A cryptic transactivation domain of EZH2 binds AR and AR's splice variant, promoting oncogene activation and tumorous transformation.

Abstract

Enhancer of Zeste Homolog 2 (EZH2) and androgen receptor (AR) are crucial chromatin/gene regulators involved in the development and/or progression of prostate cancer, including advanced castration-resistant prostate cancer (CRPC). To sustain prostate tumorigenicity, EZH2 establishes non-canonical 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 a therapeutic strategy for targeting EZH2:AR-mediated oncogene activation is also lacking. Here, we report that a cryptic transactivation domain of EZH2 (EZH2TAD) binds both AR and AR spliced variant 7 (AR-V7), a constitutively active AR variant enriched in CRPC, mediating assembly and/or recruitment of transactivation-related machineries at genomic sites that lack PRC2 binding. Such non-canonical 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 to oncogenes, 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 non-canonical (EZH2TAD:AR/AR-V7:co-activators) complexes in prostate cancer cells, eliciting far more potent antitumor effects than the catalytic inhibitors of EZH2. Overall, this study reports a previously unappreciated requirement for EZH2TAD for mediating EZH2's non-canonical (co-)activator recruitment and gene activation functions in prostate cancer and suggests EZH2-targeting PROTACs as a potentially attractive therapeutic for the treatment of aggressive prostate cancer that rely on the circuits wired by EZH2 and AR.

• Authors: Jun Wang, Kwang-Su Park, Xufen Yu, Weida Gong, H Shelton Earp, Gang Greg Wang, Jian Jin, Ling Cai
• Journal: Nucleic acids research (Nucleic Acids Res) Vol. 50 Issue 19 Pg. 10929-10946 (10 28 2022) ISSN: 1362-4962 [Electronic] England
• PMID: 36300627 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, N.I.H., Extramural)
• Copyright: © The Author(s) 2022. Published by Oxford University Press on behalf of Nucleic Acids Research.

Chemical References

• Chromatin
• Enhancer of Zeste Homolog 2 Protein
• EZH2 protein, human
• Polycomb Repressive Complex 2
• Receptors, Androgen
• Protein Isoforms

Topics

• Humans
• Male
• Cell Line, Tumor
• Chromatin (genetics)
• Enhancer of Zeste Homolog 2 Protein (metabolism)
• Gene Expression Regulation, Neoplastic
• Oncogenes
• Polycomb Repressive Complex 2 (genetics, metabolism)
• Prostatic Neoplasms, Castration-Resistant (pathology)
• Receptors, Androgen (genetics, metabolism)
• Transcriptional Activation
• Protein Isoforms