TY - JOUR
T1 - Inhibition of histone acetyltransferase function radiosensitizes CREBBP/EP300 mutants via repression of homologous recombination, potentially targeting a gain of function
AU - Kumar, Manish
AU - Molkentine, David
AU - Molkentine, Jessica
AU - Bridges, Kathleen
AU - Xie, Tongxin
AU - Yang, Liangpeng
AU - Hefner, Andrew
AU - Gao, Meng
AU - Bahri, Reshub
AU - Dhawan, Annika
AU - Frederick, Mitchell J
AU - Seth, Sahil
AU - Abdelhakiem, Mohamed
AU - Beadle, Beth M.
AU - Johnson, Faye
AU - Wang, Jing
AU - Shen, Li
AU - Heffernan, Timothy
AU - Sheth, Aakash
AU - Ferris, Robert L.
AU - Myers, Jeffrey N.
AU - Pickering, Curtis R.
AU - Skinner, Heath
N1 - Funding Information:
This work was supported by: (i) the National Cancer Institute R01CA168485-08 (HS) and P50CA097190-15 (RF), (ii) the National Institute for Dental and Craniofacial Research R01 DE028105 (HS) and R01DE028061 (HS and CP), and (iii) The Cancer Prevention Institute of Texas RP150293 (HS and CP). We thank Dr. Alma Faust for her assistance in editing this paper. Potential mechanism figure created with Biorender.com.
Publisher Copyright:
© 2021, The Author(s).
PY - 2021/12/1
Y1 - 2021/12/1
N2 - 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.
AB - 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.
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U2 - 10.1038/s41467-021-26570-8
DO - 10.1038/s41467-021-26570-8
M3 - Article
C2 - 34732714
AN - SCOPUS:85118534946
SN - 2041-1723
VL - 12
JO - Nature communications
JF - Nature communications
IS - 1
M1 - 6340
ER -