- Histone deacetylase
Histone deacetylases (HDAC) (
EC number3.5.1) are a class of enzymes that remove acetyl groups from an ε-N-acetyl lysine amino acidon a histone. Its action is opposite to that of histone acetyltransferase.
HDAC proteins are found in three groups, the first two groups belong to the classical HDACs and their activities are inhibited by trichostatin A (TSA) whereas the third group is a family of NAD+-dependent proteins not affected by TSA. Homologues to all three groups are found in yeast having the names reduced potassium dependency 3 (Rpd3) - corresponds to class 1, histone deacetylase 1 (hda1) – to class 2 and silent information regulator 2(Sir2) – class3.cite journal | author = Sengupta N, Seto E | title = Regulation of histone deacetylase activities | journal = J. Cell. Biochem. | volume = 93 | issue = 1 | pages = 57–67 | year = 2004 | month = September | pmid = 15352162 | doi = 10.1002/jcb.20179 | url = | issn = ]
Within the class I HDACs, HDAC 1, 2 and 8 are primarily found in the nucleus, whereas HDAC 3 is found both in the nucleus, cytoplasm and also membrane associated. Class II HDACs (HDAC 4, 5, 6, 7 9 and 10) are able to shuttle in and out of the nucelus depending on different signals.cite journal | author = de Ruijter AJ, van Gennip AH, Caron HN, Kemp S, van Kuilenburg AB | title = Histone deacetylases (HDACs): characterization of the classical HDAC family | journal = Biochem. J. | volume = 370 | issue = Pt 3 | pages = 737–49 | year = 2003 | month = March | pmid = 12429021 | pmc = 1223209 | doi = 10.1042/BJ20021321 | url = | issn = ] cite journal | author = 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 = 4495–500 | year = 2006 | month = July | pmid = 16532030 | doi = 10.1038/sj.onc.1209473 | url = | issn = ]
HDAC 6 is a cytoplasmic, microtuble-associated enzyme. HDAC 6 deacetylates tubulin, Hsp90 and cortactin, and forms complexes with other partner proteins and is therefore involved in a variety of biological processes.cite journal | author = 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 Cell Biol. | volume = 18 | issue = 6 | pages = 291–7 | year = 2008 | month = June | pmid = 18472263 | doi = 10.1016/j.tcb.2008.04.003 | url = | issn = ]
Histone tails are normally positively charged due to
aminegroups present on their lysineand arginineamino 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 amidesand decreases the ability of the histones to bind to DNA. This process allows chromatin expansion, allowing for genetic transcription to take place. Histone deacetylase removes those acetyl groups, increasing positive charges to the histone tails and encourages high-affinity binding between the histones and DNA backbone. This process 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]
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 |author=Zupkovitz G, Tischler J, Posch M, "et al" |title=Negative and positive regulation of gene expression by mouse histone deacetylase 1 |journal=Mol. Cell. Biol. |volume=26 |issue=21 |pages=7913–28 |year=2006 |pmid=16940178 |doi=10.1128/MCB.01220-06] Their study also found a regulatory crosstalk between
HDAC1and HDAC2and 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 |author=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= |pages= 111|year=2007 |pmid=17961987 |doi=10.1016/j.schres.2007.09.020] negatively correlating with the expression of GAD67mRNA.
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 phosphorylationis 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 acetylationof lysine residues is emerging as an analogus mechanism, in which non-histone proteins are acted on by acetylases and deacetylases cite journal|author=Glozak MA, Sengupta N, Zhang X, Seto E|title=Acetylation and deacetylation of non-histone proteins|journal= Gene|volume= 363|pages= 15-23|year=2005 |pmid=16289629 ] . 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:
HDAC6is associated with aggresomes. Misfolded protein aggregates are tagged by ubiquitination and removed from the cytoplasm by dyneinmotors 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 | author = 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 Res. | volume = 68 | issue = 8 | pages = 2557-60 | year = 2008 | pmid = 18413721 | doi = | url = | issn = ]
PTENis an important phosphatase involved in cell signaling via phosphoinositols and the AKT/ PI3 kinasepathway. 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 stimulate its activity; conversely, deacetylation of PTEN by SIRT1deacetylase and apparently by HDAC1can repress its activity.cite journal | author = Ikenoue T, Inoki K, Zhao B, Guan KL | title = PTEN acetylation modulates its interaction with PDZ domain | journal = Cancer Res. | volume = 68 | issue = 17 | pages = 6908-12 | year = 2008 | pmid = 18757404 | doi = | url = | issn = ] cite journal | author = 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 = Am J Physiol Regul Integr Comp Physiol | volume = 294 | issue = 6 | pages = R1797-806 | year = 2008 | pmid = 18385463 | doi = | url = | issn = ]
* APE1/Ref-1 (
APEX) 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; conversely 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 repairactivity, but it does regulate its transcriptional activity such as its ability to bind to the PTH promoter and initiate transcription of the parathyroid hormonegene.cite journal | author = 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 = EMBO J. | volume = 22 | issue = 23 | pages = 6299-309 | year = 2003 | pmid = 14633989| doi = | url = | issn = ] cite journal | author = Fantini D, Vascotto C, Deganuto M, Bivi N, Gustincich S, Marcon G, Quadrifoglio F, Damante G, Bhakat KK, Mitra S, Tell G | title = APE1/Ref-1 regulates PTEN expression mediated by Egr-1 | journal = Free Radic Res. | volume = 42 | issue = 1 | pages = 20-9 | year = 2008 | pmid = 18324520 | doi = | url = | issn = ]
NF-kBis 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 HDAC3and HDAC6.cite journal | author = Hasselgren PO | title = Ubiquitination, phosphorylation, and acetylation--triple threat in muscle wasting | journal = J Cell Physiol. | volume = 213 | issue = 3 | pages = 679-89 | year = 2007 | pmid = 17657723 | doi = | url = | issn = ] These are just some examples of constantly emerging non-histone, non-chromatin roles for HDACs.
Histone deacetylase inhibitors (HDIs) have a long history of use in psychiatry and neurology as mood stabilizers and anti-epilectics, for example,
valproic acid. More recently, HDIs are being studied as a mitigator or treatment for neurodegenerative diseases.cite journal | author = Hahnen E, Hauke J, Tränkle C, Eyüpoglu IY, Wirth B, Blümcke I | title = Histone deacetylase inhibitors: possible implications for neurodegenerative disorders | journal = Expert Opin Investig Drugs | volume = 17 | issue = 2 | pages = 169–84 | year = 2008 | month = February | pmid = 18230051 | doi = 10.1517/135437220.127.116.11 | url = | issn = ] [cite web |url=http://news.bbc.co.uk/2/hi/health/6606315.stm |title=Scientists 'reverse' memory loss | Health | Scientists 'reverse' memory loss |accessdate=2007-07-08 |format= |work= | publisher = BBC News] Also in recent years, there has been an effort to develop HDIs for cancer therapy, and Vorinostat (SAHA) has recently been approved for treatment of cutaneous T cell lymphoma (CTCL). The exact mechanisms by which the compounds may work are unclear, but epigeneticpathways are proposed.cite journal | author = Monneret C | title = Histone deacetylase inhibitors for epigenetic therapy of cancer | journal = Anticancer Drugs | volume = 18 | issue = 4 | pages = 363–70 | year = 2007 | pmid = 17351388 | doi = 10.1097/CAD.0b013e328012a5db ] 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 ] ]
HDAC inhibitors have effects on non-histone proteins that are related to acetylation. HDIs can alter the degree of acetylation of these molecules and thereby 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.cite journal | author = Drummond DC, Noble CO, Kirpotin DB, Guo Z, Scott GK, Benz CC | title = Clinical development of histone deacetylase inhibitors as anticancer agents | journal = Annu Rev Pharmacol Toxicol | volume = 45 | issue = | pages = 495-528 | year = 2005 | pmid = 15822187 | doi = ] cite journal | author = 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 = | pages = 5310-5318 | year = 2007 | pmid = 17694074 | doi = ]
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 | author = Leipe DD, Landsman D | title = Histone deacetylases, acetoin utilization proteins and acetylpolyamine amidohydrolases are members of an ancient protein superfamily | journal = Nucleic Acids Res. | volume = 25 | issue = 18 | pages = 3693–7 | year = 1997 | pmid = 9278492 | doi = 10.1093/nar/25.18.3693 ] Histone deacetylases, acetoin utilization proteins and acetylpolyamine amidohydrolases are members of an ancient protein superfamily.InterPro|IPR000286
Classes of HDACs in higher eukaryotes
HDACs, are classified in four classes depending on sequence identity and domain organization:cite journal | author = Dokmanovic M, Clarke C, Marks PA | title = Histone deacetylase inhibitors: overview and perspectives | journal = Mol. Cancer Res. | volume = 5 | issue = 10 | pages = 981–9 | year = 2007 | pmid = 17951399 | doi = 10.1158/1541-7786.MCR-07-0324 ]
* Class I
HDAC1, HDAC2, HDAC3, HDAC8
* Class II
HDAC4, HDAC5, HDAC6, HDAC7A, HDAC9, HDAC10
* Class III
** Homologs of
Sir2in the yeast "Saccharomyces cerevisiae"
sirtuins in mammals (SIRT1, SIRT2, SIRT3, gene|SIRT4, SIRT5, SIRT6, SIRT7)
* Class IV
Histone deacetylase inhibitor
RNA polymerase control by chromatin structure
* [http://veille-srv.inist.fr/bin/dilib/AppliHuman2/desc.cgi?/applis/veille/home/apache/users/genomique/human/Server/EN.Human.EC.wsh+EC%203.5.1.-%20Histone%20Deacetylases Literature list on histone deacetylases, EC 3.5.1]
* [http://www.targethdac.com/hdac/targethdac/histone_deacetylase/index.jsp?WT.srch=1&WT.mc_id=ZL016 Animation] at Merck
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