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

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.

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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.

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.

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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).

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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.

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The authors declare no competing interests.

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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.

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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

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