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Gene Review

HDAC3  -  histone deacetylase 3

Homo sapiens

Synonyms: HD3, Histone deacetylase 3, RPD3, RPD3-2, SMAP45
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Disease relevance of HDAC3

  • Silencing of HDAC3 expression in colon cancer cell lines resulted in growth inhibition, a decrease in cell survival, and increased apoptosis [1].
  • Here we demonstrate increased protein expression of HDAC3 in human colon tumors and in duodenal adenomas from Apc1638(N/+) mice [1].
  • Comparison with gene microarray data revealed that 31% of the differentially regulated proteins correlate with altered mRNA expression in squamous cell lung carcinomas, including PEX1, MKK7 and HDAC3 for up-regulated proteins [2].
  • Antisense RNA oligonucleotides for HDAC3 enhanced apoptosis 48 h after hyperthermia at 43 degrees C for 30 min in vivo [3].
  • To further explore the catalytic activity of HDACs, we expressed two additional human class I HDACs, HDAC1 and HDAC3, in baculovirus [4].

High impact information on HDAC3

  • Here we report that HDAC3 is a critical, transcription-independent regulator of mitosis [5].
  • HDAC3 forms a complex with A-Kinase-Anchoring Proteins AKAP95 and HA95, which are targeted to mitotic chromosomes [5].
  • Early studies have suggested that HDAC3 activity is regulated by association with the corepressors N-CoR and SMRT [6].
  • Interestingly, unlike other class I HDACs, HDAC3 uniquely copurifies with the catalytic and regulatory subunits of the protein serine/threonine phosphatase 4 complex (PP4c/PP4R1) [6].
  • Here we demonstrate that, in addition to protein-protein interactions with NCoR/SMRT, the activity of HDAC3 is regulated by both phosphorylation and dephosphorylation [6].

Chemical compound and disease context of HDAC3


Biological context of HDAC3


Anatomical context of HDAC3


Associations of HDAC3 with chemical compounds


Physical interactions of HDAC3

  • Based on Western blotting using antibodies against known subunits, the only HDAC found in the N-CoR-1 complex was HDAC3 [19].
  • Here we report that HDAC3 interacts with SMRT only after priming by cellular chaperones including the TCP-1 ring complex (TRiC), which is required for proper folding of HDAC3 in an ATP-dependent process [8].
  • In an immunoaffinity purification using anti-HDAC3, transcription factor TFII-I copurified with HDAC3 [20].
  • Assembly of the SMRT-histone deacetylase 3 repression complex requires the TCP-1 ring complex [8].
  • Further investigations showed that this domain is sufficient for AR interaction and possesses the ability to bind histone deacetylase 3 [21].

Regulatory relationships of HDAC3


Other interactions of HDAC3

  • PML-RARalpha recruits MBD1 to its target promoter through an HDAC3-mediated mechanism [9].
  • GATA-2 directly associates with HDAC3 but not with HDAC1 [25].
  • This is the first demonstration that a tissue-specific transcription factor directly and selectively interacts with HDAC3 and HDAC5 among HDAC family members [25].
  • These results provide a possible molecular mechanism for HDAC3 regulation and argue that N-CoR is a platform in which distinct domains can interact with most of the known HDACs [26].
  • In addition, HDAC3 associated with the acetyltransferases p300 and p300/CBP-associated factor (PCAF) to reverse autoacetylation [11].

Analytical, diagnostic and therapeutic context of HDAC3


  1. Histone Deacetylase 3 (HDAC3) and Other Class I HDACs Regulate Colon Cell Maturation and p21 Expression and Are Deregulated in Human Colon Cancer. Wilson, A.J., Byun, D.S., Popova, N., Murray, L.B., L'italien, K., Sowa, Y., Arango, D., Velcich, A., Augenlicht, L.H., Mariadason, J.M. J. Biol. Chem. (2006) [Pubmed]
  2. Comparative application of antibody and gene array for expression profiling in human squamous cell lung carcinoma. Bartling, B., Hofmann, H.S., Boettger, T., Hansen, G., Burdach, S., Silber, R.E., Simm, A. Lung Cancer (2005) [Pubmed]
  3. Inhibition of histone deacetylase 3 stimulates apoptosis induced by heat shock under acidic conditions in human maxillary cancer. Narita, N., Fujieda, S., Tokuriki, M., Takahashi, N., Tsuzuki, H., Ohtsubo, T., Matsumoto, H. Oncogene (2005) [Pubmed]
  4. 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]
  5. A novel histone deacetylase pathway regulates mitosis by modulating Aurora B kinase activity. Li, Y., Kao, G.D., Garcia, B.A., Shabanowitz, J., Hunt, D.F., Qin, J., Phelan, C., Lazar, M.A. Genes Dev. (2006) [Pubmed]
  6. Histone deacetylase 3 (HDAC3) activity is regulated by interaction with protein serine/threonine phosphatase 4. Zhang, X., Ozawa, Y., Lee, H., Wen, Y.D., Tan, T.H., Wadzinski, B.E., Seto, E. Genes Dev. (2005) [Pubmed]
  7. Chemotherapy of Hodgkin's lymphoma with alternating cycles of COPP (cyclophosphamide, vincristin, procarbazine, prednisone) and ABVD (doxorubicin, bleomycin, vinblastine and dacarbazine). Results of the HD1 and HD3 trials of the German Hodgkin Study Group. Diehl, V., Pfreundschuh, M., Löffler, M., Rühl, U., Hiller, E., Gerhartz, H., Wilmanns, W., Kirchner, H., Schoppe, W., Petsch, S. Medical oncology and tumor pharmacotherapy. (1989) [Pubmed]
  8. Assembly of the SMRT-histone deacetylase 3 repression complex requires the TCP-1 ring complex. Guenther, M.G., Yu, J., Kao, G.D., Yen, T.J., Lazar, M.A. Genes Dev. (2002) [Pubmed]
  9. The methyl-CpG binding protein MBD1 is required for PML-RARalpha function. Villa, R., Morey, L., Raker, V.A., Buschbeck, M., Gutierrez, A., De Santis, F., Corsaro, M., Varas, F., Bossi, D., Minucci, S., Pelicci, P.G., Di Croce, L. Proc. Natl. Acad. Sci. U.S.A. (2006) [Pubmed]
  10. Characterization of a human RPD3 ortholog, HDAC3. Emiliani, S., Fischle, W., Van Lint, C., Al-Abed, Y., Verdin, E. Proc. Natl. Acad. Sci. U.S.A. (1998) [Pubmed]
  11. 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]
  12. Antibody response to a non-conserved C-terminal part of human histone deacetylase 3 in colon cancer patients. Shebzukhov, Y.V., Koroleva, E.P., Khlgatian, S.V., Belousov, P.V., Kuz'mina, K.E., Radko, B.V., Longpre, F., Lagarkova, M.A., Kadachigova, T.S., Gurova, O.V., Meshcheryakov, A.A., Lichinitser, M.R., Knuth, A., Jager, E., Kuprash, D.V., Nedospasov, S.A. Int. J. Cancer (2005) [Pubmed]
  13. A role for histone deacetylase activity in HDAC1-mediated transcriptional repression. Hassig, C.A., Tong, J.K., Fleischer, T.C., Owa, T., Grable, P.G., Ayer, D.E., Schreiber, S.L. Proc. Natl. Acad. Sci. U.S.A. (1998) [Pubmed]
  14. Histone deacetylase 3 interacts with runx2 to repress the osteocalcin promoter and regulate osteoblast differentiation. Schroeder, T.M., Kahler, R.A., Li, X., Westendorf, J.J. J. Biol. Chem. (2004) [Pubmed]
  15. Both corepressor proteins SMRT and N-CoR exist in large protein complexes containing HDAC3. Li, J., Wang, J., Wang, J., Nawaz, Z., Liu, J.M., Qin, J., Wong, J. EMBO J. (2000) [Pubmed]
  16. Cigarette smoke induces proinflammatory cytokine release by activation of NF-kappaB and posttranslational modifications of histone deacetylase in macrophages. Yang, S.R., Chida, A.S., Bauter, M.R., Shafiq, N., Seweryniak, K., Maggirwar, S.B., Kilty, I., Rahman, I. Am. J. Physiol. Lung Cell Mol. Physiol. (2006) [Pubmed]
  17. c-Jun downregulation by HDAC3-dependent transcriptional repression promotes osmotic stress-induced cell apoptosis. Xia, Y., Wang, J., Liu, T.J., Yung, W.K., Hunter, T., Lu, Z. Mol. Cell (2007) [Pubmed]
  18. IkappaB kinase alpha-mediated derepression of SMRT potentiates acetylation of RelA/p65 by p300. Hoberg, J.E., Popko, A.E., Ramsey, C.S., Mayo, M.W. Mol. Cell. Biol. (2006) [Pubmed]
  19. A novel nuclear receptor corepressor complex, N-CoR, contains components of the mammalian SWI/SNF complex and the corepressor KAP-1. Underhill, C., Qutob, M.S., Yee, S.P., Torchia, J. J. Biol. Chem. (2000) [Pubmed]
  20. Histone deacetylase 3 binds to and regulates the multifunctional transcription factor TFII-I. Wen, Y.D., Cress, W.D., Roy, A.L., Seto, E. J. Biol. Chem. (2003) [Pubmed]
  21. A central domain of cyclin D1 mediates nuclear receptor corepressor activity. Petre-Draviam, C.E., Williams, E.B., Burd, C.J., Gladden, A., Moghadam, H., Meller, J., Diehl, J.A., Knudsen, K.E. Oncogene (2005) [Pubmed]
  22. The SMRT and N-CoR corepressors are activating cofactors for histone deacetylase 3. Guenther, M.G., Barak, O., Lazar, M.A. Mol. Cell. Biol. (2001) [Pubmed]
  23. Histone deacetylase 3, a class I histone deacetylase, suppresses MAPK11-mediated activating transcription factor-2 activation and represses TNF gene expression. Mahlknecht, U., Will, J., Varin, A., Hoelzer, D., Herbein, G. J. Immunol. (2004) [Pubmed]
  24. 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]
  25. Histone deacetylase 3 associates with and represses the transcription factor GATA-2. Ozawa, Y., Towatari, M., Tsuzuki, S., Hayakawa, F., Maeda, T., Miyata, Y., Tanimoto, M., Saito, H. Blood (2001) [Pubmed]
  26. The histone deacetylase-3 complex contains nuclear receptor corepressors. Wen, Y.D., Perissi, V., Staszewski, L.M., Yang, W.M., Krones, A., Glass, C.K., Rosenfeld, M.G., Seto, E. Proc. Natl. Acad. Sci. U.S.A. (2000) [Pubmed]
  27. Cytoplasmic IkappaBalpha increases NF-kappaB-independent transcription through binding to histone deacetylase (HDAC) 1 and HDAC3. Viatour, P., Legrand-Poels, S., van Lint, C., Warnier, M., Merville, M.P., Gielen, J., Piette, J., Bours, V., Chariot, A. J. Biol. Chem. (2003) [Pubmed]
  28. Restoration of tamoxifen sensitivity in estrogen receptor-negative breast cancer cells: tamoxifen-bound reactivated ER recruits distinctive corepressor complexes. Sharma, D., Saxena, N.K., Davidson, N.E., Vertino, P.M. Cancer Res. (2006) [Pubmed]
  29. Elevated and deregulated expression of HDAC3 in human astrocytic glial tumours. Lib??, P., Kostrouchov??, M., Pohludka, M., Yilma, P., Hrabal, P., Sikora, J., Brozov??, E., Kostrouchov??, M., Rall, J.E., Kostrouch, Z. Folia Biol. (Praha) (2006) [Pubmed]
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