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Cited by 239Histone Deacetylase Inhibitors ResearchGenomics and Chromatin DynamicsEpigenetics and DNA Methylation

HDAC4: Mechanism of Regulation and Biological Functions

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Wang, Zhengke, Qin, Gangjian, Zhao, Ting C·2014·Epigenomics
DOI 10.2217/epi.13.73PMC PMC4380265
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Abstract

The acetylation and deacetylation of histones plays an important role in the regulation of gene transcriptions. Histone acetylation is mediated by histone acetyltransferase; the resulting modification in the structure of chromatin leads to nucleosomal relaxation and altered transcriptional activation. The reverse reaction is mediated by histone deacetylase (HDAC), which induces deacetylation, chromatin condensation and transcriptional repression. HDACs are divided into three distinct classes: I, II, and III, on the basis of size and sequence homology, as well as formation of distinct complexes. Among class II HDACs, HDAC4 is implicated in controlling gene expression important for diverse cellular functions. Basic and clinical experimental evidence has established that HDAC4 performs a wide variety of functions. Understanding the biological significance of HDAC4 will not only provide new insight into the mechanisms of HDAC4 involved in mediating biological response, but also form a platform to develop a therapeutic strategy to achieve clinical implications.

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  1. [1]Thiagalingam S Cheng KH Lee HJ Histone deacetylases: unique players in shaping the epigenetic histone code Ann N Y Acad Sci 983 84 100 2003 12724214
  2. Grozinger CM Schreiber SL Deacetylase enzymes: biological functions and the use of small-molecule inhibitors Chem Biol 9 3 16 2002 11841934
  3. [3]Chen HP Denicola M Qin X HDAC inhibition promotes cardiogenesis and the survival of embryonic stem cells through proteasome-dependent pathway J Cell Biochem 112 3246 3255 2011 21751234 PMC3357124
  4. [4]Vaquero A Sternglanz R Reinberg D NAD+-dependent deacetylation of H4 lysine 16 by class III HDACs Oncogene 26 5505 5520 2007 17694090
  5. [5]Fischle W Kiermer V Dequiedt F The emerging role of class II histone deacetylases Biochem Cell Biol 79 337 348 2001 11467747
  6. [6]Martin M Kettmann R Dequiedt F Class IIa histone deacetylases: regulating the regulators Oncogene 26 5450 5467 2007 17694086
  7. [7]Yang XJ Seto E The Rpd3/Hda1 family of lysine deacetylases: from bacteria and yeast to mice and men Nat Rev Mol Cell Biol 9 206 218 2008 18292778 PMC2667380
  8. [8]Barneda-Zahonero B Parra M Histone deacetylases and cancer Mol Oncol 6 579 589 2012 22963873 PMC5528343
  9. [9]Wang AH Bertos NR Vezmar M HDAC4, a human histone deacetylase related to yeast HDA1, is a transcriptional corepressor Mol Cell Biol 19 7816 7827 1999 10523670 PMC84849
  10. [10]Vega RB Matsuda K Oh J Histone deacetylase 4 controls chondrocyte hypertrophy during skeletogenesis Cell 119 555 566 2004 15537544
  11. [11]Stark M Hayward N Genome-wide loss of heterozygosity and copy number analysis in melanoma using high-density single-nucleotide polymorphism arrays Cancer Res 67 2632 2642 2007 17363583
  12. [12]Liu F Pore N Kim M Regulation of histone deacetylase 4 expression by the SP family of transcription factors Mol Biol Cell 17 585 597 2006 16280357 PMC1356571
  13. [13]Addis RC Prasad MK Yochem RL OCT3/4 regulates transcription of histone deacetylase 4 (Hdac4) in mouse embryonic stem cells J Cell Biochem 111 391 401 2010 20506506
  14. [14]Yuan JH Yang F Chen BF The histone deacetylase 4/SP1/microrna-200a regulatory network contributes to aberrant histone acetylation in hepatocellular carcinoma Hepatology 54 2025 2035 2011 21837748
  15. [15]Chen JF Mandel EM Thomson JM The role of microRNA-1 and microRNA-133 in skeletal muscle proliferation and differentiation Nat Genet 38 228 233 2006 16380711 PMC2538576
  16. [16]Sun Y Ge Y Drnevich J Mammalian target of rapamycin regulates miRNA-1 and follistatin in skeletal myogenesis J Cell Biol 189 1157 1169 2010 20566686 PMC2894448
  17. [17]Sluijter JP van Mil A van Vliet P MicroRNA-1 and -499 regulate differentiation and proliferation in human-derived cardiomyocyte progenitor cells Arterioscler Thromb Vasc Biol 30 859 868 2010 20081117
  18. [18]Zhang J Yang Y Yang T microRNA-22, downregulated in hepatocellular carcinoma and correlated with prognosis, suppresses cell proliferation and tumourigenicity Br J Cancer 103 1215 1220 2010 20842113 PMC2967065
  19. [19]Winbanks CE Wang B Beyer C TGF-beta regulates miR-206 and miR-29 to control myogenic differentiation through regulation of HDAC4 J Biol Chem 286 13805 13814 2011 21324893 PMC3077581
  20. [20]Tuddenham L Wheeler G Ntounia-Fousara S The cartilage specific microRNA-140 targets histone deacetylase 4 in mouse cells FEBS Lett 580 4214 4217 2006 16828749
  21. [21]Miyaki S Sato T Inoue A MicroRNA-140 plays dual roles in both cartilage development and homeostasis Genes Dev 24 1173 1185 2010 20466812 PMC2878654
  22. [22]Guan YJ Yang X Wei L MiR-365: a mechanosensitive microRNA stimulates chondrocyte differentiation through targeting histone deacetylase 4 Faseb J 25 4457 4466 2011 21856783 PMC3236620
  23. [23]Sandhu SK Volinia S Costinean S miR-155 targets histone deacetylase 4 (HDAC4) and impairs transcriptional activity of B-cell lymphoma 6 (BCL6) in the EmumiR- 155 transgenic mouse model Proc Natl Acad Sci U S A 109 20047 20052 2013 23169640 PMC3523868
  24. [24]Guo L Han A Bates DL Crystal structure of a conserved N-terminal domain of histone deacetylase 4 reveals functional insights into glutamine-rich domains Proc Natl Acad Sci U S A 104 4297 4302 2007 17360518 PMC1838596
  25. [25]Bottomley MJ Lo Surdo P Di Giovine P Structural and functional analysis of the human HDAC4 catalytic domain reveals a regulatory structural zinc-binding domain J Biol Chem 283 26694 26704 2008 18614528 PMC3258910
  26. [26]Grozinger CM Schreiber SL Regulation of histone deacetylase 4 and 5 and transcriptional activity by 14-3-3-dependent cellular localization Proc Natl Acad Sci U S A 97 7835 7840 2000 10869435 PMC16631
  27. [27]Wang AH Kruhlak MJ Wu J Regulation of histone deacetylase 4 by binding of 14-3-3 proteins Mol Cell Biol 20 6904 6912 2000 10958686 PMC88766
  28. [28]McKinsey TA Zhang CL Lu J Signal-dependent nuclear export of a histone deacetylase regulates muscle differentiation Nature 408 106 111 2000 11081517 PMC4459600
  29. Backs J Song K Bezprozvannaya S CaM kinase II selectively signals to histone deacetylase 4 during cardiomyocyte hypertrophy J Clin Invest 116 1853 1864 2006 16767219 PMC1474817
  30. [30]Nakagawa Y Kuwahara K Harada M Class II HDACs mediate CaMK-dependent signaling to NRSF in ventricular myocytes J Mol Cell Cardiol 41 1010 1022 2006 17011572
  31. [31]Backs J Backs T Neef S The delta isoform of CaM kinase II is required for pathological cardiac hypertrophy and remodeling after pressure overload Proc Natl Acad Sci U S A 106 2342 2347 2009 19179290 PMC2650158
  32. [32]Zhang T Kohlhaas M Backs J CaMKIIdelta isoforms differentially affect calcium handling but similarly regulate HDAC/MEF2 transcriptional responses J Biol Chem 282 35078 35087 2007 17923476
  33. [33]Backs J Worst BC Lehmann LH Selective repression of MEF2 activity by PKA-dependent proteolysis of HDAC4 J Cell Biol 195 403 415 2011 22042619 PMC3206346
  34. [34]Zhou X Richon VM Wang AH Histone deacetylase 4 associates with extracellular signal-regulated kinases 1 and 2, and its cellular localization is regulated by oncogenic Ras Proc Natl Acad Sci U S A 97 14329 14333 2000 11114188 PMC18918
  35. Cernotta N Clocchiatti A Florean C Ubiquitin-dependent degradation of HDAC4, a new regulator of random cell motility Mol Biol Cell 22 278 289 2011 21118993 PMC3020922
  36. Ago T Liu T Zhai P A redox-dependent pathway for regulating class II HDACs and cardiac hypertrophy Cell 133 978 993 2008 18555775
  37. Tatham MH Jaffray E Vaughan OA Polymeric chains of SUMO-2 and SUMO-3 are conjugated to protein substrates by SAE1/SAE2 and Ubc9 J Biol Chem 276 35368 35374 2001 11451954
  38. [40]Kirsh O Seeler JS Pichler A The SUMO E3 ligase RanBP2 promotes modification of the HDAC4 deacetylase Embo J 21 2682 2691 2002 12032081 PMC125385
  39. [41]Liu F Dowling M Yang XJ Caspase-mediated specific cleavage of human histone deacetylase 4 J Biol Chem 279 34537 34546 2004 15205465
  40. [42]Paroni G Fontanini A Cernotta N Dephosphorylation and caspase processing generate distinct nuclear pools of histone deacetylase 4 Mol Cell Biol 27 6718 6732 2007 17636017 PMC2099224
  41. [43]Paroni G Mizzau M Henderson C Caspase-dependent regulation of histone deacetylase 4 nuclear-cytoplasmic shuttling promotes apoptosis Mol Biol Cell 15 2804 2818 2004 15075374 PMC420104
  42. [44]Kozhemyakina E Cohen T Yao TP Parathyroid hormone-related peptide represses chondrocyte hypertrophy through a protein phosphatase 2A/histone deacetylase 4/MEF2 pathway Mol Cell Biol 29 5751 5762 2009 19704004 PMC2772746
  43. [45]McKinsey TA Zhang CL Olson EN Identification of a signal-responsive nuclear export sequence in class II histone deacetylases Mol Cell Biol 21 6312 6321 2001 11509672 PMC87361
  44. [46]McKinsey TA Kuwahara K Bezprozvannaya S Class II histone deacetylases confer signal responsiveness to the ankyrin-repeat proteins ANKRA2 and RFXANK Mol Biol Cell 17 438 447 2006 16236793 PMC1345680
  45. Wang AH Yang XJ Histone deacetylase 4 possesses intrinsic nuclear import and export signals Mol Cell Biol 21 5992 6005 2001 11486037 PMC87317
  46. [48]Kehat I Accornero F Aronow BJ Modulation of chromatin position and gene expression by HDAC4 interaction with nucleoporins J Cell Biol 193 21 29 2011 21464227 PMC3082185
  47. [49]Qian DZ Kachhap SK Collis SJ Class II histone deacetylases are associated with VHL-independent regulation of hypoxia-inducible factor 1 alpha Cancer Res 66 8814 8821 2006 16951198
  48. [50]Seo HW Kim EJ Na H Transcriptional activation of hypoxia-inducible factor-1alpha by HDAC4 and HDAC5 involves differential recruitment of p300 and FIH- 1 FEBS Lett 583 55 60 2009 19071119
  49. [51]Geng H Harvey CT Pittsenbarger J HDAC4 protein regulates HIF1alpha protein lysine acetylation and cancer cell response to hypoxia J Biol Chem 286 38095 38102 2011 21917920 PMC3207467
  50. [52]Choi MC Cohen TJ Barrientos T A direct HDAC4-MAP kinase crosstalk activates muscle atrophy program Mol Cell 47 122 132 2012 22658415 PMC3398192
  51. [55]Guenther MG Barak O Lazar MA The SMRT and N-CoR corepressors are activating cofactors for histone deacetylase 3 Mol Cell Biol 2001 21 6091 6101 11509652 PMC87326
  52. [56]Jeon EJ Lee KY Choi NS Bone morphogenetic protein-2 stimulates Runx2 acetylation J Biol Chem 281 16502 16511 2006 16613856
  53. [57]Shinkai Y Regulation and function of H3K9 methylation Subcell Biochem 41 337 50 2007 17484135
  54. [58]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 Mol Cell Biol 22 7302 7312 2002 12242305 PMC139799
  55. [59]Raychaudhuri N Raychaudhuri S Thamotharan M Histone code modifications repress glucose transporter 4 expression in the intrauterine growth-restricted offspring J Biol Chem 283 13611 13626 2008 18326493 PMC2376250
  56. [60]Hohl M Wagner M Reil JC Tauchnitz M Zimmer AM Lehmann LH Thiel G Bohm M Backs J Maack C HDAC4 controls histone methylation in response to elevated cardiac load J Clin Invest 123 1359 1370 2013 23434587 PMC3582114
  57. [62]Huang SK Scruggs AM Donaghy J Histone modifications are responsible for decreased Fas expression and apoptosis resistance in fibrotic lung fibroblasts Cell Death Dis 4 e621 2013 23640463 PMC3674355
  58. [63]Gregoire S Tremblay AM Xiao L Control of MEF2 transcriptional activity by coordinated phosphorylation and sumoylation J Biol Chem 281 4423 4433 2006 16356933
  59. [64]Zhao X Sternsdorf T Bolger TA Regulation of MEF2 by histone deacetylase 4- and SIRT1 deacetylase-mediated lysine modifications Mol Cell Biol 25 8456 8464 2005 16166628 PMC1265742
  60. [65]Gregoire S Yang XJ Association with class IIa histone deacetylases upregulates the sumoylation of MEF2 transcription factors Mol Cell Biol 25 2273 2287 2005 15743823 PMC1061617
  61. [66]Kang JS Alliston T Delston R Repression of Runx2 function by TGF-beta through recruitment of class II histone deacetylases by Smad3 Embo J 24 2543 2555 2005 15990875 PMC1176457
  62. [67]Pei M Chen D Li J Histone deacetylase 4 promotes TGF-beta1-induced synovium-derived stem cell chondrogenesis but inhibits chondrogenically differentiated stem cell hypertrophy Differentiation 78 260 268 2009 19716643
  63. [68]Lin Q Schwarz J Bucana C Control of mouse cardiac morphogenesis and myogenesis by transcription factor MEF2C Science 276 1404 1407 1997 9162005 PMC4437729
  64. [69]Karamboulas C Swedani A Ward C HDAC activity regulates entry of mesoderm cells into the cardiac muscle lineage J Cell Sci 119 4305 4314 2006 17038545
  65. [70]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 Proc Natl Acad Sci U S A 97 14400 14405 2000 11114197 PMC18930
  66. [71]Miska EA Langley E Wolf D Differential localization of HDAC4 orchestrates muscle differentiation Nucleic Acids Res 29 3439 3447 2001 11504882 PMC55849
  67. [72]Liu Y Randall WR Schneider MF Activity-dependent and -independent nuclear fluxes of HDAC4 mediated by different kinases in adult skeletal muscle J Cell Biol 168 887 897 2005 15767461 PMC2171787
  68. [73]Passier R Zeng H Frey N CaM kinase signaling induces cardiac hypertrophy and activates the MEF2 transcription factor in vivo J Clin Invest 105 1395 1406 2000 10811847 PMC315462
  69. [74]Huang ZP Chen J Seok HY MicroRNA-22 regulates cardiac hypertrophy and remodeling in response to stress Circ Res 112 1234 1243 2013 23524588 PMC3720677
  70. [75]Gupta MP Samant SA Smith SH HDAC4 and PCAF bind to cardiac sarcomeres and play a role in regulating myofilament contractile activity J Biol Chem 283 10135 10146 2008 18250163 PMC2442284
  71. [76]Cohen TJ Barrientos T Hartman ZC The deacetylase HDAC4 controls myocyte enhancing factor-2-dependent structural gene expression in response to neural activity Faseb J 23 99 106 2009 18780762 PMC2626618
  72. [77]Cohen TJ Waddell DS Barrientos T The histone deacetylase HDAC4 connects neural activity to muscle transcriptional reprogramming J Biol Chem 282 33752 33759 2007 17873280
  73. [78]Tang H Macpherson P Marvin M A histone deacetylase 4/myogenin positive feedback loop coordinates denervation-dependent gene induction and suppression Mol Biol Cell 20 1120 1131 2009 19109424 PMC2642751
  74. [80]Bolger TA Yao TP Intracellular trafficking of histone deacetylase 4 regulates neuronal cell death J Neurosci 25 9544 9553 2005 16221865 PMC6725694
  75. [81]Bolger TA Zhao X Cohen TJ The neurodegenerative disease protein ataxin-1 antagonizes the neuronal survival function of myocyte enhancer factor-2 J Biol Chem 282 29186 29192 2007 17646162
  76. [82]Chawla S Vanhoutte P Arnold FJ Neuronal activity-dependent nucleocytoplasmic shuttling of HDAC4 and HDAC5 J Neurochem 85 151 159 2003 12641737
  77. [83]Jovicic A Zaldivar Jolissaint JF MicroRNA-22 (miR-22) overexpression is neuroprotective via general anti-apoptotic effects and may also target specific Huntington’s disease-related mechanisms PLoS One 8 e54222 2013 23349832 PMC3547907
  78. [84]Chen B Cepko CL HDAC4 regulates neuronal survival in normal and diseased retinas Science 323 256 259 2009 19131628 PMC3339762
  79. [85]Yang Y Qin X Liu S Peroxisome proliferator-activated receptor gamma is inhibited by histone deacetylase 4 in cortical neurons under oxidative stress J Neurochem 118 429 439 2011 21605119
  80. [86]Williams SR Aldred MA Der Kaloustian VM Haploinsufficiency of HDAC4 causes brachydactyly mental retardation syndrome, with brachydactyly type E, developmental delays, and behavioral problems Am J Hum Genet 87 219 228 2010 20691407 PMC2917703
  81. [87]Kim T Park JK Kim HJ Association of histone deacetylase genes with schizophrenia in Korean population Psychiatry Res 178 266 269 2012 20471694
  82. Li J Chen J Ricupero CL Nuclear accumulation of HDAC4 in ATM deficiency promotes neurodegeneration in ataxia telangiectasia Nat Med 18 783 790 2013 22466704 PMC3378917
  83. [89]Lenoir O Flosseau K Ma FX Specific control of pancreatic endocrine beta-and delta-cell mass by class IIa histone deacetylases HDAC4, HDAC5, and HDAC9 Diabetes 60 2861 2871 2011 21953612 PMC3198089
  84. Chauchereau A Mathieu M de Saintignon J HDAC4 mediates transcriptional repression by the acute promyelocytic leukaemia-associated protein PLZF Oncogene 23 8777 8784 2004 15467736
  85. [91]Lemercier C Brocard MP Puvion-Dutilleul F Class II histone deacetylases are directly recruited by BCL6 transcriptional repressor J Biol Chem 277 22045 22052 2002 11929873
  86. [92]Wilson AJ Byun DS Nasser S HDAC4 promotes growth of colon cancer cells via repression of p21 Mol Biol Cell 19 4062 4075 2008 18632985 PMC2555950
  87. [93]Mottet D Pirotte S Lamour V HDAC4 represses p21(WAF1/Cip1) expression in human cancer cells through a Sp1-dependent, p53-independent mechanism Oncogene 28 243 256 2009 18850004
  88. [94]Liu R Wang L Chen G FOXP3 up-regulates p21 expression by site-specific inhibition of histone deacetylase 2/histone deacetylase 4 association to the locus Cancer Res 69 2252 2259 2009 19276356 PMC2715174
  89. [95]Barrett A Santangelo S Tan K Breast cancer associated transcriptional repressor PLU-1/JARID1B interacts directly with histone deacetylases Int J Cancer 121 265 275 2007 17373667
  90. [96]Xu XS Wang L Abrams J Histone deacetylases (HDACs) in XPC gene silencing and bladder cancer J Hematol Oncol 4 17 2011 21507255 PMC3108377
  91. [97]Geng H Harvey CT Pittsenbarger J HDAC4 protein regulates HIF1alpha protein lysine acetylation and cancer cell response to hypoxia J Biol Chem 286 38095 38102 2011 21917920 PMC3207467
  92. [98]Song B Wang Y Xi Y Mechanism of chemoresistance mediated by miR- 140 in human osteosarcoma and colon cancer cells Oncogene 28 4065 4074 2009 19734943 PMC2783211
  93. [99]Isaacs JT Antony L Dalrymple SL Tasquinimod Is an Allosteric Modulator of HDAC4 survival signaling within the compromised cancer microenvironment Cancer Res 73 1386 1399 2013 23149916 PMC3578133

Cited by

Sorted by citations

Authors
Wang, Z., Qin, G., & Zhao, T. C.
Affiliations
  • Boston University (US)
  • Northwestern University (US)
ORCID
Venue
Epigenomics
Publisher
Informa UK Limited
Published
2014-02
Volume
6
Issue
1
Pages
139-150
ISSN
  • 1750-1911 (ISSN-L)
  • 1750-192X
DOI
10.2217/epi.13.73
PMC
PMC4380265
OpenAlex
W2094714880
Cited by
239
References
6
Citations by year
2026: 11 · 2025: 21 · 2024: 28 · 2023: 30 · 2022: 37 · 2021: 20 · 2020: 22 · 2019: 26 · 2018: 17 · 2017: 11 · 2016: 10 · 2015: 4 · 2014: 2
FWCI
0.85
Type
journal article
Language
en
Open access
Locations
  • Epigenomics (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
Funders
e National Heart, Lung, and Blood Institute Grant (HL089405, HL115265)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Histone Deacetylase Inhibitors Research
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Epigenetics and DNA Methylation
Keywords
HDAC4, histone deacetylase, histone deacetylation, histone acetylation, chromatin regulation, transcriptional repression, class II HDACs, gene expression regulation, epigenetic regulation
MeSH terms
Animals, Cell Survival, Gene Expression Regulation, Histone Deacetylases, Humans, Neoplasms, Repressor Proteins, Chondrogenesis, Muscle Development, MicroRNAs, Cell Proliferation, Mice

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