HDAC10 (histone deacetylase 10; HGNC:18128, NCBI Gene ID 83933) is a human locus mapped to chromosome band 22q13.33 that encodes class IIb Zn2+-dependent N8-acetylspermidine polyamine deacetylase HDAC10 (669 aa; 71 kDa; EC 3.5.1.48). HDAC10 acts in specific hydrolysis of N8-acetylspermidine to spermidine -> polyamine homeostasis, autophagosome-lysosome fusion & homologous recombination, together with HDAC6 (Sister Class IIb Two-Domain Deacetylase Gene), MYC / MYCN Oncogene Family, and Lysosome (Autophagolysosome Fusion Regulated by HDAC10). Encodes Class IIb enzyme HDAC10, which functions primarily as a cytosolic polyamine deacetylase hydrolyzing N8-acetylspermidine to regenerate spermidine.
Specific hydrolysis of N8-acetylspermidine to spermidine -> polyamine homeostasis, autophagosome-lysosome fusion & homologous recombination
Clinical / Therapeutic Role
Catalytic gatekeeper of cellular spermidine & autophagy; high expression drives chemotherapy resistance in MYCN-amplified neuroblastoma
Gene Structure & Expression
Genomic Organization & Cytogenetic Locus: 20-exon gene near the telomere of chromosome 22q13.33, closely related to Class IIb partner HDAC6; encodes a 669-amino-acid protein featuring an active N-terminal Zn2+-dependent catalytic domain (containing a negatively charged Glu272 gatekeeper residue and a sterically constricted 310-helix loop that excludes bulky protein peptides while accommodating slender linear polyamines) and a C-terminal catalytically inactive leucine-rich pseudo-deacetylase domain.
Cellular & Tissue Expression Profile: Expressed in both the cytoplasm and nucleus of hepatic hepatocytes, renal epithelium, spleen, macrophages, and neural crest-derived tumors.
Molecular Function & Pathways
Biochemical & Physiological Mechanism: Crystallographic and biochemical breakthroughs (Hai et al., 2017) proved that vertebrate HDAC10 is not a classical protein lysine deacetylase, but rather the long-sought cytosolic Polyamine Deacetylase (PDAC): its narrow negatively charged active site specifically recognizes and hydrolyzes N8-acetylspermidine (as well as acetylputrescine and N1,N8-diacetylspermidine) back into free spermidine—directly governing intracellular spermidine pools that drive eIF5A hypusination, TFEB translation, and HSP70-mediated autophagosome-lysosome fusion.
Clinical & Therapeutic Significance
Human Genetic Variants & Disease Phenotypes: Elevated HDAC10 expression in high-risk MYCN-amplified neuroblastoma and ovarian carcinoma promotes protective autophagic flux and DNA mismatch/homologous recombination repair, conferring resistance to doxorubicin and platinum chemotherapy.
Therapeutic & Clinical Pharmacology: Selective small-molecule HDAC10 polyamine-pocket inhibitors (such as DKFZ-748 and tubastatin A analogs) block autophagolysosomal fusion and sensitize refractory neuroblastoma cells to cytotoxic chemotherapy without inhibiting HDAC6 tubulin deacetylation.