API

Relationship: 1709

Title

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Histone deacetylase inhibition leads to Histone acetylation, increase

Upstream event

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Histone deacetylase inhibition

Downstream event

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Histone acetylation, increase

Key Event Relationship Overview

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AOPs Referencing Relationship

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AOP Name Adjacency Weight of Evidence Quantitative Understanding
Histone deacetylase inhibition leading to testicular toxicity adjacent High High
Histone deacetylase inhibition leads to neural tube defects adjacent Not Specified Not Specified

Taxonomic Applicability

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

Sex Applicability

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Sex Evidence
Unspecific High

Life Stage Applicability

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Term Evidence
All life stages Moderate

Key Event Relationship Description

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The HDAC inhibitors (HDIs) inhibit deacetylation of the histone, leading to the increase in histone acetylation and gene transcription. HDACs deacetylate acetylated histone in epigenetic regulation [Falkenberg, 2014].

 

Description from EU-ToxRisk Deliverable:

Histone acetylation is one of the major epigenetic mechanisms and belongs to the posttranslational modifications of histones. Histone acetyltransferases are setting the mark and deacetylases (HDAC) are responsible for removing the acetyl group from specific lysin residues of the histones. It has been shown that the inhibition of HDACs leads to a hyperacetylation of histones and in general to an imbalance of other histone modifications.

Evidence Supporting this KER

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Biological Plausibility

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HDACs are important proteins in epigenetic regulation of gene transcription. Upon the inhibition of HDAC by HDIs, the acetylation of lysine in histone remains and it leads to transcriptional activation or repression, changes in DNA replication and DNA damage repair. The treatment by HDIs increased histone acetylation [Wade, 2008].

 

Description from EU-ToxRisk Deliverable:

In all eukaryotes the DNA containing the genetic information of an organism, is organized in chromatin. The basic unit of chromatin is the nucleosome around which the naked DNA is wrapped. A nucleosome consists of two copies of each of the core histones H2A, H2B, H3 and H4 (Luger et al., 1997). In order to dynamically regulate this highly complex structure severeal mechanism are involved, including the posttranslational modifications of histones (reviewed in (Bannister and Kouzarides, 2011; Kouzarides, 2007). For long time it is known that histones get acetylated and that this reaction is catalyzed by histone acetyl transferases (HAT) and the acetyl groups are removed by histone deacetylases (HDAC). Inhibition of HDACs by small molecule compounds lead to hyperacetylation of the histones as the homeostasis of acetylation and deacetylation is disturbed (reviewed in (Gallinari et al., 2007)).

Empirical Evidence

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  • HDAC inhibition by HDIs leads to hyperacetylation of histone and a large number of cellular proteins such as NF-kB [Falkenberg, 2014, Chen, 2018].
  • The concentrations of half-maximum inhibitory effect (IC50) for HDAC enzyme inhibition of 20 valproic acid derivatives correlated with teratogenic potential of the compounds, and HDAC inhibitory compounds showed hyperacetylation of core histone 4 in treated F9 cells [Eikel, 2006].
  • HDIs increase histone acetylation in brain [Schroeder, 2013].
  • The HDI selectivity exists, in which SAHA is a more potent inducer of histone acetylation than MS-275, and more acetylation sites on the histones H3 and H4 are responsible to SAHA than MS-275 [Choudhary, 2009].
  • HDI AR-42 induces acetylation of histone H3 in dose-response manner in human pancreatic cancer cell lines [Henderson, 2016].
  • MAA treatment in rats (650 mg/kg, for 4, 8, 12, and 24 hrs) induced hyperacetylation in histones H3 and H4 of testis nuclei [Wade, 2008].
  • HDAC inhibition induced by valproic acid (VPA) leads to histone hyperacetylation in mouse teratocarcinoma cell line F9 [Eikel, 2006].
  • Hyperacetylation of histone H3 was observed in HDAC1-deficient ES cells [Lagger, 2002].
  • The treatment of MAA induced histone acetylation in H3K9Ac and H4K12Ac, as well as p53K379Ac [Dayan, 2014].

 

Description from EU-ToxRisk Deliverable:

The major empirical evidence came from the incubation of cell culture cells with small molecule compounds that inhibit HDAC enzymes followed by western blots or acid urea gel analysis.

The first evidence was shown by Riggs et al. who showed that incubation of HeLa cells with n-butyrate leads to an accumulation of acetylated histone proteins (Riggs et al., 1977)

Later, it was shown that n-butyrate specifically increases the acetylation of histone by the incorporation of radioactive [H3] acetate and analysis of the histones on acid urea gels that allow the detection of acetylated histones (Cousens et al., 1979)

TSA was shown to be an HDAC inhibitor by acid urea gel analysis in 1990 (Yoshida et al., 1990) and good evidence for VPA as an HDAC inhibitor in vitro and in vivo was shown using acetyl-specific antibodies and western blot (Gottlicher et al., 2001).

Exposure of mouse embryos in utero to VPA and TSA (two well-known HDAC inhibitors) showed an increased histone acetylation level in whole embryo extracts and was also shown in situ immuno stainings (Menegola et al., 2005).

Uncertainties and Inconsistencies

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HDACs affect a large number of cellular proteins including histones, which reminds us the HDAC inhibition by HDIs hyperacetylates cellular proteins other than histones and exhibit biological effects. It is also noted that HDAC functions as the catalytic subunits of large protein complex, which suggests that the inhibition of HDAC by HDIs affect the function of the large multiprotein complexes of HDAC [Falkenberg, 2014].

 

Description from EU-ToxRisk Deliverable:

All above mentioned analysis are indirect or in purified systems. Therefore a direct cause-consequence relation is difficult to obtain.

Quantitative Understanding of the Linkage

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To quantify acetylation by HDAC, stable isotope labeling with amino acids in cell culture (SILAC) method is used [Choudhary, 2009].

Response-response Relationship

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SAHA and MS-275 increased acetylation of specific lysines on histones more than twofold [Choudhary, 2009]. Acetylation of the variant histone H2AZ-a mark for DNA damage sites- was upregulated almost 20-fold by SAHA, whereas a number of sites on the core histones H3 and H4 are several times more highly regulated in response to SAHA than by MS-275 [Choudhary, 2009].

TSA (100 ng/ml) accumulated the acetylated histones in a variety of mammalian cell lines, and the partially purified HDAC from wild-type FM3A cells was effectively inhibited by TSA (Ki = 3.4 nM) [Yoshida, 1990].

Time-scale

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Known modulating factors

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Known Feedforward/Feedback loops influencing this KER

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Domain of Applicability

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The relationship between HDAC inhibition and hyperacetylation is likely well conserved between species from lower organisms to mammals.

  • Hyperacetylation by HDIs such as SAHA and Cpd-60 are observed in mouse (Mus musculus) [Schroeder, 2013].
  • TSA induces acetylation of histone H4 in time-dependent manner in mouse cell lines (Mus musculus) [Alberts, 1998].
  • AR-42, a novel HDI, induces hyperacetylation in human pancreatic cancer cells (Homo sapiens) [Henderson, 2016].
  • SAHA and MS-275 hyperacetylates lysine of histones in human cell lines of epithelial (A549) and lymphoid origin (Jurkat) (Homo sapiens) [Choudhary, 2009].
  • SAHA treatment induces the H3 and H4 histone acetylation in human corneal fibroblasts and conjunctiva from rabbits after glaucoma filtration surgery (Homo sapiens, Oryctolagus cuniculus) [Sharma, 2016].
  • TSA induces the acetylation of histones H3 and H4 in Brassica napus microspore cultures (Brassica napu) [Li, 2014].

References

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Falkenberg KJ and Johnstone RW. (2014) Histone deacetylases and their inhibitors in cancer, neurological disease and immune disorders. Nat Rev Drug Discov 13:673-691Wade MG et al. (2008) Methoxyacetic acid-induced spermatocyte death is associated with histone hyperacetylation in rats. Biol Reprod 78:822-831

Chen S et al. (2018) Valproic acid attenuates traumatic spinal cord injury-induced inflammation via STAT1 and NF-kB pathway dependent of HDAC3. J Neuroinflammation 15:150

Eikel D et al. (2006) Teratogenic effects mediated by inhibition of histone deacetylases: evidence from quantitative structure activity relationships of 20 valproic acid derivatives. Chem Res Toxicol 19:272-278

Schroeder FA et al. (2013) A selective HDAC 1/2 inhibitor modulates chromatin and gene expression in brain and alters mouse behavior in two mood-related tests. PLoS One 8:e71323

Choudhary C et al. (2009) Lysine acetylation targets protein complexes and co-regulates major cellular functions. Science 325:834-840

Henderson SE et al. (2016) Suppression of tumor growth and muscle wasting in a transgenic mouse model of pancreatic cancer by the novel histone deacetylase inhibitor AR-42. Neoplasia 18:765-774

Lagger G et al. (2002) Essential function of histone deacetylase 1 in proliferation control and CDK inhibitor repression. EMBO J 21:2672-2681

Dayan C and Hales BF. (2014) Effects of ethylene glycol monomethyl ether and its metabolite, 2-methoxyacetic acid, on organogenesis stage mouse limbs in vitro. Birth Defects Res (Part B) 101:254-261

Yoshida M et al. (1990) Potent and specific inhibition of mammalian histone deacetylase both in vivo and in vitro trichostatin A. J Biol Chem 265:17174-17179

Alberts AS et al. (1998) Activation of SRF-regulated chromosomal templates by Rho-family GTPases requires a signal that also induces H4 hyperacetylation. Cell 92:475-487

Sharma A et al. (2016) Epigenetic modification prevents excessive wound healing and scar formation after glaucoma filtration surgery. Invest Ophthalmol Vis Sci 57:3381-3389

Li H et al. (2014) The histone deacetylase inhibitor trichostatin A promotes totipotentcy in the male gametophyte. Plant Cell 26:195-209

Bannister, A. J. and Kouzarides, T. (2011). Regulation of chromatin by histone modifications. Cell Res 21, 381-395. doi:10.1038/cr.2011.22

Cousens, L. S., Gallwitz, D. and Alberts, B. M. (1979). Different accessibilities in chromatin to histone acetylase. J Biol Chem 254, 1716-1723.

Gallinari, P., Di Marco, S., Jones, P. et al. (2007). Hdacs, histone deacetylation and gene transcription: From molecular biology to cancer therapeutics. Cell Res 17, 195-211. doi:7310149 [pii]

10.1038/sj.cr.7310149

Gottlicher, M., Minucci, S., Zhu, P. et al. (2001). Valproic acid defines a novel class of hdac inhibitors inducing differentiation of transformed cells. Embo J 20, 6969-6978. doi:10.1093/emboj/20.24.6969

Kouzarides, T. (2007). Chromatin modifications and their function. Cell 128, 693-705.

Luger, K., Mader, A. W., Richmond, R. K. et al. (1997). Crystal structure of the nucleosome core particle at 2.8 a resolution. Nature 389, 251-260. doi:10.1038/38444

Menegola, E., Di Renzo, F., Broccia, M. L. et al. (2005). Inhibition of histone deacetylase activity on specific embryonic tissues as a new mechanism for teratogenicity. Birth Defects Res B Dev Reprod Toxicol 74, 392-398. doi:10.1002/bdrb.20053

Riggs, M. G., Whittaker, R. G., Neumann, J. R. et al. (1977). N-butyrate causes histone modification in hela and friend erythroleukaemia cells. Nature 268, 462-464.

Yoshida, M., Kijima, M., Akita, M. et al. (1990). Potent and specific inhibition of mammalian histone deacetylase both in vivo and in vitro by trichostatin a. J Biol Chem 265, 17174-17179.