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

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 Rein, Hila Fishman, Ifat Geron, Chun-Wei Chen, Brian Raught, Qiao Liu, Heather Ogana, Elisabeth Liedke, Jean-Pierre Bourquin, Johannes Zuber, Michael Milyavsky, John Pimanda, Gilbert G. Privé () and Shai Izraeli ()
Additional contact information
Eitan Kugler: Tel Aviv University
Shreyas Madiwale: Tel Aviv University
Darren Yong: University Health Network
Julie A. I. Thoms: Lowy Cancer Research Centre, UNSW Sydney
Yehudit Birger: Tel Aviv University
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
Hila Fishman: Tel Aviv University
Ifat Geron: Tel Aviv University
Chun-Wei Chen: Beckman Research Institute, City of Hope
Brian Raught: University Health Network
Qiao Liu: Beckman Research Institute, City of Hope
Heather Ogana: University of Southern California
Elisabeth Liedke: University Health Network
Jean-Pierre Bourquin: University Children’s Hospital
Johannes Zuber: Vienna BioCenter (VBC)
Michael Milyavsky: Tel Aviv University
John Pimanda: Lowy Cancer Research Centre, UNSW Sydney
Gilbert G. Privé: University Health Network
Shai Izraeli: Tel Aviv University

Nature Communications, 2023, vol. 14, issue 1, 1-20

Abstract: 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.

Date: 2023
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DOI: 10.1038/s41467-023-41067-2

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