Histone deacetylase

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histone deacetylase
Catalytic domain of Human histone deacetylase 4 with bound inhibitor. PDB rendering based on 2vqj.[1]
EC number
CAS number 9076-57-7
IntEnz IntEnz view
ExPASy NiceZyme view
MetaCyc metabolic pathway
PRIAM profile
PDB structures RCSB PDB PDBe PDBsum
Gene Ontology AmiGO / EGO
Histone deacetylase superfamily
Symbol Hist_deacetyl
Pfam PF00850
InterPro IPR000286
SCOP 1c3s

Histone deacetylases (EC, HDAC) are a class of enzymes that remove acetyl groups (O=C-CH3) from an ε-N-acetyl lysine amino acid on a histone, allowing the histones to wrap the DNA more tightly. This is important because DNA is wrapped around histones, and DNA expression is regulated by acetylation and de-acetylation. Its action is opposite to that of histone acetyltransferase. HDAC proteins are now also called lysine deacetylases (KDAC), to describe their function rather than their target, which also includes non-histone proteins.[2]

HDAC super family[edit]

Together with the acetylpolyamine amidohydrolases and the acetoin utilization proteins, the histone deacetylases form an ancient protein superfamily known as the histone deacetylase superfamily.[3]

Classes of HDACs in higher eukaryotes[edit]

HDACs, are classified in four classes depending on sequence homology to the yeast original enzymes and domain organization:[4]

Class Members Catalytic sites Subcellular localization Tissue distribution Substrates Binding partners Knockout phenotype
I HDAC1 1 Nucleus Ubiquitous Androgen receptor, SHP, p53, MyoD, E2F1, STAT3 embryonic lethal, increased histone acetylation, increase in p21 and p27
HDAC2 1 Nucleus Ubiquitous Glucocorticoid receptor, YY1, BCL6, STAT3 Cardiac defect
HDAC3 1 Nucleus Ubiquitous SHP, YY1, GATA1, RELA, STAT3, MEF2D
HDAC8 1 Nucleus/cytoplasm Ubiquitous? EST1B
IIA HDAC4 1 Nucleus / cytoplasm heart, skeletal muscle, brain GCMA, GATA1, HP1 RFXANK Defects in chondrocyte differentiation
HDAC5 1 Nucleus / cytoplasm heart, skeletal muscle, brain GCMA, SMAD7, HP1 REA, estrogen receptor Cardiac defect
HDAC7 1 Nucleus / cytoplasm / mitochondria heart, skeletal muscle, pancreas, placenta PLAG1, PLAG2 HIF1A, BCL6, endothelin receptor, ACTN1, ACTN4, androgen receptor, Tip60 Maintenance of vascular integrity, increase in MMP10
HDAC9 1 Nucleus / cytoplasm brain, skeletal muscle FOXP3 Cardiac defect
IIB HDAC6 2 Mostly cytoplasm heart, liver, kidney, placenta α-Tubulin, HSP90, SHP, SMAD7 RUNX2
HDAC10 1 Mostly cytoplasm liver, spleen, kidney
III sirtuins in mammals (SIRT1, SIRT2, SIRT3, SIRT4, SIRT5, SIRT6, SIRT7)
Sir2 in the yeast S. cerevisiae
IV HDAC11 2 Nucleus / cytoplasm brain, heart, skeletal muscle, kidney

HDAC (except class III) contain zinc and are known as Zn-dependent histone deacetylases.[5]


HDAC proteins are grouped into four classes (see above) based on function and DNA sequence similarity. Class I, II and IV are considered "classical" HDACs whose activities are inhibited by trichostatin A (TSA) and have a zinc dependent active site, whereas Class III enzymes are a family of NAD+-dependent proteins known as sirtuins and are not affected by TSA.[6] Homologues to these three groups are found in yeast having the names: reduced potassium dependency 3 (Rpd3), which corresponds to Class I; histone deacetylase 1 (hda1), corresponding to Class II; and silent information regulator 2 (Sir2), corresponding to Class III. Class IV contains just one isoform (HDAC11), which is not highly homologous with either Rpd3 or hda1 yeast enzymes,[7] and therefore HDAC11 is assigned to its own class. The Class III enzymes are considered a separate type of enzyme and have a different mechanism of action; these enzymes are NAD+-dependent, whereas HDACs in other classes require Zn2+ as a cofactor.[8]

Subcellular distribution[edit]

Within the Class I HDACs, HDAC 1, 2, and 8 are found primarily in the nucleus, whereas HDAC3 is found in both the nucleus and the cytoplasm, and is also membrane-associated. Class II HDACs (HDAC4, 5, 6, 7 9, and 10) are able to shuttle in and out of the nucleus, depending on different signals.[9][10]

HDAC6 is a cytoplasmic, microtuble-associated enzyme. HDAC6 deacetylates tubulin, Hsp90, and cortactin, and forms complexes with other partner proteins, and is, therefore, involved in a variety of biological processes.[11]


Histone modification[edit]

Histone tails are normally positively charged due to amine groups present on their lysine and arginine amino acids. These positive charges help the histone tails to interact with and bind to the negatively charged phosphate groups on the DNA backbone. Acetylation, which occurs normally in a cell, neutralizes the positive charges on the histone by changing amines into amides and decreases the ability of the histones to bind to DNA. This decreased binding allows chromatin expansion, permitting genetic transcription to take place. Histone deacetylases remove those acetyl groups, increasing the positive charge of histone tails and encouraging high-affinity binding between the histones and DNA backbone. The increased DNA binding condenses DNA structure, preventing transcription.

Histone deacetylase is involved in a series of pathways within the living system. According to the Kyoto Encyclopedia of Genes and Genomes (KEGG), these are:

Histone acetylation plays an important role in the regulation of gene expression. Hyperacetylated chromatin is transcriptionally active, and hypoacetylated chromatin is silent. A study on mice found that a specific subset of mouse genes (7%) was deregulated in the absence of HDAC1.[12] Their study also found a regulatory crosstalk between HDAC1 and HDAC2 and suggest a novel function for HDAC1 as a transcriptional coactivator. HDAC1 expression was found to be increased in the prefrontal cortex of schizophrenia subjects,[13] negatively correlating with the expression of GAD67 mRNA.

Non-histone effects[edit]

It is a mistake to regard HDACs solely in the context of regulating gene transcription by modifying histones and chromatin structure, although that appears to be the predominant function. The function, activity, and stability of proteins can be controlled by post-translational modifications. Protein phosphorylation is perhaps the most widely studied and understood modification in which certain amino acid residues are phosphorylated by the action of protein kinases or dephosphorylated by the action of phosphatases. The acetylation of lysine residues is emerging as an analogous mechanism, in which non-histone proteins are acted on by acetylases and deacetylases.[14] It is in this context that HDACs are being found to interact with a variety of non-histone proteins—some of these are transcription factors and co-regulators, some are not. Note the following four examples:

  • HDAC6 is associated with aggresomes. Misfolded protein aggregates are tagged by ubiquitination and removed from the cytoplasm by dynein motors via the microtubule network to an organelle termed the aggresome. HDAC 6 binds polyubiquitinated misfolded proteins and links to dynein motors, thereby allowing the misfolded protein cargo to be physically transported to chaperones and proteasomes for subsequent destruction.[15]
  • PTEN is an important phosphatase involved in cell signaling via phosphoinositols and the AKT/PI3 kinase pathway. PTEN is subject to complex regulatory control via phosphorylation, ubiquitination, oxidation and acetylation. Acetylation of PTEN by the histone acetyltransferase p300/CBP-associated factor (PCAF) can repress its activity; on the converse, deacetylation of PTEN by SIRT1 deacetylase and, by HDAC1, can stimulate its activity.[16][17]
  • APE1/Ref-1 (APEX1) is a multifunctional protein possessing both DNA repair activity (on abasic and single-strand break sites) and transcriptional regulatory activity associated with oxidative stress. APE1/Ref-1 is acetylated by PCAF; on the converse, it is stably associated with and deacetylated by Class I HDACs. The acetylation state of APE1/Ref-1 does not appear to affect its DNA repair activity, but it does regulate its transcriptional activity such as its ability to bind to the PTH promoter and initiate transcription of the parathyroid hormone gene.[18][19]
  • NF-κB is a key transcription factor and effector molecule involved in responses to cell stress, consisting of a p50/p65 heterodimer. The p65 subunit is controlled by acetylation via PCAF and by deacetylation via HDAC3 and HDAC6.[20]

These are just some examples of constantly emerging non-histone, non-chromatin roles for HDACs.

HDAC inhibitors[edit]

Histone deacetylase inhibitors (HDIs) have a long history of use in psychiatry and neurology as mood stabilizers and anti-epileptics, for example, valproic acid. In more recent times, HDIs are being studied as a mitigator or treatment for neurodegenerative diseases.[21][22] Also in recent years, there has been an effort to develop HDIs for cancer therapy.[23][24] Vorinostat (SAHA) was approved in 2006 for the treatment of cutaneous manifestations in patients with cutaneous T cell lymphoma (CTCL) that have failed previous treatments. A second HDI, Istodax (romidepsin), was approved in 2009 for patients with CTCL. The exact mechanisms by which the compounds may work are unclear, but epigenetic pathways are proposed.[25] In addition, a clinical trial is studying valproic acid effects on the latent pools of HIV in infected persons.[26] HDIs are currently being investigated as chemosensitizers for cytotoxic chemotherapy or radiation therapy, or in association with DNA methylation inhibitors based on in vitro synergy.[27] Recent research has focused on developing isoform selective HDIs which can aid in elucidating role of individual HDAC isoforms and device strategy for effective treatment of diseases related to relevant HDAC isoform.[28][29][30]

HDAC inhibitors have effects on non-histone proteins that are related to acetylation. HDIs can alter the degree of acetylation of these molecules and, therefore, increase or repress their activity. For the four examples given above (see Function) on HDACs acting on non-histone proteins, in each of those instances the HDAC inhibitor Trichostatin A (TSA) blocks the effect. HDIs have been shown to alter the activity of many transcription factors, including ACTR, cMyb, E2F1, EKLF, FEN 1, GATA, HNF-4, HSP90, Ku70, NFκB, PCNA, p53, RB, Runx, SF1 Sp3, STAT, TFIIE, TCF, YY1.[31][32]

Research has shown that histone deacetylase inhibitors may modulate the latency of some viruses, resulting in reactivation.[33] This has been shown to occur, for instance, with a latent human herpesvirus-6 infection.

See also[edit]


  1. ^ Bottomley, M. J.; Lo Surdo, P.; Di Giovine, P.; Cirillo, A.; Scarpelli, R.; Ferrigno, F.; Jones, P.; Neddermann, P.; De Francesco, R.; Steinkühler, C.; Gallinari, P.; Carfí, A. (2008). "Structural and Functional Analysis of the Human HDAC4 Catalytic Domain Reveals a Regulatory Structural Zinc-binding Domain". Journal of Biological Chemistry 283 (39): 26694–26704. doi:10.1074/jbc.M803514200. PMC 3258910. PMID 18614528. 
  2. ^ Choudhary C, Kumar C, Gnad F, Nielsen ML, Rehman M, Walther TC, Olsen JV, Mann M (Aug 2009). "Lysine acetylation targets protein complexes and co-regulates major cellular functions". Science 325 (5942): 834–40. doi:10.1126/science.1175371. PMID 19608861. 
  3. ^ Leipe DD, Landsman D (Sep 1997). "Histone deacetylases, acetoin utilization proteins and acetylpolyamine amidohydrolases are members of an ancient protein superfamily". Nucleic Acids Research 25 (18): 3693–7. doi:10.1093/nar/25.18.3693. PMC 146955. PMID 9278492. 
  4. ^ Dokmanovic M, Clarke C, Marks PA (Oct 2007). "Histone deacetylase inhibitors: overview and perspectives". Molecular Cancer Research 5 (10): 981–9. doi:10.1158/1541-7786.MCR-07-0324. PMID 17951399. 
  5. ^ Marks PA, Xu WS (Jul 2009). "Histone deacetylase inhibitors: Potential in cancer therapy". Journal of Cellular Biochemistry 107 (4): 600–8. doi:10.1002/jcb.22185. PMC 2766855. PMID 19459166. 
  6. ^ Imai S, Armstrong CM, Kaeberlein M, Guarente L (Feb 2000). "Transcriptional silencing and longevity protein Sir2 is an NAD-dependent histone deacetylase". Nature 403 (6771): 795–800. doi:10.1038/35001622. PMID 10693811. 
  7. ^ Yang XJ, Seto E (Mar 2008). "The Rpd3/Hda1 family of lysine deacetylases: from bacteria and yeast to mice and men". Nature Reviews. Molecular Cell Biology 9 (3): 206–18. doi:10.1038/nrm2346. PMID 18292778. 
  8. ^ Barneda-Zahonero B, Parra M (Dec 2012). "Histone deacetylases and cancer". Molecular Oncology 6 (6): 579–89. doi:10.1016/j.molonc.2012.07.003. PMID 22963873. 
  9. ^ de Ruijter AJ, van Gennip AH, Caron HN, Kemp S, van Kuilenburg AB (Mar 2003). "Histone deacetylases (HDACs): characterization of the classical HDAC family". The Biochemical Journal 370 (Pt 3): 737–49. doi:10.1042/BJ20021321. PMC 1223209. PMID 12429021. 
  10. ^ Longworth MS, Laimins LA (Jul 2006). "Histone deacetylase 3 localizes to the plasma membrane and is a substrate of Src". Oncogene 25 (32): 4495–500. doi:10.1038/sj.onc.1209473. PMID 16532030. 
  11. ^ Valenzuela-Fernández A, Cabrero JR, Serrador JM, Sánchez-Madrid F (Jun 2008). "HDAC6: a key regulator of cytoskeleton, cell migration and cell-cell interactions". Trends in Cell Biology 18 (6): 291–7. doi:10.1016/j.tcb.2008.04.003. PMID 18472263. 
  12. ^ Zupkovitz G, Tischler J, Posch M, Sadzak I, Ramsauer K, Egger G, Grausenburger R, Schweifer N, Chiocca S, Decker T, Seiser C (Nov 2006). "Negative and positive regulation of gene expression by mouse histone deacetylase 1". Molecular and Cellular Biology 26 (21): 7913–28. doi:10.1128/MCB.01220-06. PMC 1636735. PMID 16940178. 
  13. ^ Sharma RP, Grayson DR, Gavin DP (Jan 2008). "Histone deactylase 1 expression is increased in the prefrontal cortex of schizophrenia subjects: analysis of the National Brain Databank microarray collection". Schizophrenia Research 98 (1-3): 111–7. doi:10.1016/j.schres.2007.09.020. PMC 2254186. PMID 17961987. 
  14. ^ Glozak MA, Sengupta N, Zhang X, Seto E (Dec 2005). "Acetylation and deacetylation of non-histone proteins". Gene 363: 15–23. doi:10.1016/j.gene.2005.09.010. PMID 16289629. 
  15. ^ Rodriguez-Gonzalez A, Lin T, Ikeda AK, Simms-Waldrip T, Fu C, Sakamoto KM (Apr 2008). "Role of the aggresome pathway in cancer: targeting histone deacetylase 6-dependent protein degradation". Cancer Research 68 (8): 2557–60. doi:10.1158/0008-5472.CAN-07-5989. PMID 18413721. 
  16. ^ Ikenoue T, Inoki K, Zhao B, Guan KL (Sep 2008). "PTEN acetylation modulates its interaction with PDZ domain". Cancer Research 68 (17): 6908–12. doi:10.1158/0008-5472.CAN-08-1107. PMID 18757404. 
  17. ^ Yao XH, Nyomba BL (Jun 2008). "Hepatic insulin resistance induced by prenatal alcohol exposure is associated with reduced PTEN and TRB3 acetylation in adult rat offspring". American Journal of Physiology. Regulatory, Integrative and Comparative Physiology 294 (6): R1797–806. doi:10.1152/ajpregu.00804.2007. PMID 18385463. 
  18. ^ Bhakat KK, Izumi T, Yang SH, Hazra TK, Mitra S (Dec 2003). "Role of acetylated human AP-endonuclease (APE1/Ref-1) in regulation of the parathyroid hormone gene". The EMBO Journal 22 (23): 6299–309. doi:10.1093/emboj/cdg595. PMC 291836. PMID 14633989. 
  19. ^ Fantini D, Vascotto C, Deganuto M, Bivi N, Gustincich S, Marcon G, Quadrifoglio F, Damante G, Bhakat KK, Mitra S, Tell G (Jan 2008). "APE1/Ref-1 regulates PTEN expression mediated by Egr-1". Free Radical Research 42 (1): 20–9. doi:10.1080/10715760701765616. PMC 2677450. PMID 18324520. 
  20. ^ Hasselgren PO (Dec 2007). "Ubiquitination, phosphorylation, and acetylation--triple threat in muscle wasting". Journal of Cellular Physiology 213 (3): 679–89. doi:10.1002/jcp.21190. PMID 17657723. 
  21. ^ Hahnen E, Hauke J, Tränkle C, Eyüpoglu IY, Wirth B, Blümcke I (Feb 2008). "Histone deacetylase inhibitors: possible implications for neurodegenerative disorders". Expert Opinion on Investigational Drugs 17 (2): 169–84. doi:10.1517/13543784.17.2.169. PMID 18230051. 
  22. ^ "Scientists 'reverse' memory loss". BBC News. 2007-04-29. Retrieved 2007-07-08. 
  23. ^ Mwakwari SC, Patil V, Guerrant W, Oyelere AK (2010). "Macrocyclic histone deacetylase inhibitors". Curr Top Med Chem 10 (14): 1423–40. PMC 3144151. PMID 20536416. 
  24. ^ Miller TA, Witter DJ, Belvedere S (Nov 2003). "Histone deacetylase inhibitors". Journal of Medicinal Chemistry 46 (24): 5097–116. doi:10.1021/jm0303094. PMID 14613312. 
  25. ^ Monneret C (Apr 2007). "Histone deacetylase inhibitors for epigenetic therapy of cancer". Anti-Cancer Drugs 18 (4): 363–70. doi:10.1097/CAD.0b013e328012a5db. PMID 17351388. 
  26. ^ Depletion of Latent HIV in CD4 Cells - Full Text View - ClinicalTrials.gov
  27. ^ Batty N, Malouf GG, Issa JP (Aug 2009). "Histone deacetylase inhibitors as anti-neoplastic agents". Cancer Letters 280 (2): 192–200. doi:10.1016/j.canlet.2009.03.013. PMID 19345475. 
  28. ^ Patil V, Sodji QH, Kornacki JR, Mrksich M, Oyelere AK (May 2013). "3-Hydroxypyridin-2-thione as novel zinc binding group for selective histone deacetylase inhibition". Journal of Medicinal Chemistry 56 (9): 3492–506. doi:10.1021/jm301769u. PMID 23547652. 
  29. ^ Mwakwari SC, Guerrant W, Patil V, Khan SI, Tekwani BL, Gurard-Levin ZA, Mrksich M, Oyelere AK (Aug 2010). "Non-peptide macrocyclic histone deacetylase inhibitors derived from tricyclic ketolide skeleton". Journal of Medicinal Chemistry 53 (16): 6100–11. doi:10.1021/jm100507q. PMID 20669972. 
  30. ^ Butler KV, Kalin J, Brochier C, Vistoli G, Langley B, Kozikowski AP (Aug 2010). "Rational design and simple chemistry yield a superior, neuroprotective HDAC6 inhibitor, tubastatin A". Journal of the American Chemical Society 132 (31): 10842–6. doi:10.1021/ja102758v. PMID 20614936. 
  31. ^ Drummond DC, Noble CO, Kirpotin DB, Guo Z, Scott GK, Benz CC (2005). "Clinical development of histone deacetylase inhibitors as anticancer agents". Annual Review of Pharmacology and Toxicology 45: 495–528. doi:10.1146/annurev.pharmtox.45.120403.095825. PMID 15822187. 
  32. ^ Yang XJ, Seto E (Aug 2007). "HATs and HDACs: from structure, function and regulation to novel strategies for therapy and prevention". Oncogene 26 (37): 5310–8. doi:10.1038/sj.onc.1210599. PMID 17694074. 
  33. ^ Arbuckle JH, Medveczky PG (Aug 2011). "The molecular biology of human herpesvirus-6 latency and telomere integration". Microbes and Infection / Institut Pasteur 13 (8-9): 731–41. doi:10.1016/j.micinf.2011.03.006. PMC 3130849. PMID 21458587. 

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