EZH2 inhibition enhances the activity of platinum chemotherapy in aggressive variant prostate cancer

BackgroundEZH2 promotes aggressive-variant prostate cancer (AVPC) progression via histone H3-Lysine-27 tri-methylation (H3K27me3). We hypothesize that epigenetic reprogramming via EZH2 inhibitors (EZH2i) improves the efficacy of chemotherapy in AVPC. MethodsWe studied the expression of EZH2 in clinical prostate cancer cohorts (bioinformatics). We determined the effect of EZH2i on both cellular- and cell-free-H3K27me3 levels. We measured effects of carboplatin with/without EZH2i on AVPC cell viability (IC50). We studied how EZH2i modulate gene expression (RNA Seq). ResultsEZH2 was significantly up-regulated in AVPC vs other prostate cancer types. EZH2i reduced both cellular and cell free-H3K27me3 levels. EZH2i significantly reduced carboplatin IC50. EZH2i reduced the expression of DNA repair and increased the expression of pro-apoptotic genes. Article HighlightsO_LIPolycomb-mediated gene silencing promotes prostate cancer progression C_LIO_LIAggressive-variant prostate cancers (AVPCs) are characterized by increased activity of the Polycomb-Repressive Complex 2 (PRC2) C_LIO_LIHere we show that PRC2 inhibitors are scarcely effective as monotherapy in ACPC cells C_LIO_LIHowever the combination of PRC2 inhibitors and carboplatin is highly synergistic C_LIO_LIRNA Seq studies revealed that PRC2 inhibitors enhance carboplatin activity by modulating several key pathways, including DNA repair and apoptosis. C_LI