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Polycomb Group Proteins EZH2 and EED Directly Regulate Androgen Receptor in Advanced Prostate Cancer

ABSTRACT: Polycomb group proteins are important epigenetic regulators for organ development, cell proliferation and differentiation, as well as initiation and progression of lethal diseases, including cancer. Upregulated Polycomb group proteins, including EZH2, promote proliferation, migration, invasion and metastasis of cancer cells, as well as self-renewal of cancer stem cells. The canonical function of EZH2, along with its essential binding partners EED and SUZ12, is to methylate histone H3K27 and repress its downstream targets. In this study, we discover that EZH2 regulates androgen receptor (AR) expression levels and AR signaling in prostate cancer. Targeting EZH2 with the newly identified EZH2 inhibitor, astemizole, could effectively inhibit the progression of castration-resistant prostate cancer.

ORGANISM(S): Homo sapiens

PROVIDER: GSE124268 | GEO | 2018/12/22

REPOSITORIES: GEO

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Project description:Enhancer of Zeste Homolog 2 (EZH2) and androgen receptor (AR) are both crucial for the development and progression of prostate tumor, including advanced castration-resistant prostate cancer (CRPC). Previously, it was reported that, in order to sustain tumorigenicity of prostate cancer, EZH2 has noncanonical functions in interaction with AR for mediating gene 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 far from clear, and therapeutic strategies for targeting EZH2:AR-mediated gene-activation activities are also lacking. Here, we report that a hidden transactivation domain of EZH2 (EZH2TAD) binds both AR and AR’s variants enriched in CRPCs, notably AR splice variant 7 (AR-V7), mediating the assembly and/or recruitment of a gene-activation-related complex at genomic sites that lack PRC2 binding. Such noncanonical targets of EZH2:AR/AR-V7:(co)activators are enriched for the clinically-relevant prostate oncogenes. EZH2TAD is crucial for EZH2-mediated transactivation of oncogenes 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. 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 existing catalytic inhibitors of EZH2. Overall, this study reports previously unappreciated requirements of EZH2TAD for mediating EZH2’s noncanonical 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 reply on circuits wired by EZH2 and AR.

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Polycomb Group Proteins EZH2 and EED Directly Regulate Androgen Receptor in Advanced Prostate Cancer

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