Histone deacetylase (Class I and II) (HDAC (Class I/II))

Histone deacetylases (HDACs) of Class I and II are a group of zinc-dependent enzymes that play a critical role in epigenetic regulation by removing acetyl groups from lysine residues on histones and various non-histone proteins [1, 2]. Class I HDACs (HDAC1, 2, 3, and 8) are primarily nuclear and ubiquitously expressed, while Class II HDACs (Class IIa: HDAC4, 5, 7, 9; Class IIb: HDAC6, 10) exhibit tissue-specific expression and can shuttle between the nucleus and cytoplasm [1, 3]. These enzymes are frequently dysregulated in various diseases, particularly cancer, where they contribute to the silencing of tumor suppressor genes and the promotion of cell proliferation and survival [2, 4]. Consequently, they have become significant therapeutic targets, with several pan-HDAC and class-selective inhibitors approved for treating hematological malignancies like cutaneous T-cell lymphoma and multiple myeloma [4, 5]. Beyond oncology, Class I/II HDACs are being investigated for their roles in neurodegeneration, inflammation, and cardiac diseases, although clinical use is often limited by class-related toxicities such as myelosuppression and cardiotoxicity [3, 6].

Other names

HDACsLysine deacetylasesKDACsClassical histone deacetylasesZinc-dependent histone deacetylases

Histone deacetylase inhibitors (HDACis) target the zinc-dependent catalytic domain of Class I and II HDACs, inhibiting their ability to remove acetyl groups from lysine residues on histones and non-histone proteins [1, 2]. This inhibition leads to the accumulation of acetylated histones, which promotes an open chromatin configuration and the transcriptional activation of genes involved in cell cycle regulation (e.g., p21/WAF1), apoptosis, and differentiation [3, 4]. Furthermore, the hyperacetylation of non-histone substrates, such as p53, alpha-tubulin, and molecular chaperones, modulates various cellular signaling pathways, leading to growth arrest and cell death in malignant cells [1, 5].