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

Autor: Kugler E; Department of Human Molecular Genetics and Biochemistry, Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.; Institute of Hematology, Davidoff Cancer Center, Rabin Medical Center, Petah Tikva, Israel., Madiwale S; Department of Human Molecular Genetics and Biochemistry, Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.; The Rina Zaizov Pediatric Hematology and Oncology Division Schneider Children's Medical Center of Israel, Petach Tikva, Israel., Yong D; Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada.; Department of Biochemistry, University of Toronto, Toronto, ON, Canada., Thoms JAI; Adult Cancer Program, Lowy Cancer Research Centre, UNSW Sydney, Sydney, NSW, Australia.; School of Biomedical Sciences, Faculty of Medicine, UNSW Sydney, Sydney, NSW, Australia., Birger Y; Department of Human Molecular Genetics and Biochemistry, Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.; The Rina Zaizov Pediatric Hematology and Oncology Division Schneider Children's Medical Center of Israel, Petach Tikva, Israel., Sykes DB; Center for Regenerative Medicine, Massachusetts General Hospital, Boston, MA, USA & Harvard Stem Cell Institute, Cambridge, MA, USA., Schmoellerl J; Research Institute of Molecular Pathology (IMP), Vienna BioCenter (VBC), Vienna, Austria., Drakul A; Division of Pediatric Oncology, and Children Research Center, University Children's Hospital, Zurich, Switzerland., Priebe V; Division of Pediatric Oncology, and Children Research Center, University Children's Hospital, Zurich, Switzerland., Yassin M; Department of Pathology, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel., Aqaqe N; Department of Pathology, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel., Rein A; Department of Human Molecular Genetics and Biochemistry, Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.; The Rina Zaizov Pediatric Hematology and Oncology Division Schneider Children's Medical Center of Israel, Petach Tikva, Israel., Fishman H; Department of Human Molecular Genetics and Biochemistry, Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.; The Rina Zaizov Pediatric Hematology and Oncology Division Schneider Children's Medical Center of Israel, Petach Tikva, Israel., Geron I; Department of Human Molecular Genetics and Biochemistry, Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.; The Rina Zaizov Pediatric Hematology and Oncology Division Schneider Children's Medical Center of Israel, Petach Tikva, Israel., Chen CW; Department of Systems Biology, Beckman Research Institute, City of Hope, Duarte, CA, USA.; Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.; City of Hope Comprehensive Cancer Center, Duarte, CA, USA., Raught B; Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada., Liu Q; Department of Systems Biology, Beckman Research Institute, City of Hope, Duarte, CA, USA., Ogana H; Department of Pediatrics, Division of Hematology and Oncology, Children's Hospital Los Angeles, University of Southern California, Los Angeles, CA, USA., Liedke E; Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada.; Department of Biochemistry, University of Toronto, Toronto, ON, Canada., Bourquin JP; Division of Pediatric Oncology, and Children Research Center, University Children's Hospital, Zurich, Switzerland., Zuber J; Research Institute of Molecular Pathology (IMP), Vienna BioCenter (VBC), Vienna, Austria.; Medical University of Vienna, Vienna, Austria., Milyavsky M; Department of Pathology, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel., Pimanda J; Adult Cancer Program, Lowy Cancer Research Centre, UNSW Sydney, Sydney, NSW, Australia.; School of Biomedical Sciences, Faculty of Medicine, UNSW Sydney, Sydney, NSW, Australia., Privé GG; Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada. Gil.Prive@uhnresearch.ca.; Department of Biochemistry, University of Toronto, Toronto, ON, Canada. Gil.Prive@uhnresearch.ca., Izraeli S; Department of Human Molecular Genetics and Biochemistry, Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel. sizraeli@gmail.com.; The Rina Zaizov Pediatric Hematology and Oncology Division Schneider Children's Medical Center of Israel, Petach Tikva, Israel. sizraeli@gmail.com.
Jazyk: angličtina
Zdroj: Nature communications [Nat Commun] 2023 Sep 21; Vol. 14 (1), pp. 5871. Date of Electronic Publication: 2023 Sep 21.
DOI: 10.1038/s41467-023-41067-2
Abstrakt: 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.
(© 2023. Springer Nature Limited.)
Databáze: MEDLINE
Externí odkaz: