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

Bing Lu1, Jiatian Wei2, Houhong Zhou1

  • 1Institute of Urology of Shenzhen University, The Third Affiliated Hospital of Shenzhen University, Shenzhen Luohu Hospital Group, Shenzhen, 518000, China.

Cell Death & Disease
|June 13, 2022
PubMed

Insights

The KDM2A gene promotes high-grade bladder cancer by suppressing RARRES3. Inhibiting KDM2A and targeting RARRES3 offers a potential new therapy for bladder cancer.

Area of Science:

  • Oncology
  • Epigenetics
  • Molecular Biology

Background:

  • Epigenetic alterations are crucial in bladder cancer development.
  • KDM2A, an H3K36me2 demethylase, regulates cell fate in various cancers, but its role in bladder cancer is uncharacterized.

Purpose of the Study:

  • To investigate the function of KDM2A in bladder cancer.
  • To identify KDM2A's molecular targets and therapeutic potential in high-grade bladder cancer.

Main Methods:

  • Correlation analysis of KDM2A gene copy number and mRNA expression.
  • Super-enhancer (SE) identification and analysis.
  • KDM2A knockdown (KD) experiments in bladder cancer cells and xenograft models.
  • Chromatin immunoprecipitation (ChIP) assays to assess H3K36me2 demethylation.
  • RARRES3 knockdown and combination therapy studies.

Main Results:

  • KDM2A expression is upregulated in high-grade bladder cancer, correlated with gene copy number gains and driven by a super-enhancer.
  • KDM2A knockdown inhibited bladder cancer cell proliferation, invasion, and tumor growth.
  • KDM2A directly suppresses RARRES3 expression by demethylating H3K36me2 at the RARRES3 promoter.
  • RARRES3 knockdown partially reversed the anti-tumor effects of KDM2A depletion.
  • Combined inhibition of KDM2A and targeting RARRES3 synergistically reduced cancer cell proliferation.

Conclusions:

  • The KDM2A/RARRES3 axis is a key driver of high-grade bladder cancer progression.
  • Targeting KDM2A and RARRES3 represents a promising therapeutic strategy for high-grade bladder cancer.

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