Class I histone deacetylases (HDAC1, HDAC2, HDAC3) (HDAC1-3)

Class I histone deacetylases (HDAC1, HDAC2, and HDAC3) are zinc-dependent enzymes that play a critical role in epigenetic regulation by removing acetyl groups from lysine residues on histone tails and various non-histone proteins [2, 10]. This deacetylation process leads to chromatin condensation and the repression of gene transcription, particularly of tumor suppressor genes [3, 6]. HDAC1 and HDAC2 are often found together in multi-protein complexes like NuRD, Sin3, and CoREST, while HDAC3 is a key component of the N-CoR/SMRT complex [2, 13]. These enzymes are frequently overexpressed in various cancers, where they contribute to tumor progression by silencing genes involved in cell cycle control, apoptosis, and differentiation [5, 15]. Consequently, they have become significant therapeutic targets, with several HDAC inhibitors (HDACis) like vorinostat and romidepsin approved for treating hematological malignancies [3, 7]. Beyond oncology, HDAC1-3 are implicated in inflammatory, neurodegenerative, and cardiovascular diseases, making them versatile targets for drug development [7, 16]. However, the lack of isoform selectivity in many current inhibitors often leads to systemic toxicities, such as thrombocytopenia and fatigue, highlighting the need for more selective therapeutic agents [7, 16]. Recent research has also identified HDAC1-3 as primary delactylases, expanding their known biological roles to the regulation of histone lactylation [8, 9].

Other names

Histone deacetylase 1Histone deacetylase 2Histone deacetylase 3Class I HDACsZinc-dependent histone deacetylasesRPD3Lysine deacetylasesKDACsHD1HD2HD3

HDAC1-3 inhibitors bind to the zinc-containing catalytic site of the enzymes, preventing the removal of acetyl groups from lysine residues on histones and non-histone proteins [1, 10]. This leads to hyperacetylation, which relaxes chromatin structure and restores the expression of silenced genes, such as the cyclin-dependent kinase inhibitor p21 [1, 5]. Additionally, hyperacetylation of non-histone proteins (e.g., p53, alpha-tubulin, Hsp90) modulates their stability and function, collectively inducing cell cycle arrest, differentiation, and apoptosis in cancer cells while often sparing normal cells [4, 5].