Polycomb protein EZH2 suppresses apoptosis by silencing the proapoptotic miR-31

Enhancer of zeste homolog 2 (EZH2) is the catalytic subunit of the polycomb repressive complex 2 and suppresses gene expression by catalyzing histone H3 methylation on lysine 27. EZH2 is overexpressed in metastatic prostate cancer and has been shown to promote cell proliferation and metastasis. Here we show that EZH2 also suppresses prostate cancer apoptosis by coordinating the epigenetic silencing of two proapoptotic microRNAs (miRNA), miR-205 and miR-31. We previously reported that miR-205 promotes apoptosis by targeting antiapoptotic protein Bcl-w and miR-205 is silenced in prostate cancer through promoter methylation. In this study, we found that EZH2 suppresses miR-31 expression by trimethylation of lysine 27 on histone 3 on the miR-31 promoter. SiRNA knockdown of EZH2 increased miR-31 expression and decreased the antiapoptotic protein E2F6 (E2F transcription factor 6) (a target of miR-31), resulting in the sensitization of prostate cancer cells to docetaxel-induced apoptosis. Conversely, overexpression of EZH2 blocked docetaxel-induced apoptosis. We further demonstrated that miR-205 silencing is linked to miR-31 silencing through EZH2. Suppression of miR-205 with an miRNA inhibitor caused an increase of EZH2 protein, which in turn inhibited miR-31 expression. Conversely, overexpression of miR-205 decreased EZH2 protein and increased miR-31 expression. In paired human prostate cancer specimens and adjacent normal tissues, we observed that the decrease of miR-205 expression correlated with EZH2 overexpression and miR-31 silencing. Thus, EZH2 integrates the epigenetic silencing of miR-205 and miR-31 to confer resistance to chemotherapy-induced apoptosis.