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Updated: Oct 14, 2025

Assays for Validating Histone Acetyltransferase Inhibitors
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Assays for Validating Histone Acetyltransferase Inhibitors

Published on: August 6, 2020

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Inhibition of histone acetyltransferase function radiosensitizes CREBBP/EP300 mutants via repression of homologous

Manish Kumar1, David Molkentine2, Jessica Molkentine2

  • 1Department of Biochemistry, All India Institute of Medical Sciences (AIIMS), Bilaspur, Himachal Pradesh, India.

Nature Communications
|November 4, 2021
PubMed

Insights

Targeting histone acetyltransferases CREBBP/EP300 with HAT inhibitors can sensitize tumors to radiation therapy. This approach shows promise for genomically-driven cancer treatment, particularly in tumors with specific CREBBP/EP300 mutations.

Area of Science:

  • Oncology
  • Molecular Biology
  • Genetics

Background:

  • Radiation therapy is a cornerstone of cancer treatment, yet effective genomically-driven radiosensitizers are lacking.
  • Understanding the molecular mechanisms of radiation response and resistance is crucial for improving therapeutic outcomes.

Purpose of the Study:

  • To identify novel molecular targets for radiosensitization based on genomic dependencies.
  • To investigate the role of histone acetyltransferases CREBBP/EP300 in radiation response.

Main Methods:

  • In vivo shRNA screening to identify genes associated with radiation response.
  • In vitro and in vivo validation of CREBBP/EP300 as radiosensitization targets.
  • Assessment of homologous recombination repair and protein acetylation following DNA damage.

Main Results:

  • Histone acetyltransferases CREBBP/EP300 were identified as key targets for radiosensitization in tumors with corresponding mutations.
  • Inhibition of CREBBP/EP300 repressed homologous recombination after DNA damage, enhancing radiation sensitivity.
  • Chemical inhibition of histone acetyltransferase (HAT) activity, but not bromodomain function, mimicked this effect.
  • Specific CREBBP mutations led to increased CBP and BRCA1 acetylation, a gain-of-function targeted by HAT inhibition.
  • Mutations in CREBBP/EP300 correlated with increased recurrence rates after radiation in squamous cell carcinoma.

Conclusions:

  • CREBBP/EP300 are critical regulators of homologous recombination repair and radiosensitivity.
  • Targeting HAT activity of CREBBP/EP300 offers a genomically-driven strategy for radiosensitization.
  • These findings elucidate a mechanism of radiation resistance and suggest a novel therapeutic approach for specific cancer patient populations.

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