Cited by 179Genomics and Chromatin DynamicsEpigenetics and DNA MethylationChromatin Remodeling and Cancer

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

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Hogg, Simon J., Motorna, Olga, Cluse, Leonie A., Johanson, Timothy M., Coughlan, Hannah D., Raviram, Ramya, Myers, Robert M., Costacurta, Matteo +34 more·2021·Molecular Cell

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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Crossref · 10.1016/j.molcel.2021.04.015

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  • These HATs can be coopted in different cancer contexts to sustain transcriptional addiction required for cell fitness.

    “It is important to note that these HATs can be coopted, in different cancer contexts, to sustain the transcriptional addiction required for cell fitness (Hogg et al., 2021).”

    From HDACs and the epigenetic plasticity of cancer cells: target the complexity (2022) · cites this paper as Hogg et al., 2021

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  1. Gryder BE, Wu L, Woldemichael GM, Pomella S, Quinn TR, Park PM, Cleveland A, Stanton BZ, Song Y, and Rota R.J.N.c. (2019c). Chemical genomics reveals histone deacetylases are required for core regulatory transcription. 10, 1– 12. PMC6614369 31285436
  2. Matthews GM, Mehdipour P, Cluse LA, Falkenberg KJ, Wang E, Roth M, Santoro F, Vidacs E, Stanley K, and House CMJB, The Journal of the American Society of Hematology (2015).
  3. Orlando DA, Chen MW, Brown VE, Solanki S, Choi YJ, Olson ER, Fritz CC, Bradner JE, and Guenther MG (2014b). Quantitative ChIP-Seq normalization reveals global modulation of the epigenome. Cell reports 9, 1163– 1170. 25437568

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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.
Affiliations
  • Memorial Sloan Kettering Cancer Center (US)
  • The University of Melbourne (AU)
  • Peter MacCallum Cancer Centre (AU)
  • New York Genome Center (US)
  • University of Tasmania (AU)
  • University of Florida (US)
  • Monash University (AU)
  • The Royal Melbourne Hospital (AU)
  • Monash Medical Centre (AU)
  • AbbVie (United States) (US)
Corresponding author
  • Vervoort, Stephin J.
  • Johnstone, Ricky W.
Venue
Molecular Cell
Publisher
Elsevier BV
Published
2021-05
Volume
81
Issue
10
Pages
2183-2200.e13
ISSN
1097-2765 (ISSN-L)
OpenAlex
W3163735930
Cited by
170
References
87
Citations by year
2026: 32 · 2025: 44 · 2024: 37 · 2023: 30 · 2022: 21 · 2021: 6
FWCI
8.08
Type
journal article
Language
en
Open access
Locations
  • Molecular Cell (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
  • UTAS Research Repository (submittedVersion)
  • Figshare (submittedVersion, cc-by)
  • Minerva Access (University of Melbourne) (submittedVersion)
Funders
  • National Institutes of Health
  • National Health and Medical Research Council
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Epigenetics and DNA Methylation
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Chromatin Remodeling and Cancer
Keywords
histone acetylation, P300, CBP, oncogenic transcription, chromatin accessibility, H3K27 methylation, KDM6A, NCOR1, HDAC3, corepressors, hematologic malignancies
MeSH terms
Histone Deacetylase 3, Acetylation, Cell Line, Chromatin, Histone Deacetylases, Histones, Humans, Kinetics, Methylation, Models, Biological, Oncogenes, RNA Polymerase II, Transcription, Genetic, Genome, Conserved Sequence, Evolution, Molecular, p300-CBP Transcription Factors, Gene Regulatory Networks, Biocatalysis, Co-Repressor Proteins

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