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Gene Review

HDAC8  -  histone deacetylase 8

Homo sapiens

Synonyms: CDA07, CDLS5, HD8, HDACL1, Histone deacetylase 8, ...
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Disease relevance of HDAC8


High impact information on HDAC8

  • RPD3 can deacetylate all histone H4 acetylation sites in cell extracts [6].
  • Here, we describe four Rpd3 derivatives with mutations in evolutionarily invariant histidine residues in a putative deacetylation motif [7].
  • In addition, structural and biochemical studies of these enzymes have focused on the histone lysine deacetylases HDAC8 and sirtuins, and on the arginine and lysine demethylases PAD and BHC110/LSD1, respectively [8].
  • Crystal structure of a eukaryotic zinc-dependent histone deacetylase, human HDAC8, complexed with a hydroxamic acid inhibitor [9].
  • However, significant differences are observed in the length and structure of the loops surrounding the active site, including the presence of two potassium ions in HDAC8 structure, one of which interacts with key catalytic residues [9].

Biological context of HDAC8

  • In contrast, mutation of Ser(39) to Glu or induction of HDAC8 phosphorylation by forskolin, a potent activator of adenyl cyclase, decreases HDAC8's enzymatic activity [10].
  • Mutation of two adjacent histidine residues within the predicted active site severely decreases activity, confirming these residues as important for HDAC8 enzyme activity [11].
  • Here we present the complete nucleotide sequence of a cDNA clone, termed HDAC8, that encodes a protein product with similarity to the RPD3 class (I) of HDACs [11].
  • Knockdown of HDAC8 by RNA interference inhibits growth of human lung, colon, and cervical cancer cell lines, highlighting the importance of this HDAC subtype for tumor cell proliferation [9].
  • Co-transfection experiments demonstrated that expression of HDAC8 repressed a viral SV40 early promoter activity [2].

Anatomical context of HDAC8

  • Unexpectedly, HDAC8, another class I HDAC, was not detected in epithelial cells but was uniquely expressed in the cytoplasm of stromal cells [12].
  • These findings were confirmed in vitro by nucleo-cytoplasmic fractionation and immunoblot experiments performed on human primary smooth muscle cells, and by the cytosolic detection of epitope-tagged HDAC8 overexpressed in fibroblasts [13].
  • Using immunohistochemistry, we unexpectedly found that, in normal human tissues, HDAC8 is exclusively expressed by cells showing smooth muscle differentiation, including visceral and vascular smooth muscle cells, myoepithelial cells, and myofibroblasts, and is mainly detected in their cytosol [13].
  • In this study, we examined HDAC8 expression in SMTs and ESTs of the uterus to determine whether HDAC8 may be a useful diagnostic tool in the classification of problematic uterine mesenchymal tumors [3].
  • Two such lines, HD6 and HD8, differentiate to 97 and 76% mucus-secreting goblet cells, respectively, in columnar monolayers in postconfluent culture [14].

Associations of HDAC8 with chemical compounds

  • Here we report that HDAC8 is phosphorylated by cyclic AMP-dependent protein kinase A (PKA) in vitro and in vivo [10].
  • After expression in two cell systems, immunopurified HDAC8 is shown to possess trichostatin A- and sodium butyrate-inhibitable HDAC activity on histone H4 peptide substrates as well as on core histones [11].
  • Here we demonstrate that histone deacetylase 8 (HDAC8) is catalytically active with a number of divalent metal ions in a 1:1 stoichiometry with the following order of specific activity: Co(II) > Fe(II) > Zn(II) > Ni(II) [15].
  • Analysis of the predicted amino acid sequence of HDAC-A revealed an open reading frame of 967 amino acids containing two domains: a NH2-terminal domain with no homology to known proteins and a COOH-terminal domain with homology to known histone deacetylases (42% similarity to RPD3, 60% similarity to HDA1) [16].

Regulatory relationships of HDAC8

  • TGF alpha induced a 2-fold increase in growth of the HD8 subline but inhibited the growth of the more differentiated HD6 subline by 40% [17].
  • Our findings reveal a novel mechanism by which HDAC8 contributes to tumorigenesis by regulating telomerase activity [18].

Other interactions of HDAC8

  • Human cells overexpressing HDAC8 localize the protein in sub-nuclear compartments whereas HDAC1 shows an even nuclear distribution [1].
  • This was specific, since HDAC1, HDAC2, and HDAC8 failed to do so [19].
  • HDAC1 protein was more abundantly expressed in SW620 cells compared with that of HDAC3 and HDAC8 [20].
  • Phosphorylated HDAC8 preferentially recruits Hsp70 to a complex that inhibits the CHIP (C-terminal heat shock protein interacting protein) E3 ligase-mediated degradation of hEST1B [18].
  • In contrast, the more differentiated HD6 cells showed an increase in 105 kDa MBP kinase activity with EGF treatment, while HD8 cells displayed constitutively elevated levels of this kinase [17].

Analytical, diagnostic and therapeutic context of HDAC8


  1. Cloning and characterization of human histone deacetylase 8. Van den Wyngaert, I., de Vries, W., Kremer, A., Neefs, J., Verhasselt, P., Luyten, W.H., Kass, S.U. FEBS Lett. (2000) [Pubmed]
  2. Cloning and characterization of a novel human class I histone deacetylase that functions as a transcription repressor. Hu, E., Chen, Z., Fredrickson, T., Zhu, Y., Kirkpatrick, R., Zhang, G.F., Johanson, K., Sung, C.M., Liu, R., Winkler, J. J. Biol. Chem. (2000) [Pubmed]
  3. Use of histone deacetylase 8 (HDAC8), a new marker of smooth muscle differentiation, in the classification of mesenchymal tumors of the uterus. de Leval, L., Waltregny, D., Boniver, J., Young, R.H., Castronovo, V., Oliva, E. Am. J. Surg. Pathol. (2006) [Pubmed]
  4. Novel smooth muscle markers reveal abnormalities of the intestinal musculature in severe colorectal motility disorders. Wedel, T., Van Eys, G.J., Waltregny, D., Glénisson, W., Castronovo, V., Vanderwinden, J.M. Neurogastroenterol. Motil. (2006) [Pubmed]
  5. A maize histone deacetylase and retinoblastoma-related protein physically interact and cooperate in repressing gene transcription. Rossi, V., Locatelli, S., Lanzanova, C., Boniotti, M.B., Varotto, S., Pipal, A., Goralik-Schramel, M., Lusser, A., Gatz, C., Gutierrez, C., Motto, M. Plant Mol. Biol. (2003) [Pubmed]
  6. Transcriptional repression by UME6 involves deacetylation of lysine 5 of histone H4 by RPD3. Rundlett, S.E., Carmen, A.A., Suka, N., Turner, B.M., Grunstein, M. Nature (1998) [Pubmed]
  7. Histone deacetylase activity of Rpd3 is important for transcriptional repression in vivo. Kadosh, D., Struhl, K. Genes Dev. (1998) [Pubmed]
  8. Structure and activity of enzymes that remove histone modifications. Holbert, M.A., Marmorstein, R. Curr. Opin. Struct. Biol. (2005) [Pubmed]
  9. Crystal structure of a eukaryotic zinc-dependent histone deacetylase, human HDAC8, complexed with a hydroxamic acid inhibitor. Vannini, A., Volpari, C., Filocamo, G., Casavola, E.C., Brunetti, M., Renzoni, D., Chakravarty, P., Paolini, C., De Francesco, R., Gallinari, P., Steinkühler, C., Di Marco, S. Proc. Natl. Acad. Sci. U.S.A. (2004) [Pubmed]
  10. Negative regulation of histone deacetylase 8 activity by cyclic AMP-dependent protein kinase A. Lee, H., Rezai-Zadeh, N., Seto, E. Mol. Cell. Biol. (2004) [Pubmed]
  11. Cloning and characterization of a novel human histone deacetylase, HDAC8. Buggy, J.J., Sideris, M.L., Mak, P., Lorimer, D.D., McIntosh, B., Clark, J.M. Biochem. J. (2000) [Pubmed]
  12. Screening of histone deacetylases (HDAC) expression in human prostate cancer reveals distinct class I HDAC profiles between epithelial and stromal cells. Waltregny, D., North, B., Van Mellaert, F., de Leval, J., Verdin, E., Castronovo, V. European journal of histochemistry : EJH. (2004) [Pubmed]
  13. Expression of histone deacetylase 8, a class I histone deacetylase, is restricted to cells showing smooth muscle differentiation in normal human tissues. Waltregny, D., De Leval, L., Glénisson, W., Ly Tran, S., North, B.J., Bellahcène, A., Weidle, U., Verdin, E., Castronovo, V. Am. J. Pathol. (2004) [Pubmed]
  14. Transforming growth factor beta 1 acts as an autocrine-negative growth regulator in colon enterocytic differentiation but not in goblet cell maturation. Hafez, M.M., Infante, D., Winawer, S., Friedman, E. Cell Growth Differ. (1990) [Pubmed]
  15. Catalytic activity and inhibition of human histone deacetylase 8 is dependent on the identity of the active site metal ion. Gantt, S.L., Gattis, S.G., Fierke, C.A. Biochemistry (2006) [Pubmed]
  16. A new family of human histone deacetylases related to Saccharomyces cerevisiae HDA1p. Fischle, W., Emiliani, S., Hendzel, M.J., Nagase, T., Nomura, N., Voelter, W., Verdin, E. J. Biol. Chem. (1999) [Pubmed]
  17. Colon goblet cells lose proliferative response to TGF alpha as they differentiate. Sauma, S., Huang, F., Winawer, S., Friedman, E. Int. J. Cancer (1995) [Pubmed]
  18. Histone deacetylase 8 safeguards the human ever-shorter telomeres 1B (hEST1B) protein from ubiquitin-mediated degradation. Lee, H., Sengupta, N., Villagra, A., Rezai-Zadeh, N., Seto, E. Mol. Cell. Biol. (2006) [Pubmed]
  19. Histone deacetylase 3 interacts with and deacetylates myocyte enhancer factor 2. Grégoire, S., Xiao, L., Nie, J., Zhang, X., Xu, M., Li, J., Wong, J., Seto, E., Yang, X.J. Mol. Cell. Biol. (2007) [Pubmed]
  20. Identification of novel isoform-selective inhibitors within class I histone deacetylases. Hu, E., Dul, E., Sung, C.M., Chen, Z., Kirkpatrick, R., Zhang, G.F., Johanson, K., Liu, R., Lago, A., Hofmann, G., Macarron, R., de los Frailes, M., Perez, P., Krawiec, J., Winkler, J., Jaye, M. J. Pharmacol. Exp. Ther. (2003) [Pubmed]
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