histone deacetylase 1
histone deacetylase 1
Overview
Histone deacetylase 1 (HDAC1) is a member of the class I histone deacetylase family and a nuclear enzyme that removes acetyl groups from lysine residues on histone and non-histone proteins. By promoting chromatin condensation and altering transcriptional accessibility, HDAC1 helps regulate gene expression programs involved in cell proliferation, differentiation, stress responses, inflammation, and metabolic control. It is therefore an important epigenetic regulator in both normal physiology and disease.
In biomedical research, HDAC1 is frequently studied as a therapeutic target because altered HDAC1 activity or expression can contribute to inflammatory signaling, endothelial dysfunction, metabolic disease, and other pathological states. It is also used as a reference selectivity target in drug discovery, particularly in the development of HDAC inhibitors designed to distinguish HDAC1 from related isoforms such as HDAC6.
Focus of Latest Publications
Recent publications have focused on histone deacetylase 1 (HDAC1) as a regulator of disease-associated transcriptional programs, particularly in cancer, vascular dysfunction, and inflammatory conditions. In pancreatic ductal adenocarcinoma, HDAC1/2 were identified as critical regulators of the DNA damage response by controlling the genomic distribution of H3K27ac and maintaining BRD4 and RNA polymerase II occupancy at DNA damage response gene promoters. Pharmacologic HDAC inhibition with entinostat shifted H3K27ac toward intergenic regions, reduced promoter-associated transcriptional machinery, suppressed DNA damage response gene expression, and increased sensitivity of pancreatic tumors to DNA-damaging and DDR-targeting agents. The same study also developed bottlebrush prodrug nanoparticles for tumor-selective entinostat delivery, aiming to improve efficacy while reducing systemic toxicity.
Several studies examined HDAC1 in inflammatory and metabolic disease contexts. In diabetes-associated endothelial dysfunction, intermittent high glucose was associated with increased HDAC1 expression, reduced H4K5 acetylation, and repression of the KLF2-eNOS axis in endothelial cells and diabetic rat glomeruli. Pharmacological inhibition of HDAC1 with pyroxamide or HDAC1 siRNA restored H4K5 acetylation, reinstated KLF2 and eNOS expression, and reduced ICAM1-associated endothelial activation and THP1 cell binding. Another study linked HDAC1 to the miR-34a-5p/HDAC1 axis in sepsis, evaluating lncRNA PAX8-AS1 as a diagnostic and prognostic biomarker and exploring its regulatory role in inflammatory responses. In metabolic dysfunction-associated steatohepatitis, HLWDD was reported to attenuate hepatic inflammation and lipogenesis via inhibition of the NF-κB/HDAC1/SREBP-1c axis.
HDAC1 has also been a target in medicinal chemistry efforts to develop selective epigenetic modulators. One study synthesized indole-based derivatives derived from vorinostat and entinostat and evaluated them against HDAC1 and HDAC6, identifying benzamide compounds with preferential HDAC1 inhibition and hydroxamate compounds with stronger HDAC6 preference. These compounds showed antiproliferative activity in cancer cell and NCI-60 screening assays, supporting HDAC1/6 inhibition as a strategy for cancer therapy. A separate computational study of vernomenin from Vernonia amygdalina included HDAC1 among fever-related targets identified by network pharmacology and docking, although the strongest predicted binding was to sirtuin 1 rather than HDAC1.
Overall, the recent literature portrays HDAC1 as a transcriptional and epigenetic regulator implicated in DNA damage responses, endothelial inflammation, and inflammatory-metabolic signaling, while also remaining an important target for inhibitor design. Across these studies, HDAC1-directed interventions were associated with altered histone acetylation, changes in promoter occupancy by transcriptional machinery, and downstream effects on genes such as KLF2, eNOS, BRD4-associated DDR genes, and SREBP-1c.