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

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].

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].

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].

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].

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