Inhibition of EZH2 enhances the antitumor efficacy of metformin in prostate cancer.

Upregulation of EZH2 is associated with advanced stage and poor prognosis of PCa, it is therefore likely to be a promising therapeutic target. Metformin, a drug that has been used to treat type II diabetes, was found to have anti-neoplastic activity in different cancers. Herein, we report that the combination of metformin and EZH2 inhibitor GSK126 exerts synergistic inhibition on PCa cell growth, both in vitro and in vivo. Mechanistically, we identify that metformin can reduce EZH29s expression through upregulating miR-26a-5p, which is antagonized by androgen receptor (AR). Furthermore, we show that AR binds to the promoter of miR-26a-5p and suppresses its transcription. Although metformin can remove AR from the miR-26a-5p promoter, the interaction between AR and EZH2, which usually exists in androgen-refractory PCa cells, strongly impedes the removal. However, GSK126 can inhibit the methyltransferase-dependent interaction between AR and EZH2, thus restoring metformin9s efficacy in androgen-refractory PCa cells. Collectively, our finding suggests that the combination of metformin and GSK126 would be an effective approach for future PCa therapy, and particularly effective for AR-positive CRPC.