Related Experiment Video
Updated: Jun 5, 2026
Examination of Proteins Bound to Nascent DNA in Mammalian Cells Using BrdU-ChIP-Slot-Western Technique
Published on: January 14, 2016
HDAC INHIBITION SENSITIZES PANCREATIC TUMORS TO DNA DAMAGE BY GLOBAL REDISTRIBUTION OF THE TRANSCRIPTIONAL MACHINERY
Gaoyang Liang1, Hung V-T Nguyen2,3, Jonathan Zhu1
1Gene Expression Laboratory, Salk Institute for Biological Studies, La Jolla, California 92037, USA.
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 directs 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 towards 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.
Insights
Class I histone deacetylases (HDACs) regulate DNA damage response (DDR) genes in pancreatic cancer. Inhibiting HDACs with entinostat-BPD nanoparticles sensitizes tumors to DNA-damaging agents, offering a new therapeutic strategy.
Area of Science:
- Cancer Biology
- Epigenetics
- Molecular Oncology
Background:
- Pancreatic ductal adenocarcinoma (PDAC) relies on the DNA damage response (DDR) for survival and therapeutic resistance.
- Epigenetic mechanisms, particularly chromatin regulation, play a role in DDR, but their precise function in PDAC is unclear.
Purpose of the Study:
- To identify key regulators of DDR in PDAC.
- To investigate the role of Class I histone deacetylases (HDACs) in DDR.
- To develop novel therapeutic strategies targeting HDACs for PDAC treatment.
Main Methods:
- Identified Class I HDACs as critical DDR regulators in PDAC.
- Investigated the impact of HDAC inhibition on H3K27ac distribution, BRD4, and RNA polymerase II (Pol II) occupancy at DDR gene promoters.
- Developed bottlebrush prodrug (BPD) nanoparticles for targeted delivery of the HDAC inhibitor entinostat.
- Assessed the efficacy of entinostat-BPD in preclinical models of PDAC.
Main Results:
- HDAC1/2 controls H3K27ac, BRD4, and Pol II recruitment to DDR gene promoters.
- HDAC inhibition by entinostat suppresses DDR gene expression and enhances DNA damage.
- Entinostat-BPD achieves tumor-specific HDAC inhibition, improving efficacy and reducing systemic toxicity.
- HDAC inhibition sensitizes PDAC to various DNA-damaging and DDR-targeting agents.
Conclusions:
- Class I HDACs are essential for sustaining DDR gene expression in pancreatic cancer cells.
- Targeting HDACs disrupts DDR, sensitizing PDAC to therapy.
- Tumor-selective delivery of HDAC inhibitors via BPD nanoparticles offers a promising strategy to overcome toxicity and improve treatment outcomes.
Related Concept Videos
02:36DNA Damage can Stall the Cell Cycle
02:36DNA Damage Can Stall the Cell Cycle
02:23Abnormal Proliferation
01:25Mutagenicity and Carcinogenicity