HDAC8

HDAC8, histone deacetylase 8, is an enzyme that removes acetyl groups from lysine residues on histone proteins, leading to chromatin condensation and transcriptional repression. It is a member of the class I histone deacetylases and is zinc-dependent. The HDAC8 protein is encoded by the HDAC8 gene located on the X chromosome. The enzyme uses a catalytic zinc ion in its active site to activate a water molecule that hydrolyzes the acetyl-lysine bond. In addition to histones, HDAC8 deacetylates several non-histone substrates, including components of the cohesin complex such as SMC3, linking its activity to chromosome cohesion and gene regulation.

HDAC8 predominantly resides in the nucleus, with expression in multiple tissues, and can shuttle between compartments under certain conditions. It participates in regulation of gene expression, cell cycle progression, and developmental pathways, including neural and smooth muscle differentiation. Through its action on cohesin and other substrates, HDAC8 influences chromosomal architecture and transcriptional programs.

Clinically, pathogenic variants in HDAC8 have been associated with Cornelia de Lange syndrome–like features, including developmental delay and craniofacial anomalies, highlighting a role in development. Altered HDAC8 activity has been observed in various cancers and other diseases, reflecting broader roles in epigenetic regulation.

HDAC inhibitors, including broad-spectrum or class I inhibitors, reduce HDAC8 activity, and selective HDAC8 inhibitors such as PCI-34051 have been developed for research and potential therapeutic uses. Ongoing research seeks to clarify HDAC8's substrate spectrum, regulation, and contribution to disease, and to evaluate selective inhibitors for clinical applications.