Inhibition of histone acetyltransferase function radiosensitizes CREBBP/EP300 mutants via repression of homologous recombination, potentially targeting a gain of function.
Acetylation
Animals
Apoptosis
BRCA1 Protein
/ metabolism
Biomarkers, Tumor
CREB-Binding Protein
/ genetics
Cell Line, Tumor
E1A-Associated p300 Protein
/ genetics
Gain of Function Mutation
Histone Acetyltransferases
/ chemistry
Homologous Recombination
Humans
Male
Mice, Nude
Mutation
Neoplasms
/ genetics
Protein Domains
Squamous Cell Carcinoma of Head and Neck
/ genetics
Xenograft Model Antitumor Assays
Journal
Nature communications
ISSN: 2041-1723
Titre abrégé: Nat Commun
Pays: England
ID NLM: 101528555
Informations de publication
Date de publication:
03 11 2021
03 11 2021
Historique:
received:
10
11
2020
accepted:
12
10
2021
entrez:
4
11
2021
pubmed:
5
11
2021
medline:
15
12
2021
Statut:
epublish
Résumé
Despite radiation forming the curative backbone of over 50% of malignancies, there are no genomically-driven radiosensitizers for clinical use. Herein we perform in vivo shRNA screening to identify targets generally associated with radiation response as well as those exhibiting a genomic dependency. This identifies the histone acetyltransferases CREBBP/EP300 as a target for radiosensitization in combination with radiation in cognate mutant tumors. Further in vitro and in vivo studies confirm this phenomenon to be due to repression of homologous recombination following DNA damage and reproducible using chemical inhibition of histone acetyltransferase (HAT), but not bromodomain function. Selected mutations in CREBBP lead to a hyperacetylated state that increases CBP and BRCA1 acetylation, representing a gain of function targeted by HAT inhibition. Additionally, mutations in CREBBP/EP300 are associated with recurrence following radiation in squamous cell carcinoma cohorts. These findings provide both a mechanism of resistance and the potential for genomically-driven treatment.
Identifiants
pubmed: 34732714
doi: 10.1038/s41467-021-26570-8
pii: 10.1038/s41467-021-26570-8
pmc: PMC8566594
doi:
Substances chimiques
BRCA1 Protein
0
BRCA1 protein, human
0
Biomarkers, Tumor
0
CREB-Binding Protein
EC 2.3.1.48
CREBBP protein, human
EC 2.3.1.48
E1A-Associated p300 Protein
EC 2.3.1.48
EP300 protein, human
EC 2.3.1.48
Histone Acetyltransferases
EC 2.3.1.48
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
6340Subventions
Organisme : NCI NIH HHS
ID : P50 CA097190
Pays : United States
Organisme : NIDCR NIH HHS
ID : R01 DE028105
Pays : United States
Organisme : NIDCR NIH HHS
ID : R01 DE028061
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA168485
Pays : United States
Informations de copyright
© 2021. The Author(s).
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