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; Shai Izraeli

doi:10.1038/s41467-023-41067-2

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 BourquinJohannes Zuber, Michael Milyavsky, John Pimanda, Gilbert G. Privé^*, Shai Izraeli^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

2 Scopus citations

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.

Original language	English
Article number	5871
Journal	Nature Communications
Volume	14
Issue number	1
DOIs	https://doi.org/10.1038/s41467-023-41067-2
State	Published - Dec 2023

Funding

Funders	Funder number
Brice Mouttet
Dayana Yahalomi
Dotan Research Center in Hemato-Oncology
Fight Kids Cancer
Gilgi Friedlander
Israel Children’s Cancer Foundation
Israel Children’s Cancer Foundation
Itzhak Ben Moshe
Jonatan Barel
Nancy and Stephen Grand Israel National Center for Personalized Medicine, Weizmann Institute of Science
Nevzlin Foundations
Samuel Waxman Cancer Research Foundation
Israel Cancer Research Fund
Canadian Institutes of Health Research
Israel Science Foundation
Tel Aviv University

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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Kugler, E., Madiwale, S., Yong, D., Thoms, J. A. I., Birger, Y., Sykes, D. B., Schmoellerl, J., Drakul, A., Priebe, V., Yassin, M., Aqaqe, N., Rein, A., Fishman, H., Geron, I., Chen, C. W., Raught, B., Liu, Q., Ogana, H., Liedke, E., ... Izraeli, S. (2023). The NCOR-HDAC3 co-repressive complex modulates the leukemogenic potential of the transcription factor ERG. Nature Communications, 14(1), Article 5871. https://doi.org/10.1038/s41467-023-41067-2

@article{07a70d6f530d4a5cbf6545aefc042b96,

title = "The NCOR-HDAC3 co-repressive complex modulates the leukemogenic potential of the transcription factor ERG",

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{\textquoteright} end of the PNT (pointed) domain, in ERG{\textquoteright}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{\textquoteright}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.",

author = "Eitan Kugler and Shreyas Madiwale and Darren Yong and Thoms, {Julie A.I.} and Yehudit Birger and Sykes, {David B.} and Johannes Schmoellerl and Aneta Drakul and Valdemar Priebe and Muhammad Yassin and Nasma Aqaqe and Avigail Rein and Hila Fishman and Ifat Geron and Chen, {Chun Wei} and Brian Raught and Qiao Liu and Heather Ogana and Elisabeth Liedke and Bourquin, {Jean Pierre} and Johannes Zuber and Michael Milyavsky and John Pimanda and Priv{\'e}, {Gilbert G.} and Shai Izraeli",

note = "Publisher Copyright: {\textcopyright} 2023, Springer Nature Limited.",

year = "2023",

month = dec,

doi = "10.1038/s41467-023-41067-2",

language = "אנגלית",

volume = "14",

journal = "Nature Communications",

issn = "2041-1723",

publisher = "Nature Research",

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Kugler, E, Madiwale, S, Yong, D, Thoms, JAI, Birger, Y, Sykes, DB, Schmoellerl, J, Drakul, A, Priebe, V, Yassin, M, Aqaqe, N, Rein, A, Fishman, H, Geron, I, Chen, CW, Raught, B, Liu, Q, Ogana, H, Liedke, E, Bourquin, JP, Zuber, J, Milyavsky, M, Pimanda, J, Privé, GG & Izraeli, S 2023, 'The NCOR-HDAC3 co-repressive complex modulates the leukemogenic potential of the transcription factor ERG', Nature Communications, vol. 14, no. 1, 5871. https://doi.org/10.1038/s41467-023-41067-2

TY - JOUR

T1 - The NCOR-HDAC3 co-repressive complex modulates the leukemogenic potential of the transcription factor ERG

AU - Kugler, Eitan

AU - Madiwale, Shreyas

AU - Yong, Darren

AU - Thoms, Julie A.I.

AU - Birger, Yehudit

AU - Sykes, David B.

AU - Schmoellerl, Johannes

AU - Drakul, Aneta

AU - Priebe, Valdemar

AU - Yassin, Muhammad

AU - Aqaqe, Nasma

AU - Rein, Avigail

AU - Fishman, Hila

AU - Geron, Ifat

AU - Chen, Chun Wei

AU - Raught, Brian

AU - Liu, Qiao

AU - Ogana, Heather

AU - Liedke, Elisabeth

AU - Bourquin, Jean Pierre

AU - Zuber, Johannes

AU - Milyavsky, Michael

AU - Pimanda, John

AU - Privé, Gilbert G.

AU - Izraeli, Shai

PY - 2023/12

Y1 - 2023/12

N2 - 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.

AB - 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.

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U2 - 10.1038/s41467-023-41067-2

DO - 10.1038/s41467-023-41067-2

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C2 - 37735473

AN - SCOPUS:85171859821

SN - 2041-1723

VL - 14

JO - Nature Communications

JF - Nature Communications

IS - 1

M1 - 5871

ER -

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

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