Class I and II Histone Deacetylases (HDACs) (Class I and II HDACs)

Class I and II Histone Deacetylases (HDACs) are a family of zinc-dependent enzymes that serve as critical "erasers" of epigenetic marks by removing acetyl groups from lysine residues on histones and various non-histone proteins [2, 17]. Class I HDACs (HDAC1, 2, 3, and 8) are primarily nuclear and ubiquitously expressed, playing essential roles in cell proliferation and survival, while Class II HDACs (HDAC4, 5, 6, 7, 9, and 10) exhibit tissue-specific expression and shuttle between the nucleus and cytoplasm to regulate differentiation and signal transduction [1, 3, 4]. By promoting a condensed chromatin state, these enzymes typically function as transcriptional co-repressors, and their dysregulation is a hallmark of many cancers, where they often silence tumor suppressor genes [5, 8, 9]. Beyond oncology, Class I and II HDACs are implicated in neurodegenerative disorders, inflammatory conditions, and cardiovascular diseases [14, 15, 18]. Pharmacological inhibition of these enzymes using HDAC inhibitors (HDACis) leads to the accumulation of acetylated proteins, which can restore normal gene expression, induce cell cycle arrest, and trigger apoptosis in malignant cells [6, 13]. Several HDACis, such as vorinostat and romidepsin, are clinically approved for treating hematological malignancies, although their therapeutic window is often limited by systemic toxicities including myelosuppression and cardiac effects [10, 12, 14].

Other names

Classical histone deacetylasesZn2+-dependent histone deacetylasesRpd3/Hda1-like deacetylasesHistone deacetylase family members (Class I and II)

Class I and II HDAC inhibitors bind to the zinc-containing catalytic domain of the enzymes, blocking their ability to remove acetyl groups from lysine residues on histones and non-histone proteins. This leads to hyperacetylation, which relaxes chromatin structure and allows for the transcriptional reactivation of silenced genes, particularly tumor suppressors like p21. Additionally, inhibition affects the function of non-histone proteins involved in cell signaling, DNA repair, and protein stability, ultimately inducing cell cycle arrest, apoptosis, and senescence in diseased cells.