Enhancer of zeste homolog 2 (EZH2) is a histone methyltransferase and emerging therapeutic target that is overexpressed in most castration-resistant prostate cancers and implicated as a driver of disease progression and resistance to hormonal therapies. Here we define the lineage-specific action and differential activity of EZH2 in both prostate adenocarcinoma and neuroendocrine prostate cancer (NEPC) subtypes of advanced prostate cancer to better understand the role of EZH2 in modulating differentiation, lineage plasticity, and to identify mediators of response and resistance to EZH2 inhibitor therapy. Mechanistically, EZH2 modulates bivalent genes that results in upregulation of NEPC-associated transcriptional drivers (e.g., ASCL1) and neuronal gene programs in NEPC, and leads to forward differentiation after targeting EZH2 in NEPC. Subtype-specific downstream effects of EZH2 inhibition on cell cycle genes support the potential rationale for co-targeting cyclin/CDK to overcome resistance to EZH2 inhibition.
Nature communications. 2024 Aug 08*** epublish ***
Varadha Balaji Venkadakrishnan, Adam G Presser, Richa Singh, Matthew A Booker, Nicole A Traphagen, Kenny Weng, Nathaniel C E Voss, Navin R Mahadevan, Kei Mizuno, Loredana Puca, Osasenaga Idahor, Sheng-Yu Ku, Martin K Bakht, Ashir A Borah, Zachary T Herbert, Michael Y Tolstorukov, David A Barbie, David S Rickman, Myles Brown, Himisha Beltran
Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA., Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, New York, NY, USA., Department of Informatics and Analytics, Dana-Farber Cancer Institute, Boston, MA, USA., Department of Medicine, Weill Cornell Medicine, New York, NY, USA., The Broad Institute of MIT and Harvard, Cambridge, MA, USA., Molecular Biology Core Facilities, Dana-Farber Cancer Institute, Boston, MA, USA., Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA. .