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Key Event Title
Histone deacetylase inhibition
|Level of Biological Organization|
Key Event Components
|enzyme inhibitor activity||histone deacetylase 1||decreased|
Key Event Overview
AOPs Including This Key Event
|AOP Name||Role of event in AOP||Point of Contact||Author Status||OECD Status|
|Histone deacetylase inhibition leading to testicular atrophy||MolecularInitiatingEvent||Brendan Ferreri-Hanberry (send email)||Open for citation & comment||WPHA/WNT Endorsed|
|HDAC inhibition leads to impeded craniofacial development||MolecularInitiatingEvent||Agnes Aggy (send email)||Under Development: Contributions and Comments Welcome|
|HDAC inhibition leads to neural tube defects||MolecularInitiatingEvent||Allie Always (send email)||Under Development: Contributions and Comments Welcome|
|CerS leads to NTDs||KeyEvent||Agnes Aggy (send email)||Open for citation & comment|
|All life stages||Moderate|
Key Event Description
Nucleosomes consist of eight core histones, two of each histone H2A, H2B, H3, and H4 [Damaskos et al., 2017]. DNA strands (about 200 bp) wind around the core histones, which can be modified on their N-terminal ends. One possible modification is the acetylation of lysine residues, which decreases the binding strength between DNA and the core histone. Histone deacetylases (HDACs) hydrolyze the acetyl residues [Damaskos et al., 2017]. HDACs remove the acetyl groups from the lysine residues leading to the formation of a condensed and transcriptionally silenced chromatin. Thus, the inhibition of HDAC blocks this action and can result in hyperacetylation of histones associated mostly with increases in transcriptional activation. Histone deacetylase inhibitor (HDI) inhibits HDAC, causing increased acetylation of the histones and thereby facilitating binding of transcription factors [Taunton et al., 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 and Parra, 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 and Parra, 2012]. SirT1 is highly expressed in testis, thymus, and multiple types of germ cells [Bell et al., 2014]. HDAC11 expression is enriched in the kidney, brain, testis, heart, and skeletal muscle [Barneda-Zahonero and Parra, 2012]. The members of classes 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 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 in 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 exerts 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. Some in silico methods including molecular modeling, virtual screening, and molecular dynamics are used to find the common HDAC inhibitor structures [Huang et al., 2016; Yanuar et al. 2016].
How It Is Measured or Detected
The measurement of HDAC inhibition monitors changes in histone acetylation. HDAC inhibition can be detected directly by the measurement of HDAC activity using commercially available colorimetric or fluorimetric kits or indirectly by the increase of histone acetylation as the detection of global histone acetylation changes by Western blot or mass spectrometry (MS)-based proteomics methods or as detection of site-specific histone acetylation changes using chromatin immunoprecipitation (ChIP) or ChIP-on-Chip. The measurement methods include the immunological detection of histone acetylation with anti-acetylated histone antibodies [Richon et al., 2004]. The histones are isolated from pellets of cells treated with HDIs, followed by acid-urea-triton gel electrophoresis, western blotting, and immunohistochemistry [Richon et al., 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 et al., 2016]. HDAC inhibition can be predicted by perturbations in gene expression patterns as well; an 81-gene transcriptomic biomarker of HDAC inhibition, called TGx-HDACi, has shown to accurately predict HDAC inhibition after 4 hour exposures to HDI in TK6 human lymphoblastoid cells [Cho et al., 2021].
Domain of Applicability
The inhibition of HDAC by HDIs is well conserved between species from lower organisms to mammals.
- HDAC inhibition restores the rate of resorption of subretinal blebs in hyperglycemia in brown Norway rat and HDAC activity was inhibited with HDIs in human ARPE19 cells [Desjardins et al., 2016].
- Treatment of HDIs inducing HDAC inhibition showed anti-tumor effects in human non-small cell lung cancer cells [Ansari et al., 2016; Miyanaga et al., 2008].
- HDAC acetylation level was increased by HDIs in the MRL-lpr/lpr murine model of lupus splenocytes [Mishra et al., 2003].
- SAHA increased histone acetylation in the brain and spleen of mice [Hockly et al., 2003].
- MAA inhibits HDAC activity in HeLa cells and spleens from C57BL/6 mice [Jansen et al., 2004].
- It is also reported that MAA inhibits HDAC activity in testis cytosolic and nuclear extract of juvenile rats (27 days old) [Wade et al., 2008].
- VPA and TSA inhibit HDAC enzymatic activity in the mouse embryo and human HeLa cell nuclear extract [Di Renzo et al., 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 et al., 2003].
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