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Gene Review

HDAC6  -  histone deacetylase 6

Homo sapiens

Synonyms: CPBHM, FLJ16239, HD6, Histone deacetylase 6, JM21, ...
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Disease relevance of HDAC6


Psychiatry related information on HDAC6


High impact information on HDAC6

  • The deacetylase HDAC6 regulates aggresome formation and cell viability in response to misfolded protein stress [7].
  • Our results show that HDAC6 is the tubulin deacetylase, and provide evidence that reversible acetylation regulates important biological processes beyond histone metabolism and gene transcription [8].
  • Furthermore, overexpression of HDAC6 promotes chemotactic cell movement, supporting the idea that HDAC6-mediated deacetylation regulates microtubule-dependent cell motility [8].
  • Overexpression of HDAC6 but not a dead deacetylase mutant in T cells disorganized CD3 and LFA-1 at the immune synapse [9].
  • HDAC6 deacetylase activity links the tubulin cytoskeleton with immune synapse organization [9].

Chemical compound and disease context of HDAC6


Biological context of HDAC6

  • Interestingly, HDAC6 contains an internal duplication of two catalytic domains, which appear to function independently of each other [10].
  • Although the PAZ domain possesses homology with the zinc finger of deubiquitinating enzymes, it is dispensable for the deubiquitinating activity we find associated with HDAC6 following immunopurification [11].
  • Virus replication is enhanced in HDAC6-depleted cells, demonstrating HDAC6 is an essential component of innate antiviral immunity [12].
  • Trapoxin B, a weak HDAC6 inhibitor, and calyculin A, a cell-permeable phosphatase inhibitor, had no effect on the stability of the HDAC6.PP1 complexes or on tubulin acetylation [13].
  • Cell motility was increased to the same degree by stably transfecting the HDAC6 expression vector into MCF-7 cells [1].

Anatomical context of HDAC6

  • HDAC6 also colocalized and coimmunoprecipitated with the nuclear matrix-associated protein Runx2 in osteoblasts [14].
  • HDAC6 overexpression disrupted the localization of p58, a protein that mediates binding of Golgi elements to microtubules [15].
  • We show that ATG proteins, molecular determinants of autophagic vacuole formation, and lysosomes are recruited to pericentriolar cytoplasmic inclusion bodies by a process requiring an intact microtubule cytoskeleton and the cytoplasmic deacetylase HDAC6 [16].
  • Specific HDAC6 staining was found in the nucleus of some normal epithelial cells and in the cytoplasm of the majority of cancer cells [17].
  • By contrast, no relationship was found between HDAC6 mRNA expression and any of the other clinicopathologic factors, namely, age, menopausal status, and axillary lymph node involvement [17].

Associations of HDAC6 with chemical compounds

  • HDAC6, which is insensitive to trapoxin B, specifically interacted with the carboxy terminus of Runx2 [14].
  • PP1 binding was mapped to the second catalytic domain and adjacent C-terminal sequences in HDAC6, and treatment of cells with trichostatin A (TSA) disrupted endogenous HDAC6.PP1 complexes [13].
  • These results indicate the biological significance of HDAC6 regulation via estrogen signaling [1].
  • Our findings reveal that HDAC6 inhibition and acetylation at lysine 40 of alpha-tubulin may be therapeutic targets of interest in disorders such as HD in which intracellular transport is altered [6].
  • To prove this hypothesis, we used bortezomib and tubacin to inhibit the proteasome and HDAC6, respectively [18].

Physical interactions of HDAC6

  • Depletion of HDAC6 levels also inhibited the binding of HSP90 to ATP, reduced the chaperone association of HSP90 with its client proteins, e.g. Bcr-Abl, and induced polyubiquitylation and partial depletion of Bcr-Abl [19].

Co-localisations of HDAC6

  • SIRT2 colocalizes and interacts in vivo with HDAC6, another tubulin deacetylase [20].

Regulatory relationships of HDAC6

  • Either the selective estrogen receptor modulator tamoxifen (TAM) or the pure antiestrogen ICI 182,780 prevented estradiol-induced HDAC6 accumulation and deacetylation of alpha-tubulin, leading to reduced cell motility [1].
  • 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% [21].
  • We showed that TGF-beta1-induced EMT is accompanied by HDAC6-dependent deacetylation of alpha-tubulin [22].

Other interactions of HDAC6

  • HDAC10 was classified as a class II subfamily member based upon similarity to HDAC6 [23].
  • In vitro biochemical studies showed that recombinant HDAC6, but not HDAC4, bound directly to the protein phosphatase (PP)1 catalytic subunit [13].
  • Complexes shown to contain HDAC1, HDAC3, HDAC6, and HDAC1+2 as their catalytic subunits have been used in an antibody-based assay that detects deacetylation of whole histones at defined lysines [24].
  • Both HDAC6 and HDAC9 possess unique structural modules, so they may have special biological functions [25].
  • Only SIRT1 was consistently overexpressed (>2 fold) in AML samples compared with all controls, while HDAC6 was overexpressed relative to adult, but not neo-natal cells [26].

Analytical, diagnostic and therapeutic context of HDAC6


  1. Significance of HDAC6 regulation via estrogen signaling for cell motility and prognosis in estrogen receptor-positive breast cancer. Saji, S., Kawakami, M., Hayashi, S., Yoshida, N., Hirose, M., Horiguchi, S., Itoh, A., Funata, N., Schreiber, S.L., Yoshida, M., Toi, M. Oncogene (2005) [Pubmed]
  2. Histone deacetylase 6 regulates human immunodeficiency virus type 1 infection. Valenzuela-Fernández, A., Alvarez, S., Gordon-Alonso, M., Barrero, M., Ursa, A., Cabrero, J.R., Fernández, G., Naranjo-Suárez, S., Yáñez-Mo, M., Serrador, J.M., Muñoz-Fernández, M.A., Sánchez-Madrid, F. Mol. Biol. Cell (2005) [Pubmed]
  3. Aberrant expression of histone deacetylase 6 in oral squamous cell carcinoma. Sakuma, T., Uzawa, K., Onda, T., Shiiba, M., Yokoe, H., Shibahara, T., Tanzawa, H. Int. J. Oncol. (2006) [Pubmed]
  4. Low acute hematological toxicity during chemotherapy predicts reduced disease control in advanced Hodgkin's disease. Brosteanu, O., Hasenclever, D., Loeffler, M., Diehl, V. Ann. Hematol. (2004) [Pubmed]
  5. Ubiquitin proteasome system stress underlies synergistic killing of ovarian cancer cells by bortezomib and a novel HDAC6 inhibitor. Bazzaro, M., Lin, Z., Santillan, A., Lee, M.K., Wang, M.C., Chan, K.C., Bristow, R.E., Mazitschek, R., Bradner, J., Roden, R.B. Clin. Cancer Res. (2008) [Pubmed]
  6. Histone deacetylase 6 inhibition compensates for the transport deficit in Huntington's disease by increasing tubulin acetylation. Dompierre, J.P., Godin, J.D., Charrin, B.C., Cordelières, F.P., King, S.J., Humbert, S., Saudou, F. J. Neurosci. (2007) [Pubmed]
  7. The deacetylase HDAC6 regulates aggresome formation and cell viability in response to misfolded protein stress. Kawaguchi, Y., Kovacs, J.J., McLaurin, A., Vance, J.M., Ito, A., Yao, T.P. Cell (2003) [Pubmed]
  8. HDAC6 is a microtubule-associated deacetylase. Hubbert, C., Guardiola, A., Shao, R., Kawaguchi, Y., Ito, A., Nixon, A., Yoshida, M., Wang, X.F., Yao, T.P. Nature (2002) [Pubmed]
  9. HDAC6 deacetylase activity links the tubulin cytoskeleton with immune synapse organization. Serrador, J.M., Cabrero, J.R., Sancho, D., Mittelbrunn, M., Urzainqui, A., Sánchez-Madrid, F. Immunity (2004) [Pubmed]
  10. Three proteins define a class of human histone deacetylases related to yeast Hda1p. Grozinger, C.M., Hassig, C.A., Schreiber, S.L. Proc. Natl. Acad. Sci. U.S.A. (1999) [Pubmed]
  11. Histone deacetylase 6 binds polyubiquitin through its zinc finger (PAZ domain) and copurifies with deubiquitinating enzymes. Hook, S.S., Orian, A., Cowley, S.M., Eisenman, R.N. Proc. Natl. Acad. Sci. U.S.A. (2002) [Pubmed]
  12. Positive and negative regulation of the innate antiviral response and beta interferon gene expression by deacetylation. Nusinzon, I., Horvath, C.M. Mol. Cell. Biol. (2006) [Pubmed]
  13. Deactylase inhibitors disrupt cellular complexes containing protein phosphatases and deacetylases. Brush, M.H., Guardiola, A., Connor, J.H., Yao, T.P., Shenolikar, S. J. Biol. Chem. (2004) [Pubmed]
  14. Runx2 (Cbfa1, AML-3) interacts with histone deacetylase 6 and represses the p21(CIP1/WAF1) promoter. Westendorf, J.J., Zaidi, S.K., Cascino, J.E., Kahler, R., van Wijnen, A.J., Lian, J.B., Yoshida, M., Stein, G.S., Li, X. Mol. Cell. Biol. (2002) [Pubmed]
  15. Domain-selective small-molecule inhibitor of histone deacetylase 6 (HDAC6)-mediated tubulin deacetylation. Haggarty, S.J., Koeller, K.M., Wong, J.C., Grozinger, C.M., Schreiber, S.L. Proc. Natl. Acad. Sci. U.S.A. (2003) [Pubmed]
  16. HDAC6 and microtubules are required for autophagic degradation of aggregated huntingtin. Iwata, A., Riley, B.E., Johnston, J.A., Kopito, R.R. J. Biol. Chem. (2005) [Pubmed]
  17. HDAC6 expression is correlated with better survival in breast cancer. Zhang, Z., Yamashita, H., Toyama, T., Sugiura, H., Omoto, Y., Ando, Y., Mita, K., Hamaguchi, M., Hayashi, S., Iwase, H. Clin. Cancer Res. (2004) [Pubmed]
  18. Small-molecule inhibition of proteasome and aggresome function induces synergistic antitumor activity in multiple myeloma. Hideshima, T., Bradner, J.E., Wong, J., Chauhan, D., Richardson, P., Schreiber, S.L., Anderson, K.C. Proc. Natl. Acad. Sci. U.S.A. (2005) [Pubmed]
  19. Inhibition of histone deacetylase 6 acetylates and disrupts the chaperone function of heat shock protein 90: a novel basis for antileukemia activity of histone deacetylase inhibitors. Bali, P., Pranpat, M., Bradner, J., Balasis, M., Fiskus, W., Guo, F., Rocha, K., Kumaraswamy, S., Boyapalle, S., Atadja, P., Seto, E., Bhalla, K. J. Biol. Chem. (2005) [Pubmed]
  20. The human Sir2 ortholog, SIRT2, is an NAD+-dependent tubulin deacetylase. North, B.J., Marshall, B.L., Borra, M.T., Denu, J.M., Verdin, E. Mol. Cell (2003) [Pubmed]
  21. 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]
  22. Requirement of HDAC6 for transforming growth factor-beta1-induced epithelial-mesenchymal transition. Shan, B., Yao, T.P., Nguyen, H.T., Zhuo, Y., Levy, D.R., Klingsberg, R.C., Tao, H., Palmer, M.L., Holder, K.N., Lasky, J.A. J. Biol. Chem. (2008) [Pubmed]
  23. Isolation and characterization of a novel class II histone deacetylase, HDAC10. Fischer, D.D., Cai, R., Bhatia, U., Asselbergs, F.A., Song, C., Terry, R., Trogani, N., Widmer, R., Atadja, P., Cohen, D. J. Biol. Chem. (2002) [Pubmed]
  24. Human class I histone deacetylase complexes show enhanced catalytic activity in the presence of ATP and co-immunoprecipitate with the ATP-dependent chaperone protein Hsp70. Johnson, C.A., White, D.A., Lavender, J.S., O'Neill, L.P., Turner, B.M. J. Biol. Chem. (2002) [Pubmed]
  25. Class II histone deacetylases: structure, function, and regulation. Bertos, N.R., Wang, A.H., Yang, X.J. Biochem. Cell Biol. (2001) [Pubmed]
  26. Histone deacetylases in acute myeloid leukaemia show a distinctive pattern of expression that changes selectively in response to deacetylase inhibitors. Bradbury, C.A., Khanim, F.L., Hayden, R., Bunce, C.M., White, D.A., Drayson, M.T., Craddock, C., Turner, B.M. Leukemia (2005) [Pubmed]
  27. Cloning and structural characterization of the human histone deacetylase 6 gene. Voelter-Mahlknecht, S., Mahlknecht, U. Int. J. Mol. Med. (2003) [Pubmed]
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