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Gene Review

HDAC9  -  histone deacetylase 9

Homo sapiens

Synonyms: HD7, HD7b, HD9, HDAC, HDAC7, ...
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Disease relevance of HDAC9


High impact information on HDAC9

  • We show that histone deacetylase 7 (HDAC7) is specifically expressed in the vascular endothelium during early embryogenesis, where it maintains vascular integrity by repressing the expression of matrix metalloproteinase (MMP) 10, a secreted endoproteinase that degrades the extracellular matrix [6].
  • Disruption of the HDAC7 gene in mice results in embryonic lethality due to a failure in endothelial cell-cell adhesion and consequent dilatation and rupture of blood vessels [6].
  • We present evidence that Rb forms a repressor containing histone deacetylase (HDAC) and the hSWI/SNF nucleosome remodeling complex, which inhibits transcription of genes for cyclins E and A and arrests cells in the G1 phase of the cell cycle [7].
  • Myosin phosphatase dephosphorylates HDAC7, controls its nucleocytoplasmic shuttling, and inhibits apoptosis in thymocytes [8].
  • After T-cell receptor (TCR) activation, the serine/threonine kinase PKD1 phosphorylates HDAC7, resulting in its nuclear export and the derepression of its target genes [8].

Chemical compound and disease context of HDAC9


Biological context of HDAC9

  • HDAC9 and HDAC9a contain the HDAC catalytic domain, and Flag-tagged HDAC9 and HDAC9a possess deacetylase activity [14].
  • Regulation of HDAC9 Gene Expression by MEF2 Establishes a Negative-Feedback Loop in the Transcriptional Circuitry of Muscle Differentiation [15].
  • These results suggest that HDAC9 plays a role in hematopoiesis; its deregulated expression may be associated with some human cancers [16].
  • Inappropriate or inadequate TGFbeta2 expression, together with deficient mediation of these signals at the transcription level, due to an altered HDAC9 isoforms ratio, may also lead to the observed ocular phenotype [17].
  • A candidate gene from each breakpoint was identified: on chromosome 7, histone deacetylase 9 (HDAC9), disrupted by the translocation breakpoint, and on chromosome 1, transforming growth factor-beta2 (TGFbeta2) located 500 kb proximal to the breakpoint [17].

Anatomical context of HDAC9


Associations of HDAC9 with chemical compounds


Physical interactions of HDAC9


Regulatory relationships of HDAC9

  • MEF2-interacting transcription repressor (MITR) is an amino-terminal splice variant of HDAC9 that also potently inhibits MEF2 transcriptional activity despite lacking a catalytic domain [24].
  • HDAC9 is expressed in a tissue-specific pattern that partially overlaps that of HDAC4 [16].
  • HDAC7 inhibits Nur77 expression, an orphan receptor involved in antigen-induced cell death and in negative selection [25].

Other interactions of HDAC9

  • Herein, we report the identification of a protein HDRP (HDAC-related protein) that shares 50% identity in deduced amino acid sequence to the noncatalytic N-terminal domain of HDAC4 and 5 [26].
  • The data also suggest that the promoter bound MEF2 is potentially capable of remodeling adjacent nucleosomes via the recruitment of HDAC7 [18].
  • Consequently, we show that ICP0 is able to overcome the HDAC5 amino-terminal- and MITR-induced MEF2A repression in gene reporter assays [27].
  • Both HDAC6 and HDAC9 possess unique structural modules, so they may have special biological functions [28].
  • During T cell receptor activation, HDAC7 is exported from the nucleus leading to the derepression of Nur77 expression and the induction of apoptosis [25].

Analytical, diagnostic and therapeutic context of HDAC9

  • Although only the HDAC9 gene is disrupted by the breakpoint, we consider that TGFbeta2 represents the main candidate gene in this family, which is elicited in mice by the Tgfbeta2-null status and by the TGFbeta2-induced cataractus changes in animal models [17].
  • Fluorescence in situ hybridization analysis localized the human HDAC9 gene to chromosome 7p21, a region which has been associated particularly with the pathogenesis of gynecological tumors [29].
  • Hydroxamic acid (HA)-based histone deacetylase (HDAC) inhibitors, with trichostatin A (TSA) as the reference compound, are potential antitumoral drugs and show promise in the creation of long-term primary cell cultures [30].
  • Based on the Western blot analysis, this HDAC inhibitory effect of IN-2001 was confirmed by an increase in histone H4 acetylation from the IN-2001-treated breast cancer cells [31].
  • PATIENTS AND METHODS: This analysis comprises 4,626 HL patients of all prognostic risk groups who were enrolled onto the multicenter studies HD4 to HD9 of the German Hodgkin Study Group. At 5.5 years, 2,050 female and 2,576 male patients were analyzed [32].


  1. Antitumor activity of SK-7041, a novel histone deacetylase inhibitor, in human lung and breast cancer cells. Lee, K.W., Kim, J.H., Park, J.H., Kim, H.P., Song, S.H., Kim, S.G., Kim, T.Y., Jong, H.S., Jung, K.H., Im, S.A., Kim, T.Y., Kim, N.K., Bang, Y.J. Anticancer Res. (2006) [Pubmed]
  2. Sulforaphane retards the growth of human PC-3 xenografts and inhibits HDAC activity in human subjects. Myzak, M.C., Tong, P., Dashwood, W.M., Dashwood, R.H., Ho, E. Exp. Biol. Med. (Maywood) (2007) [Pubmed]
  3. Induction of fetal hemoglobin expression by the histone deacetylase inhibitor apicidin. Witt, O., Monkemeyer, S., Rönndahl, G., Erdlenbruch, B., Reinhardt, D., Kanbach, K., Pekrun, A. Blood (2003) [Pubmed]
  4. Aggresome induction by proteasome inhibitor bortezomib and {alpha}-tubulin hyperacetylation by tubulin deacetylase (TDAC) inhibitor LBH589 are synergistic in myeloma cells. Catley, L., Weisberg, E., Kiziltepe, T., Tai, Y.T., Hideshima, T., Neri, P., Tassone, P., Atadja, P., Chauhan, D., Munshi, N.C., Anderson, K.C. Blood (2006) [Pubmed]
  5. Sequential Valproic Acid/All-trans Retinoic Acid Treatment Reprograms Differentiation in Refractory and High-Risk Acute Myeloid Leukemia. Cimino, G., Lo-Coco, F., Fenu, S., Travaglini, L., Finolezzi, E., Mancini, M., Nanni, M., Careddu, A., Fazi, F., Padula, F., Fiorini, R., Aloe Spiriti, M.A., Petti, M.C., Venditti, A., Amadori, S., Mandelli, F., Pelicci, P.G., Nervi, C. Cancer Res. (2006) [Pubmed]
  6. Histone deacetylase 7 maintains vascular integrity by repressing matrix metalloproteinase 10. Chang, S., Young, B.D., Li, S., Qi, X., Richardson, J.A., Olson, E.N. Cell (2006) [Pubmed]
  7. Exit from G1 and S phase of the cell cycle is regulated by repressor complexes containing HDAC-Rb-hSWI/SNF and Rb-hSWI/SNF. Zhang, H.S., Gavin, M., Dahiya, A., Postigo, A.A., Ma, D., Luo, R.X., Harbour, J.W., Dean, D.C. Cell (2000) [Pubmed]
  8. Myosin phosphatase dephosphorylates HDAC7, controls its nucleocytoplasmic shuttling, and inhibits apoptosis in thymocytes. Parra, M., Mahmoudi, T., Verdin, E. Genes Dev. (2007) [Pubmed]
  9. Valproic acid induces extracellular signal-regulated kinase 1/2 activation and inhibits apoptosis in endothelial cells. Michaelis, M., Suhan, T., Michaelis, U.R., Beek, K., Rothweiler, F., Tausch, L., Werz, O., Eikel, D., Zörnig, M., Nau, H., Fleming, I., Doerr, H.W., Cinatl, J. Cell Death Differ. (2006) [Pubmed]
  10. Aggresome disruption: a novel strategy to enhance bortezomib-induced apoptosis in pancreatic cancer cells. Nawrocki, S.T., Carew, J.S., Pino, M.S., Highshaw, R.A., Andtbacka, R.H., Dunner, K., Pal, A., Bornmann, W.G., Chiao, P.J., Huang, P., Xiong, H., Abbruzzese, J.L., McConkey, D.J. Cancer Res. (2006) [Pubmed]
  11. Glial cell-specific regulation of the JC virus early promoter by histone deacetylase inhibitors. Kim, S.Y., Woo, M.S., Kim, W.K., Choi, E.C., Henson, J.W., Kim, H.S. J. Virol. (2003) [Pubmed]
  12. Antitumor effects of a novel phenylbutyrate-based histone deacetylase inhibitor, (S)-HDAC-42, in prostate cancer. Kulp, S.K., Chen, C.S., Wang, D.S., Chen, C.Y., Chen, C.S. Clin. Cancer Res. (2006) [Pubmed]
  13. The effects of histone deacetylase inhibitors on the induction of differentiation in chondrosarcoma cells. Sakimura, R., Tanaka, K., Yamamoto, S., Matsunobu, T., Li, X., Hanada, M., Okada, T., Nakamura, T., Li, Y., Iwamoto, Y. Clin. Cancer Res. (2007) [Pubmed]
  14. Cloning and characterization of a histone deacetylase, HDAC9. Zhou, X., Marks, P.A., Rifkind, R.A., Richon, V.M. Proc. Natl. Acad. Sci. U.S.A. (2001) [Pubmed]
  15. Regulation of HDAC9 Gene Expression by MEF2 Establishes a Negative-Feedback Loop in the Transcriptional Circuitry of Muscle Differentiation. Haberland, M., Arnold, M.A., McAnally, J., Phan, D., Kim, Y., Olson, E.N. Mol. Cell. Biol. (2007) [Pubmed]
  16. The histone deacetylase 9 gene encodes multiple protein isoforms. Petrie, K., Guidez, F., Howell, L., Healy, L., Waxman, S., Greaves, M., Zelent, A. J. Biol. Chem. (2003) [Pubmed]
  17. Molecular characterization of a familial translocation implicates disruption of HDAC9 and possible position effect on TGFbeta2 in the pathogenesis of Peters' anomaly. David, D., Cardoso, J., Marques, B., Marques, R., Silva, E.D., Santos, H., Boavida, M.G. Genomics (2003) [Pubmed]
  18. Mechanism for nucleocytoplasmic shuttling of histone deacetylase 7. Kao, H.Y., Verdel, A., Tsai, C.C., Simon, C., Juguilon, H., Khochbin, S. J. Biol. Chem. (2001) [Pubmed]
  19. Bone morphogenetic protein-2 stimulates Runx2 acetylation. Jeon, E.J., Lee, K.Y., Choi, N.S., Lee, M.H., Kim, H.N., Jin, Y.H., Ryoo, H.M., Choi, J.Y., Yoshida, M., Nishino, N., Oh, B.C., Lee, K.S., Lee, Y.H., Bae, S.C. J. Biol. Chem. (2006) [Pubmed]
  20. Histone deacetylase 1 inactivation by an adenovirus early gene product. Chiocca, S., Kurtev, V., Colombo, R., Boggio, R., Sciurpi, M.T., Brosch, G., Seiser, C., Draetta, G.F., Cotten, M. Curr. Biol. (2002) [Pubmed]
  21. The antiepileptic and anticancer agent, valproic acid, induces P-glycoprotein in human tumour cell lines and in rat liver. Eyal, S., Lamb, J.G., Smith-Yockman, M., Yagen, B., Fibach, E., Altschuler, Y., White, H.S., Bialer, M. Br. J. Pharmacol. (2006) [Pubmed]
  22. Histone deacetylase inhibitor FK228 is a potent inducer of human fetal hemoglobin. Cao, H., Stamatoyannopoulos, G. Am. J. Hematol. (2006) [Pubmed]
  23. Neuroprotection by histone deacetylase-related protein. Morrison, B.E., Majdzadeh, N., Zhang, X., Lyles, A., Bassel-Duby, R., Olson, E.N., D'Mello, S.R. Mol. Cell. Biol. (2006) [Pubmed]
  24. Association of class II histone deacetylases with heterochromatin protein 1: potential role for histone methylation in control of muscle differentiation. Zhang, C.L., McKinsey, T.A., Olson, E.N. Mol. Cell. Biol. (2002) [Pubmed]
  25. HDAC7 regulates apoptosis in developing thymocytes. Verdin, E., Dequiedt, F., Kasler, H. Novartis Found. Symp. (2004) [Pubmed]
  26. Identification of a transcriptional repressor related to the noncatalytic domain of histone deacetylases 4 and 5. Zhou, X., Richon, V.M., Rifkind, R.A., Marks, P.A. Proc. Natl. Acad. Sci. U.S.A. (2000) [Pubmed]
  27. Functional interaction between class II histone deacetylases and ICP0 of herpes simplex virus type 1. Lomonte, P., Thomas, J., Texier, P., Caron, C., Khochbin, S., Epstein, A.L. J. Virol. (2004) [Pubmed]
  28. Class II histone deacetylases: structure, function, and regulation. Bertos, N.R., Wang, A.H., Yang, X.J. Biochem. Cell Biol. (2001) [Pubmed]
  29. Chromosomal organization and localization of the human histone deacetylase 9 gene (HDAC9). Mahlknecht, U., Schnittger, S., Will, J., Cicek, N., Hoelzer, D. Biochem. Biophys. Res. Commun. (2002) [Pubmed]
  30. A Metabolic Screening Study of Trichostatin A (TSA) and TSA-Like Histone Deacetylase Inhibitors in Rat and Human Primary Hepatocyte Cultures. Elaut, G., Laus, G., Alexandre, E., Richert, L., Bachellier, P., Tourwé, D., Rogiers, V., Vanhaecke, T. J. Pharmacol. Exp. Ther. (2007) [Pubmed]
  31. Potent in vivo anti-breast cancer activity of IN-2001, a novel inhibitor of histone deacetylase, in MMTV/c-Neu mice. Joung, K.E., Min, K.N., An, J.Y., Kim, D.K., Kong, G., Sheen, Y.Y. Cancer Res. (2006) [Pubmed]
  32. Role of hematotoxicity and sex in patients with Hodgkin's lymphoma: an analysis from the German Hodgkin Study Group. Klimm, B., Reineke, T., Haverkamp, H., Behringer, K., Eich, H.T., Josting, A., Pfistner, B., Diehl, V., Engert, A. J. Clin. Oncol. (2005) [Pubmed]
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