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Histone deacetylase inhibition leads to Histone acetylation, increase
Key Event Relationship Overview
AOPs Referencing Relationship
|AOP Name||Adjacency||Weight of Evidence||Quantitative Understanding||Point of Contact||Author Status||OECD Status|
|Histone deacetylase inhibition leading to testicular atrophy||adjacent||High||Moderate||Brendan Ferreri-Hanberry (send email)||Open for citation & comment||WPHA/WNT Endorsed|
|Histone deacetylase inhibition leads to neural tube defects||adjacent||Not Specified||Not Specified||Allie Always (send email)||Under Development: Contributions and Comments Welcome|
Life Stage Applicability
|All life stages||Moderate|
Key Event Relationship Description
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 and Johnstone, 2014].
Histone acetylation is one of the major epigenetic mechanisms and belongs to the posttranslational modifications of histones. Histone acetyltransferase is setting the mark, and deacetylase (HDAC) is responsible for removing the acetyl group from specific lysine 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 Collection Strategy
Evidence Supporting this KER
HDACs are important proteins in the epigenetic regulation of gene transcription. Upon the inhibition of HDAC by HDIs, lysine in histone remains acetylated which leads to transcriptional activation or repression, changes in DNA replication, and DNA damage repair [Wade et al., 2008].
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 several mechanisms are involved, including the posttranslational modifications of histones (reviewed in [Bannister and Kouzarides, 2011; Kouzarides, 2007]. For a long time, it is known that histones get acetylated and that this reaction is catalyzed by histone acetyltransferases (HAT) whereas the acetyl groups are removed by histone deacetylases (HDAC). Inhibition of HDACs by small-molecule compounds leads to hyperacetylation of the histones as the homeostasis of acetylation and deacetylation is disturbed (reviewed in [Gallinari et al., 2007]).
Uncertainties and Inconsistencies
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 additional biological effects. It is also noted that HDAC functions as the catalytic subunits of the large protein complex, which suggests that the inhibition of HDAC by HDIs affects the function of the large multiprotein complexes of HDAC [Falkenberg and Johnstone, 2014]. Related-analysis are usually indirect or in purified systems, therefore a direct cause-consequence relation is difficult to obtain.
Known modulating factors
SAHA or MS-275 treatment leads to an increase in acetylation of specific lysine residues on histones more than two-fold [Choudhary et al., 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 et al., 2009].
TSA (100 ng/ml) treatment leads to accumulation of 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 et al., 1990].
Known Feedforward/Feedback loops influencing this KER
Domain of Applicability
The relationship between HDAC inhibition and increase in histone acetylation is conceivably well conserved among various species including mammals.
- Hyperacetylation by HDIs such as SAHA and Cpd-60 are observed in mice (Mus musculus) [Schroeder et al., 2013].
- TSA induces acetylation of histone H4 in a time-dependent manner in mouse cell lines (Mus musculus) [Alberts et al., 1998].
- AR-42, a novel HDI, induces hyperacetylation in human pancreatic cancer cells (Homo sapiens) [Henderson et al., 2016].
- SAHA and MS-275 lead to the hyperacetylation of lysine residues of histones in human cell lines of epithelial (A549) and lymphoid origin (Jurkat) (Homo sapiens) [Choudhary et al., 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 et al., 2016].
- TSA induces the acetylation of histones H3 and H4 in Brassica napus microspore cultures (Brassica napu) [Li et al., 2014].
Alberts, A.S. 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
Bannister, A. J. and Kouzarides, T. (2011), "Regulation of chromatin by histone modifications", Cell Res 21:381-395
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
Choudhary, C. et al. (2009), "Lysine acetylation targets protein complexes and co-regulates major cellular functions", Science 325:834-840
Cousens, L. S. et al. (1979), "Different accessibilities in chromatin to histone acetylase", J Biol Chem 254:1716-1723
Dayan, C. and Hales, B.F. (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
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
Falkenberg, K.J. and Johnstone, R.W. (2014), "Histone deacetylases and their inhibitors in cancer, neurological disease and immune disorders", Nat Rev Drug Discov 13:673-691
Gallinari, P. et al. (2007), "HDACs, histone deacetylation and gene transcription: From molecular biology to cancer therapeutics", Cell Res 17:195-211
Gottlicher, M. et al. (2001), "Valproic acid defines a novel class of HDAC inhibitors inducing differentiation of transformed cells", EMBO J 20:6969-6978
Henderson, S.E. 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
Kouzarides, T. (2007), "Chromatin modifications and their function", Cell 128:693-705
Lagger, G. et al. (2002), "Essential function of histone deacetylase 1 in proliferation control and CDK inhibitor repression", EMBO J 21:2672-2681
Li, H. et al. (2014), "The histone deacetylase inhibitor trichostatin A promotes totipotentcy in the male gametophyte", Plant Cell 26:195-209
Luger, K. et al. (1997), "Crystal structure of the nucleosome core particle at 2.8 a resolution", Nature 389:251-260
Menegola, E. 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
Riggs, M.G. et al. (1977), "N-butyrate causes histone modification in HeLa and friend erythroleukaemia cells", Nature 268:462-464
Schroeder, F.A. 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
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
Wade, M.G. et al. (2008), "Methoxyacetic acid-induced spermatocyte death is associated with histone hyperacetylation in rats", Biol Reprod 78:822-831
Yoshida, 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