EZH2 inhibition enhances the activity of Carboplatin in aggressive-variant prostate cancer cell lines

Epigenomics. 2025 Feb;17(3):145-154. doi: 10.1080/17501911.2025.2453419. Epub 2025 Jan 29.

Abstract

Background: Aggressive Variant Prostate Cancers (AVPCs) are incurable malignancies. Platinum-based chemotherapies are used for the palliative treatment of AVPC. The Polycomb Repressive Complex 2 (PRC2) promotes prostate cancer progression via histone H3 Lysine 27 tri-methylation (H3K27me3). EZH2 encodes the catalytic subunit of PRC2. A recently developed nucleosome capture technology (Nu.QⓇ).measures H3K27me3 levels in biological fluids. EZH2 inhibitors (EZH2i) are being tested in clinical trials. We hypothesize that epigenetic reprogramming via EZH2i improves the efficacy of Carboplatin in AVPC and that EZH2i activity can be measured via both cellular- and cell-free nucleosomal H3K27me3 (cf-H3K27me3) levels.

Methods: We studied the expression of PRC2 genes in clinical prostate cancer cohorts (bioinformatics). We determined the effect of EZH2i on cellular- and cf-H3K27me3 levels. We measured dose-dependent effects of Carboplatin with/without EZH2i on AVPC cell viability (IC50). We used RNA-Seq to study how EZH2i modulates gene expression in AVPC cells.

Results: PRC2 genes were significantly up-regulated in AVPC vs other prostate cancer types. EZH2i reduced both cellular and cf-H3K27me3 levels. EZH2i significantly reduced Carboplatin IC50. EZH2i reduced the expression of DNA repair genes and increased the expression of p53-dependent pro-apoptotic factors.

Conclusions: EZH2i plus Carboplatin is a promising combination treatment for AVPC.

Keywords: Carboplatin; EZH2; Tazemetostat; aggressive variant prostate cancer; epigenetics; neuroendocrine prostate cancer; personalized epigenetic therapies.

MeSH terms

  • Antineoplastic Agents / pharmacology
  • Antineoplastic Agents / therapeutic use
  • Carboplatin* / pharmacology
  • Carboplatin* / therapeutic use
  • Cell Line, Tumor
  • Cell Survival / drug effects
  • Drug Synergism
  • Enhancer of Zeste Homolog 2 Protein* / antagonists & inhibitors
  • Enhancer of Zeste Homolog 2 Protein* / genetics
  • Enhancer of Zeste Homolog 2 Protein* / metabolism
  • Epigenesis, Genetic / drug effects
  • Gene Expression Regulation, Neoplastic / drug effects
  • Histones / metabolism
  • Humans
  • Male
  • Prostatic Neoplasms* / drug therapy
  • Prostatic Neoplasms* / genetics
  • Prostatic Neoplasms* / metabolism
  • Prostatic Neoplasms* / pathology

Substances

  • Carboplatin
  • Enhancer of Zeste Homolog 2 Protein
  • EZH2 protein, human
  • Histones
  • Antineoplastic Agents

Grants and funding

This work was supported by Prostate Cancer UK through a Research Innovation Award [RIA22-ST2-006]. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.