@article{6bcacbb8923545778c89de859e8d22e3,
title = "Targeting histone acetylation dynamics and oncogenic transcription by catalytic P300/CBP inhibition",
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 = "cancer, chromatin biology, epigenetics, H3K27ac, histone acetylation, histone deacetylase, histone methylation, lysine acetylation, P300/CBP, transcription",
author = "Hogg, {Simon J.} and Olga Motorna and Cluse, {Leonie A.} and Johanson, {Timothy M.} and Coughlan, {Hannah D.} and Ramya Raviram and Myers, {Robert M.} and Matteo Costacurta and Izabela Todorovski and Lizzy Pijpers and Stefan Bjelosevic and Tobias Williams and Huskins, {Shannon N.} and Kearney, {Conor J.} and Devlin, {Jennifer R.} and Zheng Fan and Jabbari, {Jafar S.} and Martin, {Ben P.} and Mohamed Fareh and Kelly, {Madison J.} and Daphn{\'e} Dup{\'e}r{\'e}-Richer and Sandow, {Jarrod J.} and Breon Feran and Deborah Knight and Tiffany Khong and Andrew Spencer and Harrison, {Simon J.} and Gareth Gregory and Wickramasinghe, {Vihandha O.} and Webb, {Andrew I.} and Taberlay, {Phillippa C.} and Bromberg, {Kenneth D.} and Albert Lai and Papenfuss, {Anthony T.} and Smyth, {Gordon K.} and Allan, {Rhys S.} and Licht, {Jonathan D.} and Landau, {Dan A.} and Omar Abdel-Wahab and Jake Shortt and Vervoort, {Stephin J.} and Johnstone, {Ricky W.}",
note = "Funding Information: The Peter MacCallum Foundation and Australian Cancer Research Foundation provide generous support for equipment and core facilities. S.J. Hogg was supported by the Cancer Council of Victoria (CCV), a National Health and Medical Research Council of Australia (NHMRC) Investigator Grant, and a Haematology Society of Australia & New Zealand (HSANZ) Educational Grant. R.W.J. was supported by the CCV , the NHMRC , and The Kids{\textquoteright} Cancer Project . S.J.V. was supported by a Rubicon fellowship ( Nederlandse Organisatie voor Wetenschappelijk Onderzoek [NWO]), an NHMRC Investigator Grant, and The Kids{\textquoteright} Cancer Project . A.T.P., G.K.S., H.D.C., R.S.A., and T.M.J. received funding from the NHMRC (grants 1049307 and 1100451 to R.S.A. and T.M.J.; grant 1124081 to T.M.J.). J.D.L. was supported by National Institutes of Health (NIH) grant R01 CA 180475 , a Specialized Center of Research Excellence grant from the Leukemia and Lymphoma Society (LLS), the Multiple Myeloma Research Foundation , and the Samuel Waxman Cancer Research Foundation . D.D.-R. was supported by an LLS Special Fellow Award. V.O.W. is supported by a Veski Innovation Fellowship, a Victorian Cancer Agency mid-career fellowship, and the NHMRC . J.S. is supported by a Medical Research Future Fund Clinician Researcher Fellowship. P.C.T. was supported by an NHMRC Project Grant ( APP1161985 ), an NHMRC Career Development Fellowship ( APP1109696 ), and an NHMRC Investigator Grant ( APP1176417 ). R.M.M. is supported by a Medical Scientist Training Program grant from the National Institute of General Medical Sciences of the NIH under award T32GM007739 to the Weill Cornell/Rockefeller/Sloan Kettering Tri-Institutional MD-PhD Program. We acknowledge the use of the Integrated Genomics Operation Core, funded by the National Cancer Institute (NCI) Cancer Center Support Grant (CCSG; P30 CA08748 ), Cycle for Survival , and the Marie-Jos{\'e}e and Henry R. Kravis Center for Molecular Oncology . Funding Information: The Johnstone laboratory receives funding support from Roche, Bristol Myers Squibb (BMS), AstraZeneca, and MecRx. R.W.J. is a shareholder in and consultant for MecRx. A.L. and K.D.B. are employees of and shareholders in AbbVie. A.S. has participated on advisory boards for and received research funding from Celgene, Juno, BMS, Janssen-Cilag, Novartis, Amgen, Haemalogix, Abbvie, and Takeda. J.S. has participated on advisory boards for and received honoraria from Celgene. O.A.-W. has served as a consultant for H3B Biomedicine, Foundation Medicine Inc., Merck, Prelude Therapeutics, and Janssen; is on the scientific advisory boards of Envisagenics Inc., Pfizer Boulder, and AIChemy Inc.; and has received prior research funding from Loxo Oncology and H3 Biomedicine. J.D.L. is a scientific adviser to the Samuel Waxman Cancer Research Foundation. All other authors declare no competing interests. Publisher Copyright: {\textcopyright} 2021 Copyright: Copyright 2021 Elsevier B.V., All rights reserved.",
year = "2021",
month = may,
day = "20",
doi = "10.1016/j.molcel.2021.04.015",
language = "English",
volume = "81",
pages = "2183--2200.e13",
journal = "Molecular Cell",
issn = "1097-2765",
publisher = "Elsevier",
number = "10",
}
