




Gene Review

HDAC4  -  histone deacetylase 4

Homo sapiens

Synonyms: AHO3, BDMR, HA6116, HD4, HDAC-4, ...

Disease relevance of HDAC4


High impact information on HDAC4


Chemical compound and disease context of HDAC4


Biological context of HDAC4

  • We show that HDAC4, unlike other deacetylases, shuttles between the nucleus and the cytoplasm in a process involving active nuclear export [8].
  • In the nucleus, HDAC4 associates with the myocyte enhancer factor MEF2A [8].
  • Our combined results suggest that HDAC4 is a critical component of the DNA damage response pathway that acts through 53BP1 and perhaps contributes in maintaining the G2 cell cycle checkpoint [5].
  • 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 [9].
  • Histone deacetylase 4 (HDAC4) is a class II HDAC implicated in controlling gene expression important for diverse cellular functions, but little is known about how its expression and stability are regulated [10].

Anatomical context of HDAC4

  • In the nucleus, the caspase-generated fragment of HDAC4 is able to trigger cytochrome c release from mitochondria and cell death in a caspase-9-dependent manner [11].
  • In addition, endogenous HDAC4 and at least one of its binding partners, the corepressor protein SMRT (for silencing mediator of retinoid and thyroid receptor), undergo changes in their nuclear distribution in ICP0-transfected cells [12].
  • Furthermore, the overexpression of HDAC4 inhibited cardiomyogenesis, shown by the downregulation of cardiac muscle gene expression [13].
  • Here we show that HDAC4 is cytoplasmic during myoblast differentiation, but relocates to the nucleus once fusion has occurred [14].
  • However, upon differentiation, this dynamic equilibrium is disturbed and we find that HDAC4 accumulates in the nuclei of myotubes, suggesting a positive role of nuclear HDAC4 in muscle differentiation [15].

Associations of HDAC4 with chemical compounds

  • As for nuclear export, leucine-rich sequences located in the middle part of HDAC4 do not function as nuclear export signals [16].
  • Of two potential caspase consensus motifs in HDAC4, both lying within a region containing proline-, glutamic acid-, serine-, and threonine-rich (PEST) sequences, we identified, by site-directed mutagenesis, Asp-289 as the prime cleavage site [10].
  • Cleavage of HDAC4 occurs at Asp 289 and disjoins the carboxy-terminal fragment, localized into the cytoplasm, from the amino-terminal fragment, which accumulates into the nucleus [11].
  • Here we report that serine/threonine kinases are found in association with HDAC4 and phosphorylate HDAC4 in vitro, and HDAC4 is phosphorylated in cells [17].
  • Moreover, we have found that HDAC4 interacts with the 14-3-3 family of proteins that are known to bind specifically to conserved phosphoserine-containing motifs [18].

Physical interactions of HDAC4

  • These results suggest that HDAC4 interacts with transcription factors such as MEF2C to negatively regulate gene expression [19].
  • We report that HDAC4 and MITR contain calmodulin-binding domains that overlap with their MEF2-binding domains [20].

Regulatory relationships of HDAC4

  • The results from transient transfection and co-precipitation experiments suggest that 14-3-3tau activates MEF2D by competitively inhibiting HDAC4 from binding to MEF2D and thereby affects muscle cell differentiation [21].
  • Removal of amino acids 166-289 from the caspase-cleaved fragment of HDAC4 abrogates its ability to repress MEF2 transcription and to induce cell death [11].
  • HDAC9 is expressed in a tissue-specific pattern that partially overlaps that of HDAC4 [22].
  • Furthermore, Parkin controls the intracellular levels of sumoylated HDAC4, as a result of the ubiquitination and degradation of RanBP2 [23].

Other interactions of HDAC4

  • HDAC4 and HDAC5 contain a noncatalytic N-terminal domain [9].
  • The nuclear localization domain of the MEF2 family of transcription factors shows member-specific features and mediates the nuclear import of histone deacetylase 4 [24].
  • HDAC1 and 3 siRNA produced a concentration-dependent inhibition of HeLa cell proliferation; whereas, HDAC4 and 7 siRNA showed no effect [25].
  • The caspase-cleaved amino-terminal fragment of HDAC4 acts as a strong repressor of the transcription factor MEF2C, independently from the HDAC domain [11].
  • In vitro biochemical studies showed that recombinant HDAC6, but not HDAC4, bound directly to the protein phosphatase (PP)1 catalytic subunit [26].

Analytical, diagnostic and therapeutic context of HDAC4


  1. Nuclear accumulation of histone deacetylase 4 (HDAC4) coincides with the loss of androgen sensitivity in hormone refractory cancer of the prostate. Halkidou, K., Cook, S., Leung, H.Y., Neal, D.E., Robson, C.N. Eur. Urol. (2004) [Pubmed]
  3. CaM kinase II selectively signals to histone deacetylase 4 during cardiomyocyte hypertrophy. Backs, J., Song, K., Bezprozvannaya, S., Chang, S., Olson, E.N. J. Clin. Invest. (2006) [Pubmed]
  4. Recruitment of histone deacetylase 4 to the N-terminal region of estrogen receptor alpha. Leong, H., Sloan, J.R., Nash, P.D., Greene, G.L. Mol. Endocrinol. (2005) [Pubmed]
  5. Histone deacetylase 4 interacts with 53BP1 to mediate the DNA damage response. Kao, G.D., McKenna, W.G., Guenther, M.G., Muschel, R.J., Lazar, M.A., Yen, T.J. J. Cell Biol. (2003) [Pubmed]
  6. HD4, a 180 kDa bullous pemphigoid antigen, is a major transmembrane glycoprotein of the hemidesmosome. Nishizawa, Y., Uematsu, J., Owaribe, K. J. Biochem. (1993) [Pubmed]
  7. The ability of "low G + C gram-positive" ruminal bacteria to resist monensin and counteract potassium depletion. Callaway, T.R., Adams, K.A., Russell, J.B. Curr. Microbiol. (1999) [Pubmed]
  8. HDAC4 deacetylase associates with and represses the MEF2 transcription factor. Miska, E.A., Karlsson, C., Langley, E., Nielsen, S.J., Pines, J., Kouzarides, T. EMBO J. (1999) [Pubmed]
  9. 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]
  10. Caspase-mediated specific cleavage of human histone deacetylase 4. Liu, F., Dowling, M., Yang, X.J., Kao, G.D. J. Biol. Chem. (2004) [Pubmed]
  11. Caspase-dependent regulation of histone deacetylase 4 nuclear-cytoplasmic shuttling promotes apoptosis. Paroni, G., Mizzau, M., Henderson, C., Del Sal, G., Schneider, C., Brancolini, C. Mol. Biol. Cell (2004) [Pubmed]
  12. 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]
  13. HDAC activity regulates entry of mesoderm cells into the cardiac muscle lineage. Karamboulas, C., Swedani, A., Ward, C., Al-Madhoun, A.S., Wilton, S., Boisvenue, S., Ridgeway, A.G., Skerjanc, I.S. J. Cell. Sci. (2006) [Pubmed]
  14. Differential localization of HDAC4 orchestrates muscle differentiation. Miska, E.A., Langley, E., Wolf, D., Karlsson, C., Pines, J., Kouzarides, T. Nucleic Acids Res. (2001) [Pubmed]
  15. The modular nature of histone deacetylase HDAC4 confers phosphorylation-dependent intracellular trafficking. Zhao, X., Ito, A., Kane, C.D., Liao, T.S., Bolger, T.A., Lemrow, S.M., Means, A.R., Yao, T.P. J. Biol. Chem. (2001) [Pubmed]
  16. Histone deacetylase 4 possesses intrinsic nuclear import and export signals. Wang, A.H., Yang, X.J. Mol. Cell. Biol. (2001) [Pubmed]
  17. Histone deacetylase 4 associates with extracellular signal-regulated kinases 1 and 2, and its cellular localization is regulated by oncogenic Ras. Zhou, X., Richon, V.M., Wang, A.H., Yang, X.J., Rifkind, R.A., Marks, P.A. Proc. Natl. Acad. Sci. U.S.A. (2000) [Pubmed]
  18. Regulation of histone deacetylase 4 by binding of 14-3-3 proteins. Wang, A.H., Kruhlak, M.J., Wu, J., Bertos, N.R., Vezmar, M., Posner, B.I., Bazett-Jones, D.P., Yang, X.J. Mol. Cell. Biol. (2000) [Pubmed]
  19. HDAC4, a human histone deacetylase related to yeast HDA1, is a transcriptional corepressor. Wang, A.H., Bertos, N.R., Vezmar, M., Pelletier, N., Crosato, M., Heng, H.H., Th'ng, J., Han, J., Yang, X.J. Mol. Cell. Biol. (1999) [Pubmed]
  20. Calcium regulates transcriptional repression of myocyte enhancer factor 2 by histone deacetylase 4. Youn, H.D., Grozinger, C.M., Liu, J.O. J. Biol. Chem. (2000) [Pubmed]
  21. 14-3-3tau associates with and activates the MEF2D transcription factor during muscle cell differentiation. Choi, S.J., Park, S.Y., Han, T.H. Nucleic Acids Res. (2001) [Pubmed]
  22. 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]
  23. Parkin ubiquitinates and promotes the degradation of RanBP2. Um, J.W., Min, d.o. .S., Rhim, H., Kim, J., Paik, S.R., Chung, K.C. J. Biol. Chem. (2006) [Pubmed]
  24. The nuclear localization domain of the MEF2 family of transcription factors shows member-specific features and mediates the nuclear import of histone deacetylase 4. Borghi, S., Molinari, S., Razzini, G., Parise, F., Battini, R., Ferrari, S. J. Cell. Sci. (2001) [Pubmed]
  25. Role of class I and class II histone deacetylases in carcinoma cells using siRNA. Glaser, K.B., Li, J., Staver, M.J., Wei, R.Q., Albert, D.H., Davidsen, S.K. Biochem. Biophys. Res. Commun. (2003) [Pubmed]
  26. 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]
  27. Regulation of histone deacetylase 4 and 5 and transcriptional activity by 14-3-3-dependent cellular localization. Grozinger, C.M., Schreiber, S.L. Proc. Natl. Acad. Sci. U.S.A. (2000) [Pubmed]
  28. Evidence for a reduced transcriptional state during hibernation in ground squirrels. Morin, P., Storey, K.B. Cryobiology (2006) [Pubmed]
  29. Assignment of the human histone deacetylase 4 gene (HDAC4) to chromosome 2q37.2 by in situ hybridization. Mahlknecht, U., Schnittger, S., Hoelzer, D. Cytogenet. Cell Genet. (2001) [Pubmed]
  30. 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]
  31. Is the international prognostic score for advanced stage Hodgkin's disease applicable to early stage patients? German Hodgkin Lymphoma Study Group. Franklin, J., Paulus, U., Lieberz, D., Breuer, K., Tesch, H., Diehl, V. Ann. Oncol. (2000) [Pubmed]
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