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

Hogg, SJ, Motorna, O, Cluse, LA, Johanson, TM, Coughlan, HD, Raviram, R, Myers, RM, Costacurta, M, Todorovski, I, Pijpers, L, Bjelosevic, S, Williams, T, Huskins, SN, Kearney, CJ, Devlin, JR, Fan, Z, Jabbari, JS, Martin, BP, Fareh, M, Kelly, MJ, Dupere-Richer, D, Sandow, JJ, Feran, B, Knight, D, Khong, T, Spencer, A, Harrison, SJ, Gregory, G, Wickramasinghe, VO, Webb, AI, Taberlay, PC ORCID: 0000-0002-5298-8730, Bromberg, KD, Lai, A, Papenfuss, AT, Smyth, GK, Allan, RS, Licht, JD, Landau, DA, Abdel-Wahab, O, Shortt, J, Vervoort, SJ and Johnstone, RW 2021 , 'Targeting histone acetylation dynamics and oncogenic transcription by catalytic P300/CBP inhibition' , Molecular Cell, vol. 81, no. 10 , 2183-2200.e13 , doi: 10.1016/j.molcel.2021.04.015.

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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.

Item Type: Article
Authors/Creators:Hogg, SJ and Motorna, O and Cluse, LA and Johanson, TM and Coughlan, HD and Raviram, R and Myers, RM and Costacurta, M and Todorovski, I and Pijpers, L and Bjelosevic, S and Williams, T and Huskins, SN and Kearney, CJ and Devlin, JR and Fan, Z and Jabbari, JS and Martin, BP and Fareh, M and Kelly, MJ and Dupere-Richer, D and Sandow, JJ and Feran, B and Knight, D and Khong, T and Spencer, A and Harrison, SJ and Gregory, G and Wickramasinghe, VO and Webb, AI and Taberlay, PC and Bromberg, KD and Lai, A and Papenfuss, AT and Smyth, GK and Allan, RS and Licht, JD and Landau, DA and Abdel-Wahab, O and Shortt, J and Vervoort, SJ and Johnstone, RW
Keywords: H3K27ac, P300/CBP, cancer, chromatin biology, epigenetics, histone acetylation, histone deacetylase, histone methylation, lysine acetylation, transcription
Journal or Publication Title: Molecular Cell
Publisher: Cell Press
ISSN: 1097-2765
DOI / ID Number: 10.1016/j.molcel.2021.04.015
Copyright Information:

Crown Copyright 2021 Published by Elsevier Inc.

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