Dual targeting of EZH2 and androgen receptor as a novel therapy for castration-resistant prostate cancer

Castration-resistant prostate cancer (CRPC) emerges after androgen withdrawal therapy and remains incurable due to the lack of effective treatment protocols. Treatment with enzalutamide, a second generation androgen receptor (AR) antagonist, offers an initial response followed by drug resistance and tumor relapse. Enhancer of zeste homolog 2 (EZH2), a member of PRC2 complex, is an important target that acts as a coactivator of AR-mediated gene suppression whose oncogenic activity increases during castration. We hypothesize that dual targeting of EZH2 and AR could be highly effective in CRPC treatment. The present study aimed to examine the effectiveness of combination using EZH2 inhibitor GSK126 with antiandrogen enzalutamide in the treatment of CRPC cells. Treatment of 22Rv1 and C42B CRPC cells with a combination of GSK126 and enzalutamide led to synergistic inhibition of cell proliferation, cell cycle arrest and marked increase in cell death. Mechanistically, this combination treatment significantly reduced expression of AR and AR-v7, decrease in PSA and Akt activity, diminution of EZH2 and other members of PCR2 complex including SUZ12 and EED, with simultaneous loss of H3K27 trimethylation and dissociation between AR and PRC2 complex members compared to individual treatment. This study provides preclinical proof-of-concept that combined treatment of EZH2 inhibitor with AR antagonist results in synergistic anticancer effects opening new possibilities for treatment of CRPC tumors. Effect of dual targeting EZH2 and AR in castration resistance prostate cancer (CRPC). Combined treatment with EZH2 inhibitors GSK126 and AR antagonist enzalutamide significantly inhibits proliferation and aggressiveness of CRPC cells through inhibition of EZH2, catalytic subunit of PRC2 complex (comprising of SUZ12, EED, RBBP4 and RBBP7) and AR binding to the ARE responsive elements suppressing CRPC. Abbreviations: AR, androgen receptor, GSK126, EZH2 inhibitor; enzalutamide, second generation antiandrogen; p, phosphorylation. [Display omitted] •Molecular targeting using drug combination is a promising strategy for CRPC.•Dual targeting of AR and EZH2 could be highly effective against CRPC.•Combined treatment GSK126 and enzalutamide synergistically effects CRPC.