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

• 成果类型: Article
• 署名作者: Liang, Gaoyang; Nguyen, Hung V. -T.; Zhu, Jonathan; Tiriac, Herve; Zafar, Hadiqa; Cao, Daniel Y.; Estepa, Gabriela; Nelson, Dylan C.; Dai, Yang; Oh, Tae Gyu; Liddle, Christopher; Yu, Ruth T.; Hunter, Tony; Engle, Dannielle; Shaw, Reuben; Lowy, Andrew M.; Fan, Weiwei; Truitt, Morgan L.; Atkins, Annette R.; Johnson, Jeremiah A.; Downes, Michael; Evans, Ronald M.
• 署名单位: Salk Institute; Massachusetts Institute of Technology (MIT); University of California System; University of California San Diego; University of Sydney; Westmead Institute for Medical Research; University of Sydney; Salk Institute
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.2536040123
• 发表日期: 2026-06-30
• 页码: e2536040123
• 关键词: HDAC; DNA damage response; pancreatic cancer; bottlebrush prodrug; HDAC inhibitor; HISTONE DEACETYLASES; cancer; hallmarks; chromatin; survival; adenocarcinoma; gemcitabine; expression; landscape; FAMILY

摘要

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.