API

Event: 1502

Key Event Title

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Histone deacetylase inhibition

Short name

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Histone deacetylase inhibition

Biological Context

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Level of Biological Organization
Molecular

Cell term

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Cell term
cell


Organ term

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Organ term
organ


Key Event Components

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Process Object Action
enzyme inhibitor activity histone deacetylase 1 decreased

Key Event Overview


AOPs Including This Key Event

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AOP Name Role of event in AOP
Histone deacetylase inhibition leading to testicular atrophy MolecularInitiatingEvent
HDAC inhibition leads to impeded craniofacial development MolecularInitiatingEvent
HDAC inhibition leads to neural tube defects MolecularInitiatingEvent

Stressors

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Taxonomic Applicability

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Term Scientific Term Evidence Link
rat Rattus norvegicus High NCBI
human Homo sapiens High NCBI
mouse Mus musculus High NCBI

Life Stages

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Life stage Evidence
All life stages Moderate

Sex Applicability

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Term Evidence
Unspecific High

Key Event Description

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The nucleosome consists of core histones having classes of H2A, H2B, H3 and H4 [Damaskos, 2017]. DNA strands (about 200 bp) wind around the core histones, where histone deacetylase (HDAC) effects on the lysine residue of the histone to hydrolyze the acetyl residue [Damaskos, 2017]. Histone deacetylase inhibitor (HDI) inhibits HDAC, causing acetylation of the histones, and releases the DNA strands to induce the binding of transcription factors [Taunton, 1996].

It is known that eukaryotic HDAC isoforms are classified into four classes: class I HDACs (isoforms 1, 2, 3, 8), class II HDACs (isoforms 4, 5, 6, 7, 9, 10), class III HDACs (the sirtuins), and HDAC11 [Gregoretti et al., 2004, Weichert, 2009, Barneda-Zahonero, 2012]. HDACs 1, 2 and 3 are ubiquitously expressed, whereas HDAC8 is predominantly expressed in cells with smooth muscle/myoepithelial differentiation [Weichert, 2009]. HDAC6 is not observed to be expressed in lymphocytes, stromal cells and vascular endothelial cells [Weichert, 2009]. Class III HDACs, sirtuins, are widely expressed and localized in different cellular compartments [Barneda-Zahonero, 2012]. SirT1 is highly expressed in testis, thymus and multiple types of germ cells [Bell, 2014]. HDAC11 expression is enriched in kidney, brain, testis, heart and skeletal muscle [Barneda-Zahonero, 2012]. The members of groups 1,2 and 4 are dependent on a zinc ion and a water molecule at their active sites, for their deacetylase function. The Sirtuins of class 3 depend on NAD+, and are considered impervious to most known HDAC inhibitors [Drummond et al., 2005].

Several structurally distinct groups of compounds have been found to inhibit HDACs of class 1, 2 and 4, among others short-chain fatty acids (e.g. butyrate and VPA), hydroxamic acids (e.g. TSA and SAHA) and epoxyketones (e.g. Trapoxin) [Drummond et al., 2005]. The hydroxamic acids seem to exert their inhibitory action by mimicking the acetyl-lysine target of HDACs, chelating the zinc ion in the active site and displacing the water molecule [Finnin et al., 1999]. Several recent high resolution crystal structures support this mode of inhibition [Decroos et al., 2015; Luckhurst et al., 2016]. The mode of inhibition of epoxyketones seems to function the formation of a stable transition state analog with the zinc ion in the active site [Porter and Christianson, 2017]. The inhibitory actions of the short-chain fatty acids are less well defined, but it has been speculated that VPA blocks access to the binding pocket [Göttlicher et al., 2001]. It has been shown that VPA exert similar gene regulatory effects to TSA, on a panel of migration related transcripts in neural crest cells [Dreser et al., 2015] supporting a mode of action similar to hydroxamic acid type HDAC inhibitors.


How It Is Measured or Detected

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The measurement of HDAC inhibition monitors changes in histone acetylation. HDAC inhibition can be followed by several different approaches such as western blots applying antibodies targeting specific acetylated proteins, or quantitative enzyme assays using acetylated peptides and purified HDAC enzyme. Commercial fluorimetric and colorimetric kits can be applied to assay HDAC activity from various biological extracts. The measurement methods include the immunological detection of histone acetylation with anti-acetylated histone antibodies [Richon, 2004]. The histones are isolated from pellets of cells treated with HDIs, followed by acid-urea-triton gel electrophoresis, western blotting, and immunohistochemistry [Richon, 2003]. The HDAC activity is measured directly with ultra high performance liquid chromatography-electrospray ionization-tandem mass spectrometry (UHPLC-ESI-MS/MS) by calculating the ratio of deacetylated peptide and acetylated peptide [Zwick, 2016].

 


Domain of Applicability

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The inhibition of HDAC by HDIs is well conserved between species from lower organism to mammals.

  • HDAC inhibition restores the rate of resorption of subretinal blebs in hyper glycemia in brown Norway rat and HDAC activity was inhibited with HDIs in human ARPE19 cells [Desjardins, 2016].
  • Treatment of HDIs inducing HDAC inhibition showed anti-tumor effects in human non-small cell lung cancer cells [Ansari, 2016, Miyanaga, 2008].
  • HDAC acetylation level was increased by HDIs in MRL-lpr/lpr murine model of lupus splenocytes [Mishra, 2003].
  • SAHA increased histone acetylation in brain and spleen of mice [Hockly, 2003].
  • MAA inhibits HDAC activity in HeLa cells and spleens from C57BL/6 mice [Jansen, 2004].
  • It is also reported that MAA inhibits HDAC activity in testis cytosolic and nuclear extract of juvenile rats (27 days old) [Wade, 2008].
  • VPA and TSA inhibit HDAC enzymatic activity in mouse embryo and human HeLa cell nuclear extract [Di Renzo, 2007].
  • The treatment with HDAC inhibitors, phenylbutyrate (PB) (2 mM) and TSA (200 nM), inhibits HDAC in adjuvant arthritis synovial cells derived from rats, causing higher acetylated histone [Chung, 2003].

Evidence for Perturbation by Stressor


Overview for Molecular Initiating Event

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HDIs are classified according to chemical nature and mode of mechanism: the short chain fatty acids (e.g., butyrate, valproate), hydroxamic acids (e.g., suberoylanilide hydroxamic acid or SAHA, Trichostatin A or TSA), cyclic tetrapeptides (e.g., FK-228), benzamides (e.g., N-acetyldinaline and MS-275) and epoxides (depeudecin, trapoxin A) [Richon, 2003, Ropero, 2007, Villar-Garea, 2004]. There is a report showing that TSA and butyrate competitively inhibits HDAC activity [Sekhavat, 2007]. HDIs inhibit preferentially HDACs with some selectiveness [Hu, 2003]. TSA inhibits HDAC1, HDAC3 and HDAC8, whereas MS-27-275 has inhibitory effect for HDAC1 and HDAC3 (IC50 value of ~0.2 mM and ~8 mM, respectively), but no effect for HDAC8 (IC50 value >10 mM) [Hu, 2003]. TSA inhibits HDAC1, 2, 3 of class I HDACs. [Damaskos, 2016].



References

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Damaskos C. et al. (2017) Histone deacetylase inhibitors: an attractive therapeutic strategy against breast cancer. Anticancer Research 37: 35-46.

Taunton J. et al. (1996) A mammalian histone deacetylase related to the Yeast transcriptional regulator Rpd3p. Science 272:408-411.

Gregoretti, I. V., Lee, Y.M., and Goodson, H. V. (2004) Molecular evolution of the histone deacetylase family: functional implications of phylogenetic analysis. J Mol Biol 338: 17–31.

Weichert W. (2009) HDAC expression and clinical prognosis in human malignancies. Cancer Letters 280:168-176

Barneda-Zahonero B and Parra M (2012) Histone deacetylases and cancer. Mol Oncol 6:579-589

Bell EL et al. (2014) SirT1 is required in the male germ cell for differentiation and fecundity in mice. Development 141:3495-3504

Drummond, D.C., Noble, C.O., Kirpotin, D.B., Guo, Z., Scott, G.K., and Benz, C.C. (2005) Clinical development of histone deacetylase inhibitors as anticancer agents. Annu Rev Pharmacol Toxicol 45: 495–528.

Finnin, M.S., Donigian, J.R., Cohen, a, Richon, V.M., Rifkind, R.A, Marks, P.A, et al. (1999) Structures of a histone deacetylase homologue bound to the TSA and SAHA inhibitors. Nature 401: 188–193.

Decroos, C., Christianson, N.H., Gullett, L.E., Bowman, C.M., Christianson, K.E., Deardorff, M.A., and Christianson, D.W. (2015) Biochemical and Structural Characterization of HDAC8 Mutants Associated with Cornelia de Lange Syndrome Spectrum Disorders. Biochemistry 54: 6501–6513.

Luckhurst, C.A., Breccia, P., Stott, A.J., Aziz, O., Birch, H.L., Bürli, R.W., et al. (2016) Potent, Selective, and CNS-Penetrant Tetrasubstituted Cyclopropane Class IIa Histone Deacetylase (HDAC) Inhibitors. ACS Med Chem Lett 7: 34–39.

Porter, N.J., and Christianson, D.W. (2017) Binding of the Microbial Cyclic Tetrapeptide Trapoxin A to the Class I Histone Deacetylase HDAC8. ACS Chem Biol 12: 2281–2286.

Göttlicher, M., Minucci, S., Zhu, P., Krämer, O.H., Schimpf, A., Giavara, S., et al. (2001) Valproic acid defines a novel class of HDAC inhibitors inducing differentiation of transformed cells. EMBO J 20: 6969–6978.

Dreser, N., Zimmer, B., Dietz, C., Sügis, E., Pallocca, G., Nyffeler, J., et al. (2015) Grouping of histone deacetylase inhibitors and other toxicants disturbing neural crest migration by transcriptional profiling. Neurotoxicology 50: 56–70.

Richon VM et al. (2003) Histone deacetylase inhibitors: assays to assess effectiveness in vitro and in vivo. Methods Enzymol. 376:199-205

Zwick V et al. (2016) Cell-based multi-substrate assay coupled to UHPLC-ESI-MS/MS for a quick identification of class-specific HDAC inhibitors. J Enzyme Inhib Med Chem 31: 209-214

Desjardins D et al. (2016) Histone deacetylase inhibition restores retinal pigment epithelium function in hyperglycemia. PLoS ONE 11: e0162596

Ansari J et al. (2016) Epigenetics in non-small cell lung cancer: from basics to therapeutics. Transl Lung Cancer Res 5:155-171

Miyanaga A et al. (2008) Antitumor activity of histone deacetylase inhibitors in non-small cell lung cancer cells: development of a molecular predictive model. Mol Cancer Ther 7:1923-1930

Mishra N et al. (2003) Histone deacetylase inhibitors modulate renal disease in the MRL-lpr/lpr mouse. J Clin Invest 111: 539-552

Hockly E et al. (2003) Suberoylanilide hydroxamic acid, a histone deacetylase inhibitor, ameliorates motor deficits in a mouse model of Huntington’s disease. Proc Nat Acad Sci 100:2041-2046

Jansen MS et al. (2014) Short-chain fatty acids enhance nuclear receptor activity through mitogen-activated protein kinase activation and histone deacetylase inhibition. Proc Natl Acad Sci USA 101(18):7199-7204

Wade MG et al. (2008) Methoxyacetic acid-induced spermatocyte death is associated with histone hyperacetylation in rats. Biol Reprod 78:822-831

Di Renzo F et al. (2007) Boric acid inhibits embryonic histone deacetylases: A suggested mechanism to explain boric acid-related teratogenicity. Toxicol and Appl Pharmacol 220:178-185

Chung YL et al. (2003) A therapeutic strategy uses histone deacetylase inhibitors to modulate the expression of genes involved in the pathogenesis of rheumatoid arthritis. Mol Ther 8:707-717

Ropero S and Esteller M. (2007) The role of histone deacetylases (HDACs) in human cancer. Mol Oncol 1:19-25

Villar-Garea A and Esteller M. (2004) Histone deacetylase inhibitors: understanding a new wave of anticancer agents. Int J Cancer 112:171-178

Sekhavat A et al. (2007) Competitive inhibition of histone deacetylase activity by trichostatin A and butyrate. Biochemistry and Cell Biology 85:751-758

Hu E et al. (2003) Identification of novel isoform-selective inhibitors within class I histone deacetylases. J Pharmacol Exp Ther 307:720-728

Damaskos C et al. (2016) Histone deacetylase inhibitors: a novel therapeutic weapon against medullary thyroid cancer? Anticancer Res 36:5019-5024

Description of EU-ToxRisk deliverable