HDAC8 (Histone Deacetylase 8 Class I Cohesin SMC3 Deacetylase & Cornelia de Lange Gene)
HDAC8 (histone deacetylase 8; HGNC:13315, NCBI Gene ID 55869) is a human locus mapped to chromosome band Xq13.1 that encodes monomeric Class I Zn2+-dependent protein deacetylase & long-chain deacylase HDAC8 (377 aa; 42 kDa; EC 3.5.1.98). HDAC8 acts in deacetylation of cohesin subunit SMC3 for sister-chromatid recycling, p53 regulation & smooth muscle alpha-actin contractility, together with HDAC1 (Class I Paralog Gene), HDAC2 (Class I Paralog Gene), and HDAC3 (Class I Paralog Gene). Encodes the monomeric X-linked Class I deacetylase HDAC8 that recycles the chromosomal cohesin complex subunit SMC3; mutated in Cornelia de Lange syndrome.
Approved Symbol
HDAC8
Chromosomal Locus
Xq13.1
Encoded Product
Monomeric Class I Zn2+-dependent protein deacetylase & long-chain deacylase HDAC8 (377 aa; 42 kDa; EC 3.5.1.98)
Primary Pathway
Deacetylation of cohesin subunit SMC3 for sister-chromatid recycling, p53 regulation & smooth muscle alpha-actin contractility
Clinical / Therapeutic Role
Loss-of-function mutations cause X-linked Cornelia de Lange Syndrome Type 5 (CdLS5); selective target of PCI-34051 in neuroblastoma & T-cell lymphoma
Gene Structure & Expression
Genomic Organization & Cytogenetic Locus: 11-exon X-linked gene at chromosome Xq13.1 encoding the smallest Class I deacetylase (377 amino acids), which lacks the C-terminal protein-complex-binding extension of HDAC1/2/3 and therefore functions as a self-sufficient monomer in both nucleus and cytoplasm with a flexible L1 active-site loop darkened by PKA phosphorylation at Ser39.
Cellular & Tissue Expression Profile: Expressed in the nucleus of dividing cells across all tissues and in the cytoplasm of visceral and vascular smooth muscle cells (where it colocalizes with alpha-smooth muscle actin and cortactin) and neural crest progenitors.
Molecular Function & Pathways
Biochemical & Physiological Mechanism: Its primary non-histone nuclear substrate is the Structural Maintenance of Chromosomes 3 (SMC3) subunit of the ring-shaped Cohesin complex: during S phase, ESCO1/2 acetyltransferases acetylate SMC3 at Lys105 and Lys106 to lock the cohesin ring around replicated sister chromatids and mediate enhancer-promoter chromatin looping; after anaphase chromosome segregation, HDAC8 must deacetylate displaced SMC3 so the cohesin complex can be recycled for the next cell division.
Clinical & Therapeutic Significance
Human Genetic Variants & Disease Phenotypes: Hemizygous or heterozygous loss-of-function missense mutations in HDAC8 cause X-linked Cornelia de Lange Syndrome Type 5 (CdLS5), a multisystem cohesinopathy characterized by distinctive facial dysmorphism (synophrys, long eyelashes), prenatal/postnatal growth retardation, upper-limb reduction defects, and intellectual disability due to failure of SMC3 deacetylation and cohesin recycling at developmental enhancers.
Therapeutic & Clinical Pharmacology: Because high-risk MYCN-amplified neuroblastomas and T-cell lymphomas overexpress HDAC8 to suppress p53 and differentiation, the conformational flexibility of the HDAC8 L1 pocket has enabled design of highly selective ortho-aryl-N-hydroxycinnamide inhibitors (such as PCI-34051) that spare HDAC1/2/3 hematologic toxicity.