2. Academic Validation
  3. EZH2 inhibition enhances the activity of Carboplatin in aggressive-variant prostate cancer cell lines

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.
Maryam Latarani 1,  Perla Pucci 2,  Mark Eccleston 3 4,  Massimiliano Manzo 5,  Priyadarsini Gangadharannambiar 1,  Irene Fischetti 6,  Ilaria Alborelli 5,  Vera Mongiardini 7,  Namra Mahmood 1,  Mario Paolo Colombo 6,  Benedetto Grimaldi 7,  Sushila Rigas 1,  Shusuke Akamatsu 8,  Cheryl Hawkes 9,  Yuzhuo Wang 10,  Elena Jachetti 6,  Francesco Crea 1
Affiliations

Affiliations

  • 1 Cancer Research Group, School of Life Health and Chemical Sciences, The Open University UK, Milton Keynes, UK.
  • 2 Division of Cellular and Molecular Pathology, Department of Pathology, University of Cambridge, Cambridge, UK.
  • 3 Belgian Volition SPRL, Parc Scientifique Créalys, Namur, BE, Belgium.
  • 4 ValiRx PLC, Medicity Nottingham, Nottingham, UK.
  • 5 Pathology, Institute of Medical Genetics and Pathology, University Hospital Basel, University of Basel, Basel, Switzerland.
  • 6 Molecular Immunology Unit, Department of Experimental Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.
  • 7 Molecular Medicine Research Line, Fondazione Istituto Italiano di Tecnologia (IIT), Genoa, Italy.
  • 8 Department of Urology, Nagoya University Graduate School of Medicine, Nagoya, Japan.
  • 9 Division of Biomedical and Life Sciences, Lancaster University, Lancaster, UK.
  • 10 Department of Experimental Therapeutics, BC Cancer/University of British Columbia, Vancouver, Canada.
PMID: 39878501 DOI: 10.1080/17501911.2025.2453419
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.

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