Targeting histone acetylation dynamics and oncogenic transcription by catalytic P300/CBP inhibition

Simon J Hogg; Olga Motorna; Leonie A Cluse; Timothy M Johanson; Hannah D Coughlan; Ramya Raviram; Robert M Myers; Matteo Costacurta; Izabela Todorovski; Lizzy Pijpers; Stefan Bjelosevic; Tobias Williams; Shannon N Huskins; Conor J Kearney; Jennifer R Devlin; Zheng Fan; Jafar S Jabbari; Ben P Martin; Mohamed Fareh; Madison J Kelly; Daphné Dupéré-Richer; Jarrod J Sandow; Breon Feran; Deborah Knight; Tiffany Khong; Andrew Spencer; Simon J Harrison; Gareth Gregory; Vihandha O Wickramasinghe; Andrew I Webb; Phillippa C Taberlay; Kenneth D Bromberg; Albert Lai; Anthony T Papenfuss; Gordon K Smyth; Rhys S Allan; Jonathan D Licht; Dan A Landau; Omar Abdel-Wahab; Jake Shortt; Stephin J Vervoort; Ricky W Johnstone

doi:10.1016/j.molcel.2021.04.015

Targeting histone acetylation dynamics and oncogenic transcription by catalytic P300/CBP inhibition

Mol Cell. 2021 May 20;81(10):2183-2200.e13. doi: 10.1016/j.molcel.2021.04.015.

Authors

Simon J Hogg¹, Olga Motorna², Leonie A Cluse³, Timothy M Johanson⁴, Hannah D Coughlan⁴, Ramya Raviram⁵, Robert M Myers⁶, Matteo Costacurta⁷, Izabela Todorovski⁷, Lizzy Pijpers⁷, Stefan Bjelosevic⁷, Tobias Williams⁸, Shannon N Huskins⁹, Conor J Kearney⁷, Jennifer R Devlin⁷, Zheng Fan⁷, Jafar S Jabbari¹⁰, Ben P Martin³, Mohamed Fareh⁷, Madison J Kelly⁷, Daphné Dupéré-Richer¹¹, Jarrod J Sandow⁴, Breon Feran⁴, Deborah Knight³, Tiffany Khong¹², Andrew Spencer¹², Simon J Harrison¹³, Gareth Gregory¹⁴, Vihandha O Wickramasinghe⁸, Andrew I Webb⁴, Phillippa C Taberlay⁹, Kenneth D Bromberg¹⁵, Albert Lai¹⁵, Anthony T Papenfuss¹⁶, Gordon K Smyth¹⁷, Rhys S Allan⁴, Jonathan D Licht¹¹, Dan A Landau¹⁸, Omar Abdel-Wahab¹⁹, Jake Shortt²⁰, Stephin J Vervoort²¹, Ricky W Johnstone²²

Affiliations

¹ 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 Center, New York, NY 10065, USA.
² 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 Clinical Sciences at Monash Health, Monash University, Clayton, 3800, Australia.
³ Translational Hematology Program, Gene Regulation Laboratory, Peter MacCallum Cancer Center, Melbourne, 3000, Australia.
⁴ The Walter and Eliza Hall Institute of Medical Research, Parkville, 3052, Australia; Department of Medical Biology, The University of Melbourne, Parkville, 3010, Australia.
⁵ New York Genome Center, New York, NY 10013, USA.
⁶ Tri-Institutional MD-PhD Program, Weill Cornell Medicine, Rockefeller University, Memorial Sloan Kettering Cancer Center, New York, NY 10021, USA.
⁷ 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.
⁸ 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.
⁹ Tasmanian School of Medicine, College of Health and Medicine, University of Tasmania, Hobart, 7000, Australia.
¹⁰ Department of Microbiology and Immunology, The University of Melbourne at The Peter Doherty Institute for Infection and Immunity, Melbourne, 3000, Australia.
¹¹ Division of Hematology/Oncology, The University of Florida Health Cancer Center, Gainesville, FL 32608, USA.
¹² Australian Center for Blood Diseases, Monash University, Melbourne, 3004, Australia.
¹³ 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.
¹⁴ Monash Haematology, Monash Health, Clayton, 3168, Australia; School of Clinical Sciences at Monash Health, Monash University, Clayton, 3800, Australia.
¹⁵ Discovery, Global Pharmaceutical Research and Development, AbbVie, North Chicago, IL 60064, USA.
¹⁶ 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.
¹⁷ The Walter and Eliza Hall Institute of Medical Research, Parkville, 3052, Australia; School of Mathematics and Statistics, The University of Melbourne, Parkville, 3010, Australia.
¹⁸ 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.
¹⁹ Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
²⁰ 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.
²¹ 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: [email protected].
²² 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: [email protected].

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.

Keywords: H3K27ac; P300/CBP; cancer; chromatin biology; epigenetics; histone acetylation; histone deacetylase; histone methylation; lysine acetylation; transcription.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Acetylation
Biocatalysis*
Cell Line
Chromatin / metabolism
Co-Repressor Proteins / metabolism
Conserved Sequence
Evolution, Molecular
Gene Regulatory Networks
Genome
Histone Deacetylases / metabolism
Histones / metabolism*
Humans
Kinetics
Methylation
Models, Biological
Oncogenes*
RNA Polymerase II / metabolism
Transcription, Genetic*
p300-CBP Transcription Factors / metabolism*

Substances

Chromatin
Co-Repressor Proteins
Histones
p300-CBP Transcription Factors
RNA Polymerase II
Histone Deacetylases
histone deacetylase 3

Abstract

Publication types

MeSH terms

Substances

Grants and funding