Histone deacetylase#Classes of HDACs in higher eukaryotes

Together with the acetylpolyamine amidohydrolases and the acetoin utilization proteins, the histone deacetylases form an ancient protein superfamily known as the histone deacetylase superfamily.{{cite journal | vauthors = Leipe DD, Landsman D | title = Histone deacetylases, acetoin utilization proteins and acetylpolyamine amidohydrolases are members of an ancient protein superfamily | journal = Nucleic Acids Research | volume = 25 | issue = 18 | pages = 3693–3697 | date = September 1997 | pmid = 9278492 | pmc = 146955 | doi = 10.1093/nar/25.18.3693 }}

HDACs, are classified in four classes depending on sequence homology to the yeast original enzymes and domain organization:{{cite journal | vauthors = Dokmanovic M, Clarke C, Marks PA | title = Histone deacetylase inhibitors: overview and perspectives | journal = Molecular Cancer Research | volume = 5 | issue = 10 | pages = 981–989 | date = October 2007 | pmid = 17951399 | doi = 10.1158/1541-7786.MCR-07-0324 | doi-access = }}

HDAC (except class III) contain zinc and are known as Zn²⁺-dependent histone deacetylases.{{cite journal | vauthors = Marks PA, Xu WS | title = Histone deacetylase inhibitors: Potential in cancer therapy | journal = Journal of Cellular Biochemistry | volume = 107 | issue = 4 | pages = 600–608 | date = July 2009 | pmid = 19459166 | pmc = 2766855 | doi = 10.1002/jcb.22185 }} They feature a classical arginase fold and are structurally and mechanistically distinct from sirtuins (class III), which fold into a Rossmann architecture and are NAD⁺ dependent.{{cite journal | vauthors = Bürger M, Chory J | title = Structural and chemical biology of deacetylases for carbohydrates, proteins, small molecules and histones | journal = Communications Biology | volume = 1 | pages = 217 | date = 2018 | pmid = 30534609 | pmc = 6281622 | doi = 10.1038/s42003-018-0214-4 }}

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.{{cite journal | vauthors = Imai S, Armstrong CM, Kaeberlein M, Guarente L | title = Transcriptional silencing and longevity protein Sir2 is an NAD-dependent histone deacetylase | journal = Nature | volume = 403 | issue = 6771 | pages = 795–800 | date = February 2000 | pmid = 10693811 | doi = 10.1038/35001622 | bibcode = 2000Natur.403..795I | s2cid = 2967911 }} 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,{{cite journal | vauthors = Yang XJ, Seto E | title = The Rpd3/Hda1 family of lysine deacetylases: from bacteria and yeast to mice and men | journal = Nature Reviews. Molecular Cell Biology | volume = 9 | issue = 3 | pages = 206–218 | date = March 2008 | pmid = 18292778 | pmc = 2667380 | doi = 10.1038/nrm2346 }} 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.{{cite journal | vauthors = Barneda-Zahonero B, Parra M | title = Histone deacetylases and cancer | journal = Molecular Oncology | volume = 6 | issue = 6 | pages = 579–589 | date = December 2012 | pmid = 22963873 | pmc = 5528343 | doi = 10.1016/j.molonc.2012.07.003 }}

HDACs are conserved across evolution, showing orthologs in all eukaryotes and even in Archaea. All upper eukaryotes, including vertebrates, plants and arthropods, possess at least one HDAC per class, while most vertebrates carry the 11 canonical HDACs, with the exception of bone fish, which lack HDAC2 but appears to have an extra copy of HDAC11, dubbed HDAC12. Plants carry additional HDACs compared to animals, putatively to carry out the more complex transcriptional regulation required by these sessile organisms. HDACs appear to be deriving from an ancestral acetyl-binding domain, as HDAC homologs have been found in bacteria in the form of Acetoin utilization proteins (AcuC) proteins.

File:Figure1 tree.tif

Within the Class I HDACs, HDAC1, 2, and 3 are found primarily in the nucleus, whereas HDAC8 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.{{cite journal | vauthors = de Ruijter AJ, van Gennip AH, Caron HN, Kemp S, van Kuilenburg AB | title = Histone deacetylases (HDACs): characterization of the classical HDAC family | journal = The Biochemical Journal | volume = 370 | issue = Pt 3 | pages = 737–749 | date = March 2003 | pmid = 12429021 | pmc = 1223209 | doi = 10.1042/BJ20021321 }}{{cite journal | vauthors = Longworth MS, Laimins LA | title = Histone deacetylase 3 localizes to the plasma membrane and is a substrate of Src | journal = Oncogene | volume = 25 | issue = 32 | pages = 4495–4500 | date = July 2006 | pmid = 16532030 | doi = 10.1038/sj.onc.1209473 | doi-access = }}

HDAC6 is a cytoplasmic, microtubule-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.{{cite journal | vauthors = Valenzuela-Fernández A, Cabrero JR, Serrador JM, Sánchez-Madrid F | title = HDAC6: a key regulator of cytoskeleton, cell migration and cell-cell interactions | journal = Trends in Cell Biology | volume = 18 | issue = 6 | pages = 291–297 | date = June 2008 | pmid = 18472263 | doi = 10.1016/j.tcb.2008.04.003 }}

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:

• Environmental information processing; signal transduction; notch signaling pathway [http://www.genome.jp/dbget-bin/show_pathway?ko04330+ko:K06067 PATH:ko04330]
• Cellular processes; cell growth and death; cell cycle [http://www.genome.jp/dbget-bin/show_pathway?ko04110+ko:K06067 PATH:ko04110]
• Human diseases; cancers; chronic myeloid leukemia [http://www.genome.jp/dbget-bin/show_pathway?ko05220+ko:K06067 PATH:ko05220]

File:Histone tails set for transcriptional activation.jpg: Nucleosomes consist of four pairs of histone proteins in a tightly assembled core region plus up to 30% of each histone remaining in a loosely organized tail (only one tail of each pair is shown). DNA is wrapped around the histone core proteins in chromosomes. The lysines (K) are designated with a number showing their position as, for instance (K4), indicating lysine as the 4th amino acid from the amino (N) end of the tail in the histone protein. Methylations {Me}, and acetylations [Ac] are common post-translational modifications on the lysines of the histone tails.]] File:Histone tails set for transcriptional repression.jpg.]]

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.{{cite journal | vauthors = Zupkovitz G, Tischler J, Posch M, Sadzak I, Ramsauer K, Egger G, Grausenburger R, Schweifer N, Chiocca S, Decker T, Seiser C | display-authors = 6 | title = Negative and positive regulation of gene expression by mouse histone deacetylase 1 | journal = Molecular and Cellular Biology | volume = 26 | issue = 21 | pages = 7913–7928 | date = November 2006 | pmid = 16940178 | pmc = 1636735 | doi = 10.1128/MCB.01220-06 }} 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,{{cite journal | vauthors = Sharma RP, Grayson DR, Gavin DP | title = Histone deactylase 1 expression is increased in the prefrontal cortex of schizophrenia subjects: analysis of the National Brain Databank microarray collection | journal = Schizophrenia Research | volume = 98 | issue = 1–3 | pages = 111–117 | date = January 2008 | pmid = 17961987 | pmc = 2254186 | doi = 10.1016/j.schres.2007.09.020 }} negatively correlating with the expression of GAD67 mRNA.

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.{{cite journal | vauthors = Glozak MA, Sengupta N, Zhang X, Seto E | title = Acetylation and deacetylation of non-histone proteins | journal = Gene | volume = 363 | pages = 15–23 | date = December 2005 | pmid = 16289629 | doi = 10.1016/j.gene.2005.09.010 }} 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.{{cite journal | vauthors = Rodriguez-Gonzalez A, Lin T, Ikeda AK, Simms-Waldrip T, Fu C, Sakamoto KM | title = Role of the aggresome pathway in cancer: targeting histone deacetylase 6-dependent protein degradation | journal = Cancer Research | volume = 68 | issue = 8 | pages = 2557–2560 | date = April 2008 | pmid = 18413721 | doi = 10.1158/0008-5472.CAN-07-5989 | doi-access = free }} HDAC6 is important regulator of HSP90 function and its inhibitor proposed to treat metabolic disorders.{{cite journal | vauthors = Mahla RS | title = Comment on: Winkler et al. Histone deacetylase 6 (HDAC6) is an essential modifier of glucocorticoid-induced hepatic gluconeogenesis. Diabetes 2012;61:513-523 | journal = Diabetes | volume = 61 | issue = 7 | pages = e10; author reply e11 | date = July 2012 | pmid = 22723278 | pmc = 3379673 | doi = 10.2337/db12-0323 }}
• 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.{{cite journal | vauthors = Ikenoue T, Inoki K, Zhao B, Guan KL | title = PTEN acetylation modulates its interaction with PDZ domain | journal = Cancer Research | volume = 68 | issue = 17 | pages = 6908–6912 | date = September 2008 | pmid = 18757404 | doi = 10.1158/0008-5472.CAN-08-1107 | doi-access = free }}{{cite journal | vauthors = Yao XH, Nyomba BL | title = Hepatic insulin resistance induced by prenatal alcohol exposure is associated with reduced PTEN and TRB3 acetylation in adult rat offspring | journal = American Journal of Physiology. Regulatory, Integrative and Comparative Physiology | volume = 294 | issue = 6 | pages = R1797–R1806 | date = June 2008 | pmid = 18385463 | doi = 10.1152/ajpregu.00804.2007 }}
• 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.{{cite journal | vauthors = Bhakat KK, Izumi T, Yang SH, Hazra TK, Mitra S | title = Role of acetylated human AP-endonuclease (APE1/Ref-1) in regulation of the parathyroid hormone gene | journal = The EMBO Journal | volume = 22 | issue = 23 | pages = 6299–6309 | date = December 2003 | pmid = 14633989 | pmc = 291836 | doi = 10.1093/emboj/cdg595 }}{{cite journal | vauthors = Fantini D, Vascotto C, Deganuto M, Bivi N, Gustincich S, Marcon G, Quadrifoglio F, Damante G, Bhakat KK, Mitra S, Tell G | display-authors = 6 | title = APE1/Ref-1 regulates PTEN expression mediated by Egr-1 | journal = Free Radical Research | volume = 42 | issue = 1 | pages = 20–29 | date = January 2008 | pmid = 18324520 | pmc = 2677450 | doi = 10.1080/10715760701765616 }}
• 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.{{cite journal | vauthors = Hasselgren PO | title = Ubiquitination, phosphorylation, and acetylation--triple threat in muscle wasting | journal = Journal of Cellular Physiology | volume = 213 | issue = 3 | pages = 679–689 | date = December 2007 | pmid = 17657723 | doi = 10.1002/jcp.21190 | doi-access = free }}

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

{{main|Histone deacetylase inhibitor}}

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.{{cite journal | vauthors = Hahnen E, Hauke J, Tränkle C, Eyüpoglu IY, Wirth B, Blümcke I | title = Histone deacetylase inhibitors: possible implications for neurodegenerative disorders | journal = Expert Opinion on Investigational Drugs | volume = 17 | issue = 2 | pages = 169–184 | date = February 2008 | pmid = 18230051 | doi = 10.1517/13543784.17.2.169 | s2cid = 14344174 }}{{cite web |url=http://news.bbc.co.uk/2/hi/health/6606315.stm |title=Scientists 'reverse' memory loss |access-date=2007-07-08 |work= BBC News | date=2007-04-29}}{{cite journal | vauthors = Geurs S, Clarisse D, Baele F, Franceus J, Desmet T, De Bosscher K, D'hooghe M | title = Identification of mercaptoacetamide-based HDAC6 inhibitors via a lean inhibitor strategy: screening, synthesis, and biological evaluation | journal = Chemical Communications | volume = 58 | issue = 42 | pages = 6239–6242 | date = May 2022 | pmid = 35510683 | doi = 10.1039/D2CC01550A | s2cid = 248527466 | url = https://biblio.ugent.be/publication/8752799 | hdl = 1854/LU-8752799 | hdl-access = free }} Also in recent years, there has been an effort to develop HDIs for cancer therapy.{{cite journal | vauthors = Mwakwari SC, Patil V, Guerrant W, Oyelere AK | title = Macrocyclic histone deacetylase inhibitors | journal = Current Topics in Medicinal Chemistry | volume = 10 | issue = 14 | pages = 1423–1440 | year = 2010 | pmid = 20536416 | pmc = 3144151 | doi = 10.2174/156802610792232079 }}{{cite journal | vauthors = Miller TA, Witter DJ, Belvedere S | title = Histone deacetylase inhibitors | journal = Journal of Medicinal Chemistry | volume = 46 | issue = 24 | pages = 5097–5116 | date = November 2003 | pmid = 14613312 | doi = 10.1021/jm0303094 }} Vorinostat (SAHA) was FDA 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.{{cite journal | vauthors = Monneret C | title = Histone deacetylase inhibitors for epigenetic therapy of cancer | journal = Anti-Cancer Drugs | volume = 18 | issue = 4 | pages = 363–370 | date = April 2007 | pmid = 17351388 | doi = 10.1097/CAD.0b013e328012a5db | s2cid = 39017666 }} In addition, a clinical trial is studying valproic acid effects on the latent pools of HIV in infected persons.[http://www.clinicaltrials.gov/ct2/show/NCT00576290?term=HDAC&rank=8 Depletion of Latent HIV in CD4 Cells - Full Text View - ClinicalTrials.gov] 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.{{cite journal | vauthors = Batty N, Malouf GG, Issa JP | title = Histone deacetylase inhibitors as anti-neoplastic agents | journal = Cancer Letters | volume = 280 | issue = 2 | pages = 192–200 | date = August 2009 | pmid = 19345475 | doi = 10.1016/j.canlet.2009.03.013 }} Isoform selective HDIs which can aid in elucidating role of individual HDAC isoforms have been developed.{{cite journal | vauthors = Patil V, Sodji QH, Kornacki JR, Mrksich M, Oyelere AK | title = 3-Hydroxypyridin-2-thione as novel zinc binding group for selective histone deacetylase inhibition | journal = Journal of Medicinal Chemistry | volume = 56 | issue = 9 | pages = 3492–3506 | date = May 2013 | pmid = 23547652 | pmc = 3657749 | doi = 10.1021/jm301769u }}{{cite journal | vauthors = Mwakwari SC, Guerrant W, Patil V, Khan SI, Tekwani BL, Gurard-Levin ZA, Mrksich M, Oyelere AK | display-authors = 6 | title = Non-peptide macrocyclic histone deacetylase inhibitors derived from tricyclic ketolide skeleton | journal = Journal of Medicinal Chemistry | volume = 53 | issue = 16 | pages = 6100–6111 | date = August 2010 | pmid = 20669972 | pmc = 2924451 | doi = 10.1021/jm100507q }}{{cite journal | vauthors = Butler KV, Kalin J, Brochier C, Vistoli G, Langley B, Kozikowski AP | title = Rational design and simple chemistry yield a superior, neuroprotective HDAC6 inhibitor, tubastatin A | journal = Journal of the American Chemical Society | volume = 132 | issue = 31 | pages = 10842–10846 | date = August 2010 | pmid = 20614936 | pmc = 2916045 | doi = 10.1021/ja102758v }}

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, and YY1.{{cite journal | vauthors = Drummond DC, Noble CO, Kirpotin DB, Guo Z, Scott GK, Benz CC | title = Clinical development of histone deacetylase inhibitors as anticancer agents | journal = Annual Review of Pharmacology and Toxicology | volume = 45 | pages = 495–528 | year = 2005 | pmid = 15822187 | doi = 10.1146/annurev.pharmtox.45.120403.095825 }}{{cite journal | vauthors = Yang XJ, Seto E | title = HATs and HDACs: from structure, function and regulation to novel strategies for therapy and prevention | journal = Oncogene | volume = 26 | issue = 37 | pages = 5310–5318 | date = August 2007 | pmid = 17694074 | doi = 10.1038/sj.onc.1210599 | doi-access = free }}

The ketone body β-hydroxybutyrate has been shown in mice to increase gene expression of FOXO3a by histone deacetylase inhibition.{{cite journal | vauthors = Shimazu T, Hirschey MD, Newman J, He W, Shirakawa K, Le Moan N, Grueter CA, Lim H, Saunders LR, Stevens RD, Newgard CB, Farese RV, de Cabo R, Ulrich S, Akassoglou K, Verdin E | display-authors = 6 | title = Suppression of oxidative stress by β-hydroxybutyrate, an endogenous histone deacetylase inhibitor | journal = Science | volume = 339 | issue = 6116 | pages = 211–214 | date = January 2013 | pmid = 23223453 | pmc = 3735349 | doi = 10.1126/science.1227166 | bibcode = 2013Sci...339..211S }}

Histone deacetylase inhibitors may modulate the latency of some viruses, resulting in reactivation.{{cite journal | vauthors = Arbuckle JH, Medveczky PG | title = The molecular biology of human herpesvirus-6 latency and telomere integration | journal = Microbes and Infection | volume = 13 | issue = 8–9 | pages = 731–741 | date = August 2011 | pmid = 21458587 | pmc = 3130849 | doi = 10.1016/j.micinf.2011.03.006 }} This has been shown to occur, for instance, with a latent human herpesvirus-6 infection.

Histone deacetylase inhibitors have shown activity against certain Plasmodium species and stages which may indicate they have potential in malaria treatment. It has been shown that HDIs accumulate acetylated histone H3K9/H3K14, a downstream target of class I HDACs.{{cite journal | vauthors = Beus M, Rajić Z, Maysinger D, Mlinarić Z, Antunović M, Marijanović I, Fontinha D, Prudêncio M, Held J, Olgen S, Zorc B | display-authors = 6 | title = SAHAquines, Novel Hybrids Based on SAHA and Primaquine Motifs, as Potential Cytostatic and Antiplasmodial Agents | journal = ChemistryOpen | volume = 7 | issue = 8 | pages = 624–638 | date = August 2018 | pmid = 30151334 | pmc = 6104433 | doi = 10.1002/open.201800117 }}

• Histone acetyltransferase (HAT)
• Histone deacetylase inhibitor
• Histone methyltransferase (HMT)
• Histone-modifying enzymes
• RNA polymerase control by chromatin structure

{{Reflist|2}}

• {{MeshName|Histone+deacetylase}}
• [https://web.archive.org/web/20070929235728/http://www.targethdac.com/hdac/targethdac/histone_deacetylase/index.jsp?WT.srch=1&WT.mc_id=ZL016 Animation] at Merck

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{{Carbon-nitrogen non-peptide hydrolases}}

{{Enzymes}}

{{HDAC inhibitors}}

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Category:EC 3.5.1