HDAC inhibition sensitizes pancreatic tumors to DNA damage by global redistribution of the transcriptional machinery

The DNA damage response (DDR) is critical for pancreatic ductal adenocarcinoma (PDAC) development and therapeutic responses, including to genotoxic agents. While epigenetic modulators have been shown to contribute to the DDR, how chromatin regulation dictates responses to DNA damage in PDAC remains incompletely understood. Here, we identify Class I histone deacetylases (HDACs) as critical regulators of the DDR. HDAC1/2 direct the genomic distribution of H3K27ac, ensuring sufficient BRD4 and RNA polymerase II (Pol II) occupancy at DDR gene promoters. HDAC inhibition by entinostat shifts the balance of H3K27 acetylation preferentially toward intergenic regions, diverting BRD4 and Pol II from promoters, thereby suppressing DDR gene expression. In line with this, HDAC inhibition heightens DNA damage and sensitizes PDAC to diverse DNA-damaging and DDR-targeting agents. Since the clinical development of HDAC inhibitors has been limited by systemic toxicity, we developed bottlebrush prodrug (BPD) nanoparticles for tumor-selective entinostat delivery. Entinostat-BPD achieved tumor-specific HDAC inhibition while displaying potent efficacy and reduced systemic toxicity. These findings reveal an HDAC-dependent DDR vulnerability and offer combinational and precision targeting strategies to facilitate clinical translation and improve PDAC patient outcomes.

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Publication Details

Journal
Proceedings of the National Academy of Sciences
Published
2026-06-25
DOI
https://doi.org/10.1073/pnas.2536040123
Primary Topic
Histone Deacetylase Inhibitors Research
Type
article
Field-Weighted Citation Impact
0.00

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article

HDAC inhibition sensitizes pancreatic tumors to DNA damage by global redistribution of the transcriptional machinery

Tae Gyu Oh, Tony Hunter, Hervé Tiriac, Morgan Truitt et al.
Proceedings of the National Academy of Sciences
Histone Deacetylase Inhibitors Research
article

HDAC inhibition sensitizes pancreatic tumors to DNA damage by global redistribution of the transcriptional machinery

Tae Gyu Oh, Tony Hunter, Hervé Tiriac, Morgan Truitt, Gaoyang Liang, Christopher Liddle, Gabriela Estepa, Ruth T. Yu, Jeremiah A. Johnson, Reuben J. Shaw, Annette R. Atkins, D. Nelson, Ronald M. Evans, Michael Downes, Hadiqa Zafar, Andrew M. Lowy, Weiwei Fan, Jonathan Zhu, Daniel Y. Cao, Yang Dai, Dannielle Engle, Hung V.-T. Nguyen
article en

Abstract

The DNA damage response (DDR) is critical for pancreatic ductal adenocarcinoma (PDAC) development and therapeutic responses, including to genotoxic agents. While epigenetic modulators have been shown to contribute to the DDR, how chromatin regulation dictates responses to DNA damage in PDAC remains incompletely understood. Here, we identify Class I histone deacetylases (HDACs) as critical regulators of the DDR. HDAC1/2 direct the genomic distribution of H3K27ac, ensuring sufficient BRD4 and RNA polymerase II (Pol II) occupancy at DDR gene promoters. HDAC inhibition by entinostat shifts the balance of H3K27 acetylation preferentially toward intergenic regions, diverting BRD4 and Pol II from promoters, thereby suppressing DDR gene expression. In line with this, HDAC inhibition heightens DNA damage and sensitizes PDAC to diverse DNA-damaging and DDR-targeting agents. Since the clinical development of HDAC inhibitors has been limited by systemic toxicity, we developed bottlebrush prodrug (BPD) nanoparticles for tumor-selective entinostat delivery. Entinostat-BPD achieved tumor-specific HDAC inhibition while displaying potent efficacy and reduced systemic toxicity. These findings reveal an HDAC-dependent DDR vulnerability and offer combinational and precision targeting strategies to facilitate clinical translation and improve PDAC patient outcomes.

Proceedings of the National Academy of SciencesVol. 123(26)
Dartmouth College (US), The University of Sydney (AU), Salk Institute for Biological Studies (US), Society of Surgical Oncology (US), Westmead Institute for Medical Research (AU), Massachusetts Institute of Technology (US)
March of Dimes Foundation, Lustgarten Foundation, David C. Copley Foundation, Paul M. Angell Family Foundation, NOMIS Stiftung, National Institute on Aging, National Cancer Institute
Good health and well-being
Openalex Percentile: Top 11%
Histone Deacetylase Inhibitors Research
DOIOpen Access PDFOpenAlex
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