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Increasing RB1 Expression by Targeting EZH2 in Triple-Negative Breast Cancer

Renfei Yang1, Liyan Fei1,2, Yingfei Xue1,3

  • 1Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences, Hangzhou, China.

Journal of Cellular and Molecular Medicine
|March 12, 2025
PubMed

Insights

Loss of RB1 function in triple-negative breast cancer (TNBC) is linked to drug resistance. Inhibiting EZH2 epigenetic regulator boosts RB1 expression, offering a new therapeutic strategy for TNBC.

Area of Science:

  • Oncology
  • Epigenetics
  • Molecular Biology

Background:

  • Loss of RB1 function is a hallmark of triple-negative breast cancer (TNBC).
  • RB1 dysfunction is associated with therapeutic resistance in TNBC.
  • Epigenetic regulation of RB1 in TNBC remains incompletely understood.

Purpose of the Study:

  • To investigate the epigenetic mechanisms controlling RB1 expression in TNBC.
  • To identify key regulators of RB1 in the context of TNBC.
  • To explore therapeutic strategies targeting epigenetic pathways for TNBC treatment.

Main Methods:

  • Bioinformatics analyses to identify upstream regulators of RB1.
  • Experimental validation including EZH2 inhibition and RB1 expression analysis.
  • Chromatin immunoprecipitation (ChIP-qPCR) and ATAC-sequencing to assess histone modifications and enhancer activity.

Main Results:

  • Lysine histone methyltransferase EZH2 was identified as a key upstream regulator of RB1.
  • EZH2, as part of the PRC2 complex, mediates H3K27 trimethylation at the RB1 locus.
  • Pharmacological inhibition of EZH2 upregulated RB1 expression by increasing H3K27ac enrichment at the RB1 enhancer.

Conclusions:

  • EZH2 is a critical epigenetic regulator of RB1 in TNBC.
  • Targeting EZH2 with pharmacological agents can restore RB1 expression in TNBC.
  • Restoring RB1 function via EZH2 inhibition presents a potential therapeutic strategy against RB1-mediated drug resistance in TNBC.
Keywords:
EZH2RB1TNBCenhancerepigenetics

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