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The NCOR-HDAC3 co-repressive complex modulates the leukemogenic potential of the transcription factor ERG

Author

Listed:
  • Eitan Kugler

    (Tel Aviv University
    Davidoff Cancer Center, Rabin Medical Center)

  • Shreyas Madiwale

    (Tel Aviv University
    The Rina Zaizov Pediatric Hematology and Oncology Division Schneider Children’s Medical Center of Israel)

  • Darren Yong

    (University Health Network
    University of Toronto)

  • Julie A. I. Thoms

    (Lowy Cancer Research Centre, UNSW Sydney
    Faculty of Medicine, UNSW Sydney)

  • Yehudit Birger

    (Tel Aviv University
    The Rina Zaizov Pediatric Hematology and Oncology Division Schneider Children’s Medical Center of Israel)

  • David B. Sykes

    (Massachusetts General Hospital, Boston, MA, USA & Harvard Stem Cell Institute)

  • Johannes Schmoellerl

    (Vienna BioCenter (VBC))

  • Aneta Drakul

    (University Children’s Hospital)

  • Valdemar Priebe

    (University Children’s Hospital)

  • Muhammad Yassin

    (Tel Aviv University)

  • Nasma Aqaqe

    (Tel Aviv University)

  • Avigail Rein

    (Tel Aviv University
    The Rina Zaizov Pediatric Hematology and Oncology Division Schneider Children’s Medical Center of Israel)

  • Hila Fishman

    (Tel Aviv University
    The Rina Zaizov Pediatric Hematology and Oncology Division Schneider Children’s Medical Center of Israel)

  • Ifat Geron

    (Tel Aviv University
    The Rina Zaizov Pediatric Hematology and Oncology Division Schneider Children’s Medical Center of Israel)

  • Chun-Wei Chen

    (Beckman Research Institute, City of Hope
    Dana-Farber Cancer Institute, Harvard Medical School
    City of Hope Comprehensive Cancer Center)

  • Brian Raught

    (University Health Network)

  • Qiao Liu

    (Beckman Research Institute, City of Hope)

  • Heather Ogana

    (University of Southern California)

  • Elisabeth Liedke

    (University Health Network
    University of Toronto)

  • Jean-Pierre Bourquin

    (University Children’s Hospital)

  • Johannes Zuber

    (Vienna BioCenter (VBC)
    Medical University of Vienna)

  • Michael Milyavsky

    (Tel Aviv University)

  • John Pimanda

    (Lowy Cancer Research Centre, UNSW Sydney
    Faculty of Medicine, UNSW Sydney)

  • Gilbert G. Privé

    (University Health Network
    University of Toronto)

  • Shai Izraeli

    (Tel Aviv University
    The Rina Zaizov Pediatric Hematology and Oncology Division Schneider Children’s Medical Center of Israel)

Abstract

The ERG (ETS-related gene) transcription factor is linked to various types of cancer, including leukemia. However, the specific ERG domains and co-factors contributing to leukemogenesis are poorly understood. Drug targeting a transcription factor such as ERG is challenging. Our study reveals the critical role of a conserved amino acid, proline, at position 199, located at the 3’ end of the PNT (pointed) domain, in ERG’s ability to induce leukemia. P199 is necessary for ERG to promote self-renewal, prevent myeloid differentiation in hematopoietic progenitor cells, and initiate leukemia in mouse models. Here we show that P199 facilitates ERG’s interaction with the NCoR-HDAC3 co-repressor complex. Inhibiting HDAC3 reduces the growth of ERG-dependent leukemic and prostate cancer cells, indicating that the interaction between ERG and the NCoR-HDAC3 co-repressor complex is crucial for its oncogenic activity. Thus, targeting this interaction may offer a potential therapeutic intervention.

Suggested Citation

  • Eitan Kugler & Shreyas Madiwale & Darren Yong & Julie A. I. Thoms & Yehudit Birger & David B. Sykes & Johannes Schmoellerl & Aneta Drakul & Valdemar Priebe & Muhammad Yassin & Nasma Aqaqe & Avigail Re, 2023. "The NCOR-HDAC3 co-repressive complex modulates the leukemogenic potential of the transcription factor ERG," Nature Communications, Nature, vol. 14(1), pages 1-20, December.
    • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-41067-2
    DOI: 10.1038/s41467-023-41067-2
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    References listed on IDEAS

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    1. Ralph Stadhouders & Alba Cico & Tharshana Stephen & Supat Thongjuea & Petros Kolovos & H. Irem Baymaz & Xiao Yu & Jeroen Demmers & Karel Bezstarosti & Alex Maas & Vilma Barroca & Christel Kockx & Zeli, 2015. "Control of developmentally primed erythroid genes by combinatorial co-repressor actions," Nature Communications, Nature, vol. 6(1), pages 1-17, December.
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