| http://purl.uniprot.org/citations/36300627 | http://www.w3.org/1999/02/22-rdf-syntax-ns#type | http://purl.uniprot.org/core/Journal_Citation |
| http://purl.uniprot.org/citations/36300627 | http://www.w3.org/2000/01/rdf-schema#comment | "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."xsd:string |
| http://purl.uniprot.org/citations/36300627 | http://purl.org/dc/terms/identifier | "doi:10.1093/nar/gkac861"xsd:string |
| http://purl.uniprot.org/citations/36300627 | http://purl.uniprot.org/core/author | "Cai L."xsd:string |
| http://purl.uniprot.org/citations/36300627 | http://purl.uniprot.org/core/author | "Gong W."xsd:string |
| http://purl.uniprot.org/citations/36300627 | http://purl.uniprot.org/core/author | "Jin J."xsd:string |
| http://purl.uniprot.org/citations/36300627 | http://purl.uniprot.org/core/author | "Wang J."xsd:string |
| http://purl.uniprot.org/citations/36300627 | http://purl.uniprot.org/core/author | "Yu X."xsd:string |
| http://purl.uniprot.org/citations/36300627 | http://purl.uniprot.org/core/author | "Park K.S."xsd:string |
| http://purl.uniprot.org/citations/36300627 | http://purl.uniprot.org/core/author | "Earp H.S."xsd:string |
| http://purl.uniprot.org/citations/36300627 | http://purl.uniprot.org/core/author | "Wang G.G."xsd:string |
| http://purl.uniprot.org/citations/36300627 | http://purl.uniprot.org/core/date | "2022"xsd:gYear |
| http://purl.uniprot.org/citations/36300627 | http://purl.uniprot.org/core/name | "Nucleic Acids Res"xsd:string |
| http://purl.uniprot.org/citations/36300627 | http://purl.uniprot.org/core/pages | "10929-10946"xsd:string |
| http://purl.uniprot.org/citations/36300627 | http://purl.uniprot.org/core/title | "A cryptic transactivation domain of EZH2 binds AR and AR's splice variant, promoting oncogene activation and tumorous transformation."xsd:string |
| http://purl.uniprot.org/citations/36300627 | http://purl.uniprot.org/core/volume | "50"xsd:string |
| http://purl.uniprot.org/citations/36300627 | http://www.w3.org/2004/02/skos/core#exactMatch | http://purl.uniprot.org/pubmed/36300627 |
| http://purl.uniprot.org/citations/36300627 | http://xmlns.com/foaf/0.1/primaryTopicOf | https://pubmed.ncbi.nlm.nih.gov/36300627 |
| http://purl.uniprot.org/uniprot/#_A0A087WUX9-mappedCitation-36300627 | http://www.w3.org/1999/02/22-rdf-syntax-ns#object | http://purl.uniprot.org/citations/36300627 |
| http://purl.uniprot.org/uniprot/#_F2YMM1-mappedCitation-36300627 | http://www.w3.org/1999/02/22-rdf-syntax-ns#object | http://purl.uniprot.org/citations/36300627 |
| http://purl.uniprot.org/uniprot/#_A0A090N8E9-mappedCitation-36300627 | http://www.w3.org/1999/02/22-rdf-syntax-ns#object | http://purl.uniprot.org/citations/36300627 |
| http://purl.uniprot.org/uniprot/#_D2KF13-mappedCitation-36300627 | http://www.w3.org/1999/02/22-rdf-syntax-ns#object | http://purl.uniprot.org/citations/36300627 |
| http://purl.uniprot.org/uniprot/#_C0JKD5-mappedCitation-36300627 | http://www.w3.org/1999/02/22-rdf-syntax-ns#object | http://purl.uniprot.org/citations/36300627 |
| http://purl.uniprot.org/uniprot/#_A0A3G2C3P2-mappedCitation-36300627 | http://www.w3.org/1999/02/22-rdf-syntax-ns#object | http://purl.uniprot.org/citations/36300627 |
| http://purl.uniprot.org/uniprot/#_A0A6H0MAB3-mappedCitation-36300627 | http://www.w3.org/1999/02/22-rdf-syntax-ns#object | http://purl.uniprot.org/citations/36300627 |