Histone deacetylase 5 explained

Histone deacetylase 5 is an enzyme that in humans is encoded by the HDAC5 gene.^{[1] [2] [3]}

Function

Histones play a critical role in transcriptional regulation, cell cycle progression, and developmental events. Histone acetylation/deacetylation alters chromosome structure and affects transcription factor access to DNA. The protein encoded by this gene belongs to the class II histone deacetylase/acuc/apha family. It possesses histone deacetylase activity and represses transcription when tethered to a promoter. It coimmunoprecipitates only with HDAC3 family member and might form multicomplex proteins. It also interacts with myocyte enhancer factor-2 (MEF2) proteins, resulting in repression of MEF2-dependent genes. This gene is thought to be associated with colon cancer. Two transcript variants encoding different isoforms have been found for this gene.^[3]

AMP-activated protein kinase regulation of the glucose transporter GLUT4 occurs by phosphorylation of HDAC5.^[4]

HDAC5 is involved in memory consolidation and suggests that development of more selective HDAC inhibitors for the treatment of Alzheimer's disease should avoid targeting HDAC5.^[5] Its function can be effectively examined by siRNA knockdown based on an independent validation.^[6]

HDAC5 overexpression in urothelial carcinoma cell lines inhibits long-term proliferation but can promote epithelial-to-mesenchymal transition (EMT)^[7]

Interactions

Histone deacetylase 5 has been shown to interact with:

• BCL6,
• CBX5,^[8]
• GATA1,^[9]
• HDAC3,^{[10] [11]}
• IKZF1,^[12]
• MEF2A,^[13]
• NRIP1,^[14]
• NCOR1,^{[15] [16]}
• NCOR2,^[16]
• YWHAQ,^[17] and
• ZBTB16.^{[18] [19]}

See also

• Histone deacetylase

Further reading

• Verdin E, Dequiedt F, Kasler HG . Class II histone deacetylases: versatile regulators . Trends in Genetics . 19 . 5 . 286–93 . May 2003 . 12711221 . 10.1016/S0168-9525(03)00073-8 . 2268/80861 .
• Huang EY, Zhang J, Miska EA, Guenther MG, Kouzarides T, Lazar MA . Nuclear receptor corepressors partner with class II histone deacetylases in a Sin3-independent repression pathway . Genes & Development . 14 . 1 . 45–54 . January 2000 . 10.1101/gad.14.1.45 . 10640275 . 316335 .
• Lemercier C, Verdel A, Galloo B, Curtet S, Brocard MP, Khochbin S . mHDA1/HDAC5 histone deacetylase interacts with and represses MEF2A transcriptional activity . The Journal of Biological Chemistry . 275 . 20 . 15594–9 . May 2000 . 10748098 . 10.1074/jbc.M908437199 . free .
• Grozinger CM, Schreiber SL . Regulation of histone deacetylase 4 and 5 and transcriptional activity by 14-3-3-dependent cellular localization . Proceedings of the National Academy of Sciences of the United States of America . 97 . 14 . 7835–40 . July 2000 . 10869435 . 16631 . 10.1073/pnas.140199597 . 2000PNAS...97.7835G . free .
• Huynh KD, Fischle W, Verdin E, Bardwell VJ . BCoR, a novel corepressor involved in BCL-6 repression . Genes & Development . 14 . 14 . 1810–23 . July 2000 . 10898795 . 316791 . 10.1101/gad.14.14.1810 .
• Mahlknecht U, Schnittger S, Ottmann OG, Schoch C, Mosebach M, Hiddemann W, Hoelzer D . Chromosomal organization and localization of the human histone deacetylase 5 gene (HDAC5) . Biochimica et Biophysica Acta (BBA) - Gene Structure and Expression . 1493 . 3 . 342–8 . October 2000 . 11018260 . 10.1016/S0167-4781(00)00191-3 . Mahlknecht U .
• Zhang CL, McKinsey TA, Lu JR, Olson EN . Association of COOH-terminal-binding protein (CtBP) and MEF2-interacting transcription repressor (MITR) contributes to transcriptional repression of the MEF2 transcription factor . The Journal of Biological Chemistry . 276 . 1 . 35–9 . January 2001 . 11022042 . 10.1074/jbc.M007364200 . free .
• McKinsey TA, Zhang CL, Lu J, Olson EN . Signal-dependent nuclear export of a histone deacetylase regulates muscle differentiation . Nature . 408 . 6808 . 106–11 . November 2000 . 11081517 . 4459600 . 10.1038/35040593 . 2000Natur.408..106M .
• McKinsey TA, Zhang CL, Olson EN . Activation of the myocyte enhancer factor-2 transcription factor by calcium/calmodulin-dependent protein kinase-stimulated binding of 14-3-3 to histone deacetylase 5 . Proceedings of the National Academy of Sciences of the United States of America . 97 . 26 . 14400–5 . December 2000 . 11114197 . 18930 . 10.1073/pnas.260501497 . 2000PNAS...9714400M . free .
• Fischle W, Dequiedt F, Fillion M, Hendzel MJ, Voelter W, Verdin E . Human HDAC7 histone deacetylase activity is associated with HDAC3 in vivo . The Journal of Biological Chemistry . 276 . 38 . 35826–35 . September 2001 . 11466315 . 10.1074/jbc.M104935200 . free .
• McKinsey TA, Zhang CL, Olson EN . Identification of a signal-responsive nuclear export sequence in class II histone deacetylases . Molecular and Cellular Biology . 21 . 18 . 6312–21 . September 2001 . 11509672 . 87361 . 10.1128/MCB.21.18.6312-6321.2001 .
• Ozawa Y, Towatari M, Tsuzuki S, Hayakawa F, Maeda T, Miyata Y, Tanimoto M, Saito H . 6 . Histone deacetylase 3 associates with and represses the transcription factor GATA-2 . Blood . 98 . 7 . 2116–23 . October 2001 . 11567998 . 10.1182/blood.V98.7.2116 .
• Potter GB, Beaudoin GM, DeRenzo CL, Zarach JM, Chen SH, Thompson CC . The hairless gene mutated in congenital hair loss disorders encodes a novel nuclear receptor corepressor . Genes & Development . 15 . 20 . 2687–701 . October 2001 . 11641275 . 312820 . 10.1101/gad.916701 .
• Fischle W, Dequiedt F, Hendzel MJ, Guenther MG, Lazar MA, Voelter W, Verdin E . Enzymatic activity associated with class II HDACs is dependent on a multiprotein complex containing HDAC3 and SMRT/N-CoR . Molecular Cell . 9 . 1 . 45–57 . January 2002 . 11804585 . 10.1016/S1097-2765(01)00429-4 . free . 11858/00-001M-0000-002C-9FF9-9 .
• Lemercier C, Brocard MP, Puvion-Dutilleul F, Kao HY, Albagli O, Khochbin S . Class II histone deacetylases are directly recruited by BCL6 transcriptional repressor . The Journal of Biological Chemistry . 277 . 24 . 22045–52 . June 2002 . 11929873 . 10.1074/jbc.M201736200 . free .
• Huang Y, Tan M, Gosink M, Wang KK, Sun Y . Histone deacetylase 5 is not a p53 target gene, but its overexpression inhibits tumor cell growth and induces apoptosis . Cancer Research . 62 . 10 . 2913–22 . May 2002 . 12019172 .

Notes and References

1. Grozinger CM, Hassig CA, Schreiber SL . Three proteins define a class of human histone deacetylases related to yeast Hda1p . Proceedings of the National Academy of Sciences of the United States of America . 96 . 9 . 4868–73 . April 1999 . 10220385 . 21783 . 10.1073/pnas.96.9.4868 . 1999PNAS...96.4868G . free .
2. Scanlan MJ, Chen YT, Williamson B, Gure AO, Stockert E, Gordan JD, Türeci O, Sahin U, Pfreundschuh M, Old LJ . 6 . Characterization of human colon cancer antigens recognized by autologous antibodies . International Journal of Cancer . 76 . 5 . 652–8 . May 1998 . 9610721 . 10.1002/(SICI)1097-0215(19980529)76:5<652::AID-IJC7>3.0.CO;2-P . 916155 .
3. Web site: Entrez Gene: HDAC5 histone deacetylase 5.
4. McGee SL, van Denderen BJ, Howlett KF, Mollica J, Schertzer JD, Kemp BE, Hargreaves M . AMP-activated protein kinase regulates GLUT4 transcription by phosphorylating histone deacetylase 5 . Diabetes . 57 . 4 . 860–7 . April 2008 . 18184930 . 10.2337/db07-0843 . 17274354 . free .
5. Agis-Balboa RC, Pavelka Z, Kerimoglu C, Fischer A . Loss of HDAC5 impairs memory function: implications for Alzheimer's disease . Journal of Alzheimer's Disease . 33 . 1 . 35–44 . January 2013 . 22914591 . 10.3233/JAD-2012-121009 . free . 2434/223089 .
6. Munkácsy G, Sztupinszki Z, Herman P, Bán B, Pénzváltó Z, Szarvas N, Győrffy B . Validation of RNAi Silencing Efficiency Using Gene Array Data shows 18.5% Failure Rate across 429 Independent Experiments . en . Molecular Therapy: Nucleic Acids . 5 . 9 . e366 . September 2016 . 27673562 . 5056990 . 10.1038/mtna.2016.66 .
7. Jaguva Vasudevan AA, Hoffmann MJ, Beck ML, Poschmann G, Petzsch P, Wiek C, Stühler K, Köhrer K, Schulz WA, Niegisch G . 6 . HDAC5 Expression in Urothelial Carcinoma Cell Lines Inhibits Long-Term Proliferation but Can Promote Epithelial-to-Mesenchymal Transition . International Journal of Molecular Sciences . 20 . 9 . 2135 . April 2019 . 31052182 . 6539474 . 10.3390/ijms20092135 . free .
8. Zhang CL, McKinsey TA, Olson EN . Association of class II histone deacetylases with heterochromatin protein 1: potential role for histone methylation in control of muscle differentiation . Molecular and Cellular Biology . 22 . 20 . 7302–12 . October 2002 . 12242305 . 139799 . 10.1128/MCB.22.20.7302-7312.2002 .
9. Watamoto K, Towatari M, Ozawa Y, Miyata Y, Okamoto M, Abe A, Naoe T, Saito H . 6 . Altered interaction of HDAC5 with GATA-1 during MEL cell differentiation . Oncogene . 22 . 57 . 9176–84 . December 2003 . 14668799 . 10.1038/sj.onc.1206902 . 24491249 .
10. Fischle W, Dequiedt F, Hendzel MJ, Guenther MG, Lazar MA, Voelter W, Verdin E . Enzymatic activity associated with class II HDACs is dependent on a multiprotein complex containing HDAC3 and SMRT/N-CoR . Molecular Cell . 9 . 1 . 45–57 . January 2002 . 11804585 . 10.1016/S1097-2765(01)00429-4 . free . 11858/00-001M-0000-002C-9FF9-9 .
11. Grozinger CM, Schreiber SL . Regulation of histone deacetylase 4 and 5 and transcriptional activity by 14-3-3-dependent cellular localization . Proceedings of the National Academy of Sciences of the United States of America . 97 . 14 . 7835–40 . July 2000 . 10869435 . 16631 . 10.1073/pnas.140199597 . 2000PNAS...97.7835G . free .
12. Koipally J, Georgopoulos K . A molecular dissection of the repression circuitry of Ikaros . The Journal of Biological Chemistry . 277 . 31 . 27697–705 . August 2002 . 12015313 . 10.1074/jbc.M201694200 . free .
13. Lemercier C, Verdel A, Galloo B, Curtet S, Brocard MP, Khochbin S . mHDA1/HDAC5 histone deacetylase interacts with and represses MEF2A transcriptional activity . The Journal of Biological Chemistry . 275 . 20 . 15594–9 . May 2000 . 10748098 . 10.1074/jbc.M908437199 . free .
14. Castet A, Boulahtouf A, Versini G, Bonnet S, Augereau P, Vignon F, Khochbin S, Jalaguier S, Cavaillès V . 6 . Multiple domains of the Receptor-Interacting Protein 140 contribute to transcription inhibition . Nucleic Acids Research . 32 . 6 . 1957–66 . 2004 . 15060175 . 390375 . 10.1093/nar/gkh524 .
15. Zhang J, Kalkum M, Chait BT, Roeder RG . The N-CoR-HDAC3 nuclear receptor corepressor complex inhibits the JNK pathway through the integral subunit GPS2 . Molecular Cell . 9 . 3 . 611–23 . March 2002 . 11931768 . 10.1016/S1097-2765(02)00468-9 . free .
16. Huang EY, Zhang J, Miska EA, Guenther MG, Kouzarides T, Lazar MA . Nuclear receptor corepressors partner with class II histone deacetylases in a Sin3-independent repression pathway . Genes & Development . 14 . 1 . 45–54 . January 2000 . 10.1101/gad.14.1.45 . 10640275 . 316335 .
17. Vega RB, Harrison BC, Meadows E, Roberts CR, Papst PJ, Olson EN, McKinsey TA . Protein kinases C and D mediate agonist-dependent cardiac hypertrophy through nuclear export of histone deacetylase 5 . Molecular and Cellular Biology . 24 . 19 . 8374–85 . October 2004 . 15367659 . 516754 . 10.1128/MCB.24.19.8374-8385.2004 .
18. Lemercier C, Brocard MP, Puvion-Dutilleul F, Kao HY, Albagli O, Khochbin S . Class II histone deacetylases are directly recruited by BCL6 transcriptional repressor . The Journal of Biological Chemistry . 277 . 24 . 22045–52 . June 2002 . 11929873 . 10.1074/jbc.M201736200 . free .
19. Chauchereau A, Mathieu M, de Saintignon J, Ferreira R, Pritchard LL, Mishal Z, Dejean A, Harel-Bellan A . 6 . HDAC4 mediates transcriptional repression by the acute promyelocytic leukaemia-associated protein PLZF . Oncogene . 23 . 54 . 8777–84 . November 2004 . 15467736 . 10.1038/sj.onc.1208128 . 26092755 .