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Targeting histone acetylation dynamics and oncogenic transcription by catalytic P300/CBP inhibition
Open accessAbstract
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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“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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Metadata
- 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.
- ORCID
- Hogg, Simon J.
- Motorna, Olga
- Cluse, Leonie A.
- Johanson, Timothy M.
- Coughlan, Hannah D.
- Raviram, Ramya
- Myers, Robert M.
- Costacurta, Matteo
- Todorovski, Izabela
- Pijpers, Lizzy
- Bjelosevic, Stefan
- Williams, Tobias
- Kearney, Conor J.
- Devlin, Jennifer R.
- Jabbari, Jafar S.
- Fareh, Mohamed
- Kelly, Madison J.
- Dupéré-Richer, Daphné
- Sandow, Jarrod J.
- Knight, Deborah
- Khong, Tiffany
- Spencer, Andrew
- Harrison, Simon J.
- Gregory, Gareth
- Wickramasinghe, Vihandha O.
- Webb, Andrew I.
- Taberlay, Phillippa C.
- Lai, Albert
- Papenfuss, Anthony T.
- Smyth, Gordon K.
- Allan, Rhys S.
- Licht, Jonathan D.
- Landau, Dan A.
- Abdel-Wahab, Omar
- Shortt, Jake
- 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)
- PMC
- PMC8183601
- 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
- bronze
- doi.org
- Licence
- www.elsevier.com/tdm/userlicense/1.0/ (tdm)
- www.elsevier.com/legal/tdmrep-license (tdm)
- www.elsevier.com/open-access/userlicense/1.0/ (vor, 384 d)
- doi.org/10.15223/policy-017 (stm-asf)
- doi.org/10.15223/policy-037 (stm-asf)
- doi.org/10.15223/policy-012 (stm-asf)
- doi.org/10.15223/policy-029 (stm-asf)
- doi.org/10.15223/policy-004 (stm-asf)
- 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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