LAUSR

Enhancer of Zeste Homolog 2 (EZH2) and androgen receptor (AR) are crucial chromatin regulators involved in the development and/or progression of prostate tumor, including advanced castration-resistant prostate cancer (CRPC). To sustain prostate tumorigenicity, EZH2 establishes noncanonical biochemical interaction with AR for mediating oncogene activation, in addition to its canonical role as a transcriptional repressor and enzymatic subunit of Polycomb Repressive Complex 2 (PRC2). However, the molecular basis underlying non-canonical activities of EZH2 in prostate cancer remains elusive and therapeutic strategies for targeting EZH2:AR-mediated oncogene activation activities are also lacking. Here, we report that a cryptic transactivation domain of EZH2 (EZH2TAD) binds both AR and AR spliced variant 7 (AR-V7, an AR variant enriched in CRPC), mediating assembly and/or recruitment of transactivation-related machineries at genomic sites that lack PRC2 binding. Such noncanonical targets of EZH2:AR/AR-V7:(co)activators are enriched for the clinically-relevant oncogenes. We also show that EZH2TAD is required for the chromatin recruitment of EZH2, for EZH2-mediated oncogene activation, and for CRPC growth in vitro and in vivo. To completely block EZH2’s multifaceted oncogenic activities in prostate cancer, we employed MS177, a recently developed proteolysis targeting chimera (PROTAC) of EZH2. Strikingly, MS177 achieved on-target depletion of both EZH2’s canonical (EZH2:PRC2) and noncanonical (EZH2TAD:AR/AR-V7:coactivators) complexes in prostate tumor, eliciting much more potent antitumor effects than the catalytic inhibitors of EZH2. Overall, this study reports previously unappreciated requirements of EZH2TAD for mediating EZH2’s noncanonical (co)activator recruitment and gene-activation functions in prostate tumor and suggests EZH2-targeting PROTACs as potentially attractive therapeutics for the treatment of aggressive prostate tumors that rely on the circuits wired by EZH2 and AR.