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Targeting histone acetylation dynamics and oncogenic transcription by catalytic P300/CBP inhibition.
Hogg, Simon J; Motorna, Olga; Cluse, Leonie A; Johanson, Timothy M; Coughlan, Hannah D; Raviram, Ramya; Myers, Robert M; Costacurta, Matteo; Todorovski, Izabela; Pijpers, Lizzy; Bjelosevic, Stefan; Williams, Tobias; Huskins, Shannon N; Kearney, Conor J; Devlin, Jennifer R; Fan, Zheng; Jabbari, Jafar S; Martin, Ben P; Fareh, Mohamed; Kelly, Madison J; Dupéré-Richer, Daphné; Sandow, Jarrod J; Feran, Breon; Knight, Deborah; Khong, Tiffany; Spencer, Andrew; Harrison, Simon J; Gregory, Gareth; Wickramasinghe, Vihandha O; Webb, Andrew I; Taberlay, Phillippa C; Bromberg, Kenneth D; Lai, Albert; Papenfuss, Anthony T; Smyth, Gordon K; Allan, Rhys S; Licht, Jonathan D; Landau, Dan A; Abdel-Wahab, Omar; Shortt, Jake; Vervoort, Stephin J; Johnstone, Ricky W.
Affiliation
  • Hogg SJ; Translational Hematology Program, Gene Regulation Laboratory, Peter MacCallum Cancer Center, Melbourne, 3000, Australia; Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, 3000, Australia; Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Cente
  • Motorna O; Translational Hematology Program, Gene Regulation Laboratory, Peter MacCallum Cancer Center, Melbourne, 3000, Australia; Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, 3000, Australia; Monash Haematology, Monash Health, Clayton, 3168, Australia; School of Clinica
  • Cluse LA; Translational Hematology Program, Gene Regulation Laboratory, Peter MacCallum Cancer Center, Melbourne, 3000, Australia.
  • Johanson TM; The Walter and Eliza Hall Institute of Medical Research, Parkville, 3052, Australia; Department of Medical Biology, The University of Melbourne, Parkville, 3010, Australia.
  • Coughlan HD; The Walter and Eliza Hall Institute of Medical Research, Parkville, 3052, Australia; Department of Medical Biology, The University of Melbourne, Parkville, 3010, Australia.
  • Raviram R; New York Genome Center, New York, NY 10013, USA.
  • Myers RM; Tri-Institutional MD-PhD Program, Weill Cornell Medicine, Rockefeller University, Memorial Sloan Kettering Cancer Center, New York, NY 10021, USA.
  • Costacurta M; Translational Hematology Program, Gene Regulation Laboratory, Peter MacCallum Cancer Center, Melbourne, 3000, Australia; Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, 3000, Australia.
  • Todorovski I; Translational Hematology Program, Gene Regulation Laboratory, Peter MacCallum Cancer Center, Melbourne, 3000, Australia; Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, 3000, Australia.
  • Pijpers L; Translational Hematology Program, Gene Regulation Laboratory, Peter MacCallum Cancer Center, Melbourne, 3000, Australia; Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, 3000, Australia.
  • Bjelosevic S; Translational Hematology Program, Gene Regulation Laboratory, Peter MacCallum Cancer Center, Melbourne, 3000, Australia; Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, 3000, Australia.
  • Williams T; Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, 3000, Australia; RNA Biology and Cancer Laboratory, Peter MacCallum Cancer Centre, Melbourne, 3000, Australia.
  • Huskins SN; Tasmanian School of Medicine, College of Health and Medicine, University of Tasmania, Hobart, 7000, Australia.
  • Kearney CJ; Translational Hematology Program, Gene Regulation Laboratory, Peter MacCallum Cancer Center, Melbourne, 3000, Australia; Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, 3000, Australia.
  • Devlin JR; Translational Hematology Program, Gene Regulation Laboratory, Peter MacCallum Cancer Center, Melbourne, 3000, Australia; Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, 3000, Australia.
  • Fan Z; Translational Hematology Program, Gene Regulation Laboratory, Peter MacCallum Cancer Center, Melbourne, 3000, Australia; Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, 3000, Australia.
  • Jabbari JS; Department of Microbiology and Immunology, The University of Melbourne at The Peter Doherty Institute for Infection and Immunity, Melbourne, 3000, Australia.
  • Martin BP; Translational Hematology Program, Gene Regulation Laboratory, Peter MacCallum Cancer Center, Melbourne, 3000, Australia.
  • Fareh M; Translational Hematology Program, Gene Regulation Laboratory, Peter MacCallum Cancer Center, Melbourne, 3000, Australia; Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, 3000, Australia.
  • Kelly MJ; Translational Hematology Program, Gene Regulation Laboratory, Peter MacCallum Cancer Center, Melbourne, 3000, Australia; Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, 3000, Australia.
  • Dupéré-Richer D; Division of Hematology/Oncology, The University of Florida Health Cancer Center, Gainesville, FL 32608, USA.
  • Sandow JJ; The Walter and Eliza Hall Institute of Medical Research, Parkville, 3052, Australia; Department of Medical Biology, The University of Melbourne, Parkville, 3010, Australia.
  • Feran B; The Walter and Eliza Hall Institute of Medical Research, Parkville, 3052, Australia; Department of Medical Biology, The University of Melbourne, Parkville, 3010, Australia.
  • Knight D; Translational Hematology Program, Gene Regulation Laboratory, Peter MacCallum Cancer Center, Melbourne, 3000, Australia.
  • Khong T; Australian Center for Blood Diseases, Monash University, Melbourne, 3004, Australia.
  • Spencer A; Australian Center for Blood Diseases, Monash University, Melbourne, 3004, Australia.
  • Harrison SJ; Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, 3000, Australia; Clinical Hematology, Peter MacCallum Cancer Center, Melbourne, 3000, Australia; Royal Melbourne Hospital, Melbourne, 3000, Australia.
  • Gregory G; Monash Haematology, Monash Health, Clayton, 3168, Australia; School of Clinical Sciences at Monash Health, Monash University, Clayton, 3800, Australia.
  • Wickramasinghe VO; Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, 3000, Australia; RNA Biology and Cancer Laboratory, Peter MacCallum Cancer Centre, Melbourne, 3000, Australia.
  • Webb AI; The Walter and Eliza Hall Institute of Medical Research, Parkville, 3052, Australia; Department of Medical Biology, The University of Melbourne, Parkville, 3010, Australia.
  • Taberlay PC; Tasmanian School of Medicine, College of Health and Medicine, University of Tasmania, Hobart, 7000, Australia.
  • Bromberg KD; Discovery, Global Pharmaceutical Research and Development, AbbVie, North Chicago, IL 60064, USA.
  • Lai A; Discovery, Global Pharmaceutical Research and Development, AbbVie, North Chicago, IL 60064, USA.
  • Papenfuss AT; Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, 3000, Australia; The Walter and Eliza Hall Institute of Medical Research, Parkville, 3052, Australia; Department of Medical Biology, The University of Melbourne, Parkville, 3010, Australia.
  • Smyth GK; The Walter and Eliza Hall Institute of Medical Research, Parkville, 3052, Australia; School of Mathematics and Statistics, The University of Melbourne, Parkville, 3010, Australia.
  • Allan RS; The Walter and Eliza Hall Institute of Medical Research, Parkville, 3052, Australia; Department of Medical Biology, The University of Melbourne, Parkville, 3010, Australia.
  • Licht JD; Division of Hematology/Oncology, The University of Florida Health Cancer Center, Gainesville, FL 32608, USA.
  • Landau DA; New York Genome Center, New York, NY 10013, USA; Division of Hematology and Medical Oncology, Department of Medicine, Weill Cornell Medicine, New York, NY 10021, USA.
  • Abdel-Wahab O; Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
  • Shortt J; Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, 3000, Australia; Monash Haematology, Monash Health, Clayton, 3168, Australia; School of Clinical Sciences at Monash Health, Monash University, Clayton, 3800, Australia.
  • Vervoort SJ; Translational Hematology Program, Gene Regulation Laboratory, Peter MacCallum Cancer Center, Melbourne, 3000, Australia; Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, 3000, Australia. Electronic address: stephin.vervoort@petermac.org.
  • Johnstone RW; Translational Hematology Program, Gene Regulation Laboratory, Peter MacCallum Cancer Center, Melbourne, 3000, Australia; Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, 3000, Australia. Electronic address: ricky.johnstone@petermac.org.
Mol Cell ; 81(10): 2183-2200.e13, 2021 05 20.
Article in En | MEDLINE | ID: mdl-34019788
ABSTRACT
To separate causal effects of histone acetylation on chromatin accessibility and transcriptional output, we used integrated epigenomic and transcriptomic analyses following acute inhibition of major cellular lysine acetyltransferases P300 and CBP in hematological malignancies. We found that catalytic P300/CBP inhibition dynamically perturbs steady-state acetylation kinetics and suppresses oncogenic transcriptional networks in the absence of changes to chromatin accessibility. CRISPR-Cas9 screening identified NCOR1 and HDAC3 transcriptional co-repressors as the principal antagonists of P300/CBP by counteracting acetylation turnover kinetics. Finally, deacetylation of H3K27 provides nucleation sites for reciprocal methylation switching, a feature that can be exploited therapeutically by concomitant KDM6A and P300/CBP inhibition. Overall, this study indicates that the steady-state histone acetylation-methylation equilibrium functions as a molecular rheostat governing cellular transcription that is amenable to therapeutic exploitation as an anti-cancer regimen.
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Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Oncogenes / Transcription, Genetic / Histones / P300-CBP Transcription Factors / Biocatalysis Type of study: Prognostic_studies Limits: Humans Language: En Journal: Mol Cell Journal subject: BIOLOGIA MOLECULAR Year: 2021 Type: Article
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Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Oncogenes / Transcription, Genetic / Histones / P300-CBP Transcription Factors / Biocatalysis Type of study: Prognostic_studies Limits: Humans Language: En Journal: Mol Cell Journal subject: BIOLOGIA MOLECULAR Year: 2021 Type: Article