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. KellyDaphné 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

Research output: Contribution to journalArticleResearchpeer-review

34 Citations (Scopus)


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.

Original languageEnglish
Pages (from-to)2183-2200.e13
Number of pages31
JournalMolecular Cell
Issue number10
Publication statusPublished - 20 May 2021


  • cancer
  • chromatin biology
  • epigenetics
  • H3K27ac
  • histone acetylation
  • histone deacetylase
  • histone methylation
  • lysine acetylation
  • P300/CBP
  • transcription

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