cancer through transactivation of CDCA3. Oncogene 41, 4606–4617 (2022). https://doi.org/10.1038/s41388-022-02456-x

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41388-022-02456-x

This article is cited by

Search

Advanced search

Quick links