Histone deacetylase 1, Histone deacetylase 2, Histone deacetylase 3, Histone deacetylase 6 (HDAC1, HDAC2, HDAC3, HDAC6)

Histone deacetylases 1, 2, 3, and 6 are zinc-dependent enzymes that remove acetyl groups from lysine residues on histone and non-histone proteins, thereby condensing chromatin and generally repressing gene transcription. - HDAC1, HDAC2, and HDAC3 (Class I) are mainly nuclear, playing key roles in cell proliferation, development, and transcriptional regulation, frequently in multiprotein complexes. They are essential for viability and normal organ development; their dysfunction is linked to cancer, neurological, and inflammatory diseases. - HDAC6 (Class IIb) is largely cytoplasmic, uniquely containing two catalytic domains and interacting with substrates like α-tubulin, Hsp90, and cortactin, impacting cell motility, protein folding, and degradation. All are validated therapeutic targets, with several approved anti-cancer drugs acting as HDAC inhibitors. However, drug selectivity and toxicity remain challenges due to redundancy and overlap in their biological roles.

Other names

Lysine deacetylase 1, 2, 3, 6 (KDAC1, KDAC2, KDAC3, KDAC6)HDAC (general class)Class I HDAC: HDAC1, HDAC2, HDAC3Class IIb HDAC: HDAC6

Inhibitors block deacetylase activity at the zinc-dependent (or NAD+-dependent for sirtuins) catalytic domain, causing hyperacetylation of histone and non-histone proteins, leading to transcriptional reactivation of tumor suppressors, apoptosis, and cell cycle arrest in cancer cells. HDAC6 inhibitors disrupt deacetylation of tubulin and other cytoplasmic proteins, affecting cell motility, protein degradation, and stress responses.