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  3. Histone H3K36me2 demethylase KDM2A promotes bladder cancer progression through epigenetically silencing RARRES3

Histone H3K36me2 demethylase KDM2A promotes bladder cancer progression through epigenetically silencing RARRES3

  • Cell Death Dis. 2022 Jun 13;13(6):547. doi: 10.1038/s41419-022-04983-7.
Bing Lu 1,  Jiatian Wei 2,  Houhong Zhou 1,  Jie Chen 3,  Yuqing Li 1,  Liefu Ye 4,  Wei Zhao 5,  Song Wu 6
Affiliations

Affiliations

  • 1 Institute of Urology of Shenzhen University, The Third Affiliated Hospital of Shenzhen University, Shenzhen Luohu Hospital Group, Shenzhen, 518000, China.
  • 2 Key Laboratory of Stem Cells and Tissue Engineering (Sun Yat-sen University), Ministry of Education, Guangzhou, 510080, China.
  • 3 Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, 510080, China.
  • 4 Department of Urology, Fujian Provincial Hospital, 134 Dong Street, Fuzhou, 350001, China.
  • 5 Key Laboratory of Stem Cells and Tissue Engineering (Sun Yat-sen University), Ministry of Education, Guangzhou, 510080, China. zhaowei23@mail.sysu.edu.cn.
  • 6 Institute of Urology of Shenzhen University, The Third Affiliated Hospital of Shenzhen University, Shenzhen Luohu Hospital Group, Shenzhen, 518000, China. wusong@szu.edu.cn.
PMID: 35697678 DOI: 10.1038/s41419-022-04983-7
Abstract

Epigenetic dysregulation contributes to bladder Cancer tumorigenesis. H3K36me2 demethylase KDM2A functions as an important epigenetic regulator of cell fate in many types of tumors. However, its role in bladder Cancer remains unknown. Here, we revealed a positive correlation between KDM2A gene copy number gain and upregulation of KDM2A mRNA expression in bladder Cancer. Moreover, a super-enhancer (SE) driving KDM2A transcription was found in high-grade bladder Cancer, resulting in a significantly higher expression of KDM2A mRNA compared to that in low-grade bladder tumors. KDM2A knockdown (KD) decreased the proliferation, invasion, and spheroid formation of high-grade bladder Cancer cells and inhibited tumor growth in mouse xenograft models. Furthermore, we identified RARRES3 as a key KDM2A target gene. KDM2A suppresses RARRES3 expression via demethylation of H3K36me2 in the RARRES3 promoter. Intriguingly, RARRES3 KD attenuated the inhibitory effects of KDM2A depletion on the malignant phenotypes of high-grade bladder Cancer cells. The combination of the KDM2A inhibitor IOX1 and the RARRES3 agonist all-trans retinoic acid (ATRA) synergistically inhibited the proliferation of high-grade bladder Cancer cells, suggesting that the KDM2A/RARRES3 axis may be a promising therapeutic target for the treatment of high-grade bladder Cancer.

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