Targeting histone acetylation dynamics and oncogenic transcription by catalytic P300/CBP inhibition.
Acetylation
Biocatalysis
Cell Line
Chromatin
/ metabolism
Co-Repressor Proteins
/ metabolism
Conserved Sequence
Evolution, Molecular
Gene Regulatory Networks
Genome
Histone Deacetylases
/ metabolism
Histones
/ metabolism
Humans
Kinetics
Methylation
Models, Biological
Oncogenes
RNA Polymerase II
/ metabolism
Transcription, Genetic
p300-CBP Transcription Factors
/ metabolism
H3K27ac
P300/CBP
cancer
chromatin biology
epigenetics
histone acetylation
histone deacetylase
histone methylation
lysine acetylation
transcription
Journal
Molecular cell
ISSN: 1097-4164
Titre abrégé: Mol Cell
Pays: United States
ID NLM: 9802571
Informations de publication
Date de publication:
20 05 2021
20 05 2021
Historique:
received:
28
01
2020
revised:
19
01
2021
accepted:
16
04
2021
entrez:
21
5
2021
pubmed:
22
5
2021
medline:
17
6
2021
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 34019788
pii: S1097-2765(21)00320-8
doi: 10.1016/j.molcel.2021.04.015
pmc: PMC8183601
mid: NIHMS1697213
pii:
doi:
Substances chimiques
Chromatin
0
Co-Repressor Proteins
0
Histones
0
p300-CBP Transcription Factors
EC 2.3.1.48
RNA Polymerase II
EC 2.7.7.-
Histone Deacetylases
EC 3.5.1.98
histone deacetylase 3
EC 3.5.1.98
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
2183-2200.e13Subventions
Organisme : NCI NIH HHS
ID : P30 CA008748
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA180475
Pays : United States
Organisme : NIGMS NIH HHS
ID : T32 GM007739
Pays : United States
Informations de copyright
Crown Copyright © 2021. Published by Elsevier Inc. All rights reserved.
Déclaration de conflit d'intérêts
Declaration of interests The Johnstone laboratory receives funding support from 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.
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