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Inhibition of histone acetyltransferase function radiosensitizes CREBBP/EP300 mutants via repression of homologous recombination, potentially targeting a gain of function
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Inhibition of histone acetyltransferase function radiosensitizes CREBBP/EP300 mutants via repression of homologous recombination, potentially targeting a gain of function
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Journal Article
Inhibition of histone acetyltransferase function radiosensitizes CREBBP/EP300 mutants via repression of homologous recombination, potentially targeting a gain of function
2021
Overview
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.
Mutations in histone acetyltransferases (HATs) CREBBP and EP300 are generally thought to lead to decreased function or absence of protein product. Here the authors describe a gain of function of several CREBBP mutations leading to baseline hyper-acetylation, increased homologous recombination and potential synergy between radiation and HAT inhibition in CREBBP/EP300 mutant tumors.
Publisher
Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
Subject
/ 13/109
/ 13/2
/ 13/44
/ 13/89
/ 13/95
/ 38/1
/ 38/109
/ 38/77
/ 38/90
/ 82/80
/ 96/95
/ Animals
/ CREB-Binding Protein - genetics
/ CREB-Binding Protein - metabolism
/ E1A-Associated p300 Protein - genetics
/ E1A-Associated p300 Protein - metabolism
/ Histone Acetyltransferases - chemistry
/ Histone Acetyltransferases - genetics
/ Histone Acetyltransferases - metabolism
/ Histones
/ Homology
/ Humanities and Social Sciences
/ Humans
/ Male
/ Mice
/ Mutants
/ Mutation
/ Science
/ Squamous Cell Carcinoma of Head and Neck - genetics
/ Squamous Cell Carcinoma of Head and Neck - metabolism
/ Tumors
