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

  • Nucleic Acids Res. 2022 Oct 28;50(19):10929-10946. doi: 10.1093/nar/gkac861.
Jun Wang  1  2 ,  Kwang-Su Park  3 ,  Xufen Yu  3 ,  Weida Gong  1 ,  H Shelton Earp  1  4  5 ,  Gang Greg Wang  1  2  4 ,  Jian Jin  3 ,  Ling Cai  1  6
Affiliations
  • 1. Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, NC 27599, USA.
  • 2. Department of Biochemistry and Biophysics, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, NC 27599, USA.
  • 3. Mount Sinai Center for Therapeutics Discovery, Departments of Pharmacological Sciences and Oncological Sciences, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
  • 4. Department of Pharmacology, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, NC 27599, USA.
  • 5. Department of Medicine, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, NC, 27599, USA.
  • 6. Department of Genetics, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, NC 27599, USA.
PMID: 36300627 DOI: 10.1093/nar/gkac861
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.

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