Lineage-specific canonical and non-canonical activity of EZH2 in advanced prostate cancer subtypes

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 and Himisha Beltran ()
Additional contact information
Varadha Balaji Venkadakrishnan: Dana-Farber Cancer Institute
Adam G. Presser: Dana-Farber Cancer Institute
Richa Singh: Weill Cornell Medicine
Matthew A. Booker: Dana-Farber Cancer Institute
Nicole A. Traphagen: Dana-Farber Cancer Institute
Kenny Weng: Dana-Farber Cancer Institute
Nathaniel C. E. Voss: Dana-Farber Cancer Institute
Navin R. Mahadevan: Dana-Farber Cancer Institute
Kei Mizuno: Dana-Farber Cancer Institute
Loredana Puca: Weill Cornell Medicine
Osasenaga Idahor: Dana-Farber Cancer Institute
Sheng-Yu Ku: Dana-Farber Cancer Institute
Martin K. Bakht: Dana-Farber Cancer Institute
Ashir A. Borah: The Broad Institute of MIT and Harvard
Zachary T. Herbert: Dana-Farber Cancer Institute
Michael Y. Tolstorukov: Dana-Farber Cancer Institute
David A. Barbie: Dana-Farber Cancer Institute
David S. Rickman: Weill Cornell Medicine
Myles Brown: Dana-Farber Cancer Institute
Himisha Beltran: Dana-Farber Cancer Institute

Nature Communications, 2024, vol. 15, issue 1, 1-15

Abstract: Abstract 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.

Date: 2024
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DOI: 10.1038/s41467-024-51156-5

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