Histone deacetylase (zinc-dependent) (HDAC)

Zinc-dependent histone deacetylases (HDACs) are a family of enzymes, categorized into Classes I, II, and IV, that play a fundamental role in epigenetic regulation by removing acetyl groups from lysine residues on histone and non-histone proteins [5, 12]. By promoting a condensed chromatin state, these enzymes typically repress gene transcription and influence critical cellular processes such as cell cycle progression, apoptosis, and differentiation [4, 9]. Dysregulation of HDAC activity is frequently observed in various pathologies, particularly in cancers where it contributes to the silencing of tumor suppressor genes and promotes tumor growth [7, 14]. Therapeutic targeting of these enzymes with HDAC inhibitors, such as vorinostat and panobinostat, aims to restore normal acetylation levels, thereby inducing cell cycle arrest and programmed cell death in malignant cells [14, 18]. These inhibitors typically function by chelating the essential zinc ion within the enzyme's catalytic pocket [5, 13]. Beyond oncology, zinc-dependent HDACs are being explored as targets for treating neurodegenerative disorders, cardiovascular diseases, and inflammatory conditions [16, 17, 19]. However, the clinical use of broad-spectrum HDAC inhibitors is often limited by significant side effects, including hematological toxicities and cardiac concerns [15].

Other names

Classical histone deacetylaseZn2+-dependent histone deacetylaseLysine deacetylaseKDAC

HDAC inhibitors bind to the zinc-containing catalytic domain of the enzyme and chelate the active site Zn2+ ion, thereby inhibiting the removal of acetyl groups from lysine residues on histone and non-histone proteins [5, 13]. This leads to hyperacetylation, chromatin relaxation, and the re-expression of silenced genes, particularly tumor suppressors like p21, ultimately resulting in cell cycle arrest and apoptosis [7, 14].