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

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 <i>via</i> histone H3 Lysine 27 tri-methylation (H3K27me3). <i>EZH2</i> 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 <i>via</i> 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. 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. PRC2 genes were significantly up-regulated in AVPC <i>vs</i> 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. EZH2i plus Carboplatin is a promising combination treatment for AVPC.