HDACs

HDACs, or histone deacetylases, are a group of enzymes that remove acetyl groups from lysine residues on histone proteins and a variety of non-histone proteins. By deacetylating histones, they promote a more compact chromatin structure and generally repress gene transcription. Most HDACs are zinc-dependent hydrolases, while a separate family of enzymes known as sirtuins uses NAD+ as a cofactor and is sometimes considered distinct from classical HDACs.

In humans, HDACs are grouped into four classes based on sequence similarity to yeast enzymes. Class I includes HDAC1, HDAC2, HDAC3, and HDAC8 and is primarily nuclear. Class II is subdivided into IIa (HDAC4, HDAC5, HDAC7, HDAC9) and IIb (HDAC6, HDAC10), with members found in the nucleus and cytoplasm and capable of shuttling between compartments. Class III comprises the sirtuins (SIRT1–SIRT7), NAD+-dependent rather than zinc-dependent. Class IV contains HDAC11. HDACs target histone tails and a range of non-histone substrates, such as p53 and tubulin, influencing diverse cellular processes.

Biological roles of HDACs include regulation of gene expression, development, cell cycle progression, differentiation, apoptosis, and DNA repair. They contribute to neural function, metabolism, and aging, and their dysregulation is associated with cancer, neurodegenerative and inflammatory diseases, and psychiatric disorders.

HDAC inhibitors (HDACi) are used clinically as epigenetic therapies in cancer. Approved agents include vorinostat, romidepsin, belinostat, and panobinostat, with indications such as cutaneous and peripheral T-cell lymphomas and multiple myeloma. Research continues into broader therapeutic applications and the management of side effects.