Histone deacetylase, class I and IIa (HDAC Class I and IIa)

Histone deacetylases (HDACs) are a class of enzymes that remove acetyl groups from ε-N-acetyl lysine residues on histones and various non-histone proteins [2]. Class I HDACs (HDAC1, 2, 3, and 8) are primarily nuclear and ubiquitously expressed, playing a central role in cell proliferation and survival [4, 5]. Class IIa HDACs (HDAC4, 5, 7, and 9) exhibit tissue-specific expression and shuttle between the nucleus and cytoplasm, often acting as transcriptional co-repressors by recruiting Class I enzymes like HDAC3 [1, 3]. Dysregulation of these enzymes is linked to numerous pathologies, including oncogenesis, where they silence tumor suppressor genes, and inflammatory or neurodegenerative conditions [7, 12]. Therapeutic targeting with HDAC inhibitors (HDACIs) aims to restore normal acetylation patterns, thereby inducing growth arrest, differentiation, or apoptosis in malignant cells [11, 13]. While several pan-HDAC inhibitors are FDA-approved for hematological malignancies, current research focuses on isoform-selective inhibitors to improve efficacy and reduce off-target toxicities such as myelosuppression and cardiotoxicity [9, 14].

Other names

Lysine deacetylases [2, 11]KDACs [2, 8]HDACs [1, 9]

HDAC inhibitors typically act by chelating the zinc ion in the catalytic pocket of the enzyme, thereby blocking its activity [10, 14]. This inhibition prevents the removal of acetyl groups from lysine residues on histone tails, leading to hyperacetylation and a more open chromatin structure (euchromatin), which facilitates the transcription of genes such as the cyclin-dependent kinase inhibitor p21 [11, 13]. Additionally, HDACIs affect the acetylation status of non-histone proteins (e.g., p53, Hsp90, tubulin), modulating their stability, localization, and function, ultimately leading to cell cycle arrest, differentiation, and apoptosis in cancer cells [11, 14].