Unknown,Transcriptomics,Genomics,Proteomics

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Cooperation between Androgen Receptor and Polycomb in oncogenic transformation

ABSTRACT: Androgen receptor (AR) is a hormone-activated transcription factor that plays important roles in prostate development, function, as well as malignant transformation. The downstream pathways of AR, however, are incompletely understood. AR has been primarily known as a transcriptional activator inducing prostate-specific gene expression. Through integrative analysis of genome-wide AR occupancy and androgen-regulated gene expression, here we report AR as a globally acting transcriptional repressor. This repression is mediated by androgen responsive elements (ARE) and dictated by Polycomb group protein EZH2 and repressive chromatin remodeling. In embryonic stem cells, AR-repressed genes are occupied by EZH2 and harbor bivalent H3K4me3 and H3K27me3 modifications that are characteristic of differentiation regulators, the silencing of which maintains the undifferentiated state. Concordantly, these genes are silenced in castration-resistant prostate cancer rendering a stem cell-like lack of differentiation and tumor progression. Collectively, our data reveal an unexpected role of AR as a transcriptional repressor inhibiting non-prostatic differentiation and, upon excessive signaling, resulting in cancerous de-differentiation. It provides an innovative mechanism for castration resistance and highlights novel therapeutic strategies to treat advanced prostate cancer. Keywords: Genetic Modification compare gene expression in different cell lines with or without androgen treatment or EZH2 knockdown

ORGANISM(S): Homo sapiens

SUBMITTER: Jindan Yu

PROVIDER: E-GEOD-31978 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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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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Cooperation between Androgen Receptor and Polycomb in oncogenic transformation

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