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; Dup&#233;r&#233;-Richer, D; Sandow, JJ; Feran, B; Knight, D; Khong, T; Spencer, A; Harrison, SJ; Gregory, G; Wickramasinghe, VO; Webb, AI; Taberlay, PC; Bromberg, KD; Lai, A; Papenfuss, AT; Smyth, GK; Allan, RS; Licht, JD; Landau, DA; Abdel-Wahab, O; Shortt, J; Vervoort, SJ; Johnstone, RW

Author(s): 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; Dupéré-Richer, D; Sandow, JJ; Feran, B; Knight, D; Khong, T; Spencer, A; Harrison, SJ; Gregory, G; Wickramasinghe, VO; Webb, AI; Taberlay, PC; Bromberg, KD; Lai, A; Papenfuss, AT; Smyth, GK; Allan, RS; Licht, JD; Landau, DA; Abdel-Wahab, O; Shortt, J; Vervoort, SJ; Johnstone, RW;
Details: Publication Year 2021-05-20,Volume 81,Issue #10,Page 2183-2200.e13
Journal Title: 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.
Publisher: Cell Press
Keywords: H3K27ac; P300/cbp; cancer; chromatin biology; epigenetics; histone acetylation; histone deacetylase; histone methylation; lysine acetylation; transcription; Roche, Bristol Myers Squibb (BMS), AstraZeneca, and MecRx. R.W.J. is a shareholder; in and consultant for MecRx. A.L. and K.D.B. are employees of and shareholders in; AbbVie. A.S. has participated on advisory boards for and received research funding; from Celgene, Juno, BMS, Janssen-Cilag, Novartis, Amgen, Haemalogix, Abbvie, and; Takeda. J.S. has participated on advisory boards for and received honoraria from; Celgene. O.A.-W. has served as a consultant for H3B Biomedicine, Foundation Medicine; Inc., Merck, Prelude Therapeutics, and Janssen; is on the scientific advisory boards; of Envisagenics Inc., Pfizer Boulder, and AIChemy Inc.; and has received prior; research funding from Loxo Oncology and H3 Biomedicine. J.D.L. is a scientific; adviser to the Samuel Waxman Cancer Research Foundation. All other authors declare; no competing interests.
Research Division(s): Immunology; Advanced Technology And Biology; Bioinformatics
PubMed ID: 34019788
Publisher's Version: https://doi.org/10.1016/j.molcel.2021.04.015
Terms of Use/Rights Notice: Refer to copyright notice on published article.

Creation Date: 2021-06-02 01:46:00

Last Modified: 2021-06-02 01:48:51