Imbalanced Acetylation Distribution Induced by HDAC inhibition Promotes Pancreatic Cancer Vulnerability to DNA Damage
Currently, pancreatic ductal adenocarcinoma (PDAC) is primarily treated with genotoxic agents, yet clinical benefit remained limited in part by robust DNA repair. How chromatin regulation sustains the DNA damage response (DDR) in PDAC remains incompletely understood. Here, we identify Class I histone deacetylases (HDACs) as critical regulators of DDR. HDAC1/2 maintain a balanced genomic distribution of H3K27ac, ensuring BRD4 and RNA polymerase II (Pol II) occupancy at DDR gene promoters. HDAC inhibition by entinostat disrupts this balance, enriching acetylation at intergenic regions, diverting BRD4 and Pol II from promoters, and suppressing DDR genes. This suppression heightens DNA damage and sensitizes PDAC to diverse DNA-damaging and DDR-targeting agents. To facilitate clinical translation, we developed bottlebrush prodrug (BPD) nanoparticles for tumor-selective entinostat delivery, which achieves potent efficacy with reduced systemic exposure and toxicity. These findings reveal an HDAC-dependent DDR vulnerability and offer combinational and precision targeting strategies to improve PDAC therapy.