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

   


Authors: Hogg, S. J.; Motorna, O.; Cluse, L. A.; Johanson, T. M.; Coughlan, H. D.; Raviram, R.; Myers, R. M.; Costacurta, M.; Todorovski, I.; Pijpers, L.; Bjelosevic, S.; Williams, T.; Huskins, S. N.; Kearney, C. J.; Devlin, J. R.; Fan, Z.; Jabbari, J. S.; Martin, B. P.; Fareh, M.; Kelly, M. J.; Dupéré-Richer, D.; Sandow, J. J.; Feran, B.; Knight, D.; Khong, T.; Spencer, A.; Harrison, S. J.; Gregory, G.; Wickramasinghe, V. O.; Webb, A. I.; Taberlay, P. C.; Bromberg, K. D.; Lai, A.; Papenfuss, A. T.; Smyth, G. K.; Allan, R. S.; Licht, J. D.; Landau, D. A.; Abdel-Wahab, O.; Shortt, J.; Vervoort, S. J.; Johnstone, R. W.
Article 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. © 2021
Keywords: epigenetics; transcription; histone deacetylase; histone methylation; histone acetylation; lysine acetylation; cancer; h3k27ac; chromatin biology; p300/cbp
Journal Title: Molecular Cell
Volume: 81
Issue: 10
ISSN: 1097-2765
Publisher: Cell Press  
Date Published: 2021-05-20
Start Page: 2183
End Page: 2200.e13
Language: English
DOI: 10.1016/j.molcel.2021.04.015
PROVIDER: scopus
PUBMED: 34019788
PMCID: PMC8183601
DOI/URL:

https://www.scopus.com/inward/record.uri?eid=2-s2.0-85106265307&doi=10.1016%2fj.molcel.2021.04.015&partnerID=40&md5=aeaa682b0c8d10ce6f950fce246ba42e
Notes: Article -- Export Date: 1 June 2021 -- Source: Scopus
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MSK Authors
  1. Omar Ibrahim Abdel-Wahab
    573 Abdel-Wahab
  2. Simon John Hogg
    26 Hogg
  3. Robert Myers
    5 Myers
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