Class II and IV histone deacetylases (Class II/IV HDACs)

Class II and IV histone deacetylases (HDACs) are a subset of the zinc-dependent classical HDAC family, comprising isoforms HDAC4, 5, 7, and 9 (Class IIa), HDAC6 and 10 (Class IIb), and HDAC11 (Class IV) [1, 2]. Unlike Class I HDACs, which are primarily nuclear and ubiquitously expressed, Class II and IV enzymes exhibit tissue-specific expression and frequently shuttle between the nucleus and cytoplasm to deacetylate both histones and non-histone proteins, such as alpha-tubulin and Hsp90 [1, 3]. These enzymes play critical roles in diverse physiological processes, including muscle differentiation, cardiac development, and the regulation of immune cell signaling, notably through the HDAC11-mediated repression of the anti-inflammatory cytokine IL-10 [3, 4]. In pathological contexts, Class II and IV HDACs are often dysregulated, contributing to the progression of various cancers, neurodegenerative disorders like Parkinson's disease, and chronic inflammatory conditions [1, 5]. Therapeutic targeting of these classes involves both pan-HDAC inhibitors and isoform-selective agents, such as ricolinostat (HDAC6-selective), which aim to leverage their specific roles in disease while minimizing systemic toxicities like thrombocytopenia and cardiotoxicity [4, 6]. Sources: [1] https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3433950/ [2] https://www.uniprot.org/ [3] https://pubmed.ncbi.nlm.nih.gov/22449854/ [4] https://www.ncbi.nlm.nih.gov/books/NBK560560/ [5] https://www.nature.com/articles/nrd1975 [6] https://www.fda.gov/drugs/information-on-drugs/approved-drugs

Other names

Class II and IV Histone DeacetylasesZn2+-dependent HDACs (Classes II and IV)Hda1-like and Hos3-like HDACsHDAC4, HDAC5, HDAC6, HDAC7, HDAC9, HDAC10, and HDAC11

Inhibition of the zinc-dependent catalytic site of Class II and IV histone deacetylases, preventing the removal of acetyl groups from lysine residues on histones and non-histone proteins. This leads to hyperacetylation, which alters chromatin structure to promote gene transcription (e.g., p21) or modulates the function of cytoplasmic proteins (e.g., tubulin, Hsp90), ultimately inducing cell cycle arrest, apoptosis, and anti-inflammatory effects [1, 4, 5].