A cryptic transactivation domain of EZH2 binds AR and AR’s splice variant, promoting oncogene activation and tumorous transformation
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2022-10-28
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<jats:title>Abstract</jats:title> <jats:p>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.</jats:p>
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Wang, Jun, Kwang-Su Park, Xufen Yu, Weida Gong, H Shelton Earp, Gang Greg Wang, Jian Jin, Ling Cai, et al. (2022). A cryptic transactivation domain of EZH2 binds AR and AR’s splice variant, promoting oncogene activation and tumorous transformation. Nucleic Acids Research, 50(19). pp. 10929–10946. 10.1093/nar/gkac861 Retrieved from https://hdl.handle.net/10161/28980.
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G. Greg Wang
Dr. Greg Wang is Full Professor at Department of Pharmacology and Cancer Biology, Department of Pathology (adjunct) and Duke Cancer Institute, Duke University. He received his Ph.D. degree from University of California, San Diego, followed by a postdoctoral training with Dr. C David Allis at Rockefeller University. Before joining Duke in 2023, he has been a full-time faculty member since 2011 at Lineberger Comprehensive Cancer Center and Department of Biochemistry and Biophysics, University of North Carolina (UNC) at Chapel Hill. Dr. Wang’s research programs broadly focus on mechanistic understandings of how chemical modifications of chromatin (including DNA methylation and histone modifications) regulate gene expression and cell fate determination during development, and how their deregulations lead to human diseases, notably cancer. His laboratory recently identified and characterized novel proteins that specifically bind to histone lysine methylation. These histone modification regulators are crucially involved in gene and genome regulation, development, immunity, and/or cancerous transformation. Importantly, discovery of small-molecule inhibitors to target chromatin modulators has become an area of intensive investigation and holds great promise for therapies. Dr. Wang’s research excellence and expertise in the broad fields of chromatin biology and cancer epigenetics have earned him grant funding of NIH and private foundations such as an American Cancer Society Research Scholar, an American Society of Hematology Scholar in basic science, a Janet Rowley Medical Research award from Gabrielle's Angel Foundation for Cancer Research, and a Leukemia and Lymphoma Society Scholar. Greg Wang also receives the recognitions from the institute such as the Philip and Ruth Hettleman Prize for Artistic and Scholarly Achievement (2019, UNC) and the Yang Family Biomedicine Scholar (2020, UNC), as well as the American Society for Biochemistry & Molecular Biology (ASBMB) Young Investigator Award (2021). One of Dr. Wang’s research goals is to yield potential drug candidates with preclinical cancer models, which shall pave a way for translating new therapeutic approaches in future.
Ling Cai
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