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

journal contribution
posted on 2023-05-21, 02:15 authored by Hogg, SJ, Motorna, O, Cluse, LA, Johanson, TM, Coughlan, HD, Raviram, R, Myers, RM, Costacurta, M, Todorovski, I, Pijpers, L, Bjelosevic, S, Williams, T, Shannon HuskinsShannon Huskins, 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, Phillippa TaberlayPhillippa Taberlay, Bromberg, KD, Lai, A, Papenfuss, AT, Smyth, GK, Allan, RS, Licht, JD, Landau, DA, Abdel-Wahab, O, Shortt, J, Vervoort, SJ, Johnstone, RW
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.

History

Publication title

Molecular Cell

Volume

81

Issue

10

Pagination

2183-2200.e13

ISSN

1097-2765

Department/School

Tasmanian School of Medicine

Publisher

Cell Press

Place of publication

United States

Rights statement

Crown Copyright 2021 Published by Elsevier Inc.

Repository Status

  • Restricted

Socio-economic Objectives

Treatment of human diseases and conditions

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