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

Author

Listed:
  • Varadha Balaji Venkadakrishnan

    (Dana-Farber Cancer Institute
    Harvard Medical School
    The Broad Institute of MIT and Harvard)

  • 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
    Boston College)

  • Nathaniel C. E. Voss

    (Dana-Farber Cancer Institute
    Belmont Hill School)

  • Navin R. Mahadevan

    (Dana-Farber Cancer Institute
    Brigham and Women’s Hospital)

  • Kei Mizuno

    (Dana-Farber Cancer Institute)

  • Loredana Puca

    (Weill Cornell Medicine)

  • Osasenaga Idahor

    (Dana-Farber Cancer Institute
    Harvard University)

  • Sheng-Yu Ku

    (Dana-Farber Cancer Institute
    Harvard Medical School
    The Broad Institute of MIT and Harvard)

  • Martin K. Bakht

    (Dana-Farber Cancer Institute
    Harvard Medical School
    The Broad Institute of MIT and Harvard)

  • Ashir A. Borah

    (The Broad Institute of MIT and Harvard
    University of California at San Francisco
    Arc Institute)

  • 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
    Dana-Farber Cancer Institute)

  • Himisha Beltran

    (Dana-Farber Cancer Institute
    Harvard Medical School
    The Broad Institute of MIT and Harvard)

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.

Suggested Citation

  • 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 & Osasena, 2024. "Lineage-specific canonical and non-canonical activity of EZH2 in advanced prostate cancer subtypes," Nature Communications, Nature, vol. 15(1), pages 1-15, December.
    • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-51156-5
    DOI: 10.1038/s41467-024-51156-5
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