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- Title
Lineage-specific canonical and non-canonical activity of EZH2 in advanced prostate cancer subtypes.
- Authors
Venkadakrishnan, Varadha Balaji; Presser, Adam G.; Singh, Richa; Booker, Matthew A.; Traphagen, Nicole A.; Weng, Kenny; Voss, Nathaniel C. E.; Mahadevan, Navin R.; Mizuno, Kei; Puca, Loredana; Idahor, Osasenaga; Ku, Sheng-Yu; Bakht, Martin K.; Borah, Ashir A.; Herbert, Zachary T.; Tolstorukov, Michael Y.; Barbie, David A.; Rickman, David S.; Brown, Myles; Beltran, Himisha
- 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. Enhancer of zeste homolog 2 (EZH2) has been implicated as a driver of disease progression and resistance to hormonal therapies. Here, the authors focus on EZH2 in two subtypes of advanced prostate cancer and report how it modulates the bivalent genes thereby leading to forward differentiation after being targeted in neuroendocrine prostate cancer.
- Subjects
CASTRATION-resistant prostate cancer; PROSTATE cancer; NATURAL immunity; HORMONE therapy; DISEASE progression
- Publication
Nature Communications, 2024, Vol 15, Issue 1, p1
- ISSN
2041-1723
- Publication type
Article
- DOI
10.1038/s41467-024-51156-5