API

Relationship: 1714

Title

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Histone deacetylase inhibition leads to p21 (CDKN1A) expression, increase

Upstream event

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Histone deacetylase inhibition

Downstream event

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p21 (CDKN1A) expression, 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 non-adjacent High High

Taxonomic Applicability

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Term Scientific Term Evidence Link
Homo sapiens Homo sapiens 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
Not Otherwise Specified High

Key Event Relationship Description

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HDAC inhibition leads to induction of the p21 through chromosomal hyperacetylation on promoter regions of cell cycle regulatory genes [Falkenberg, 2014]. The HDAC inhibitors, suberoylanilide hydroxamic acid (SAHA), trichostatin A (TSA), and MS-27-275 induced histone hyperacetylation and p21 up-regulation [Glaser, 2003].

Evidence Supporting this KER

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Biological Plausibility

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In human pancreatic cancer cell lines, p21 up-regulation and histone H3 hyperacetylation by HDAC inhibitor AR-42 were observed [Henderson, 2016]. Furthermore, the oral administration of AR-42 at 50 mg/kg resulted in suppression of tumor in the pancreatic cancer cell xenograft and transgenic KPfl/flC (LSL-KrasG12D; Trp53flox/flox; Pdx-1-Cre) mouse model [Henderson, 2016].

Empirical Evidence

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  • HDAC inhibitor, methoxyacetic acid (MAA), up-regulated p21 mRNA level and acetylation of histone H3 and H4 [Parajuli, 2014].
  • The expression of p21 was up-regulated with 10 mM of MAA [Dayan, 2014].
  • HDIs-induced G1/S phase arrest occurs primarily through transcriptional changes in cell cycle regulatory genes, such as induction of the CDK inhibitors p21 (CDKN1A), p15INK4B (CDKN2B), p19INK4D (CDKN2D) and p57 (CDKN1C) [Falkenberg, 2014].
  • HDAC1-deficient embryonic stem cells showed decrease in cyclin-associated kinase activities and increase in p21WAF1/CIP1 [Lagger, 2002]. Expression of p21 is up-regulated in HDAC1-null embryos [Lagger, 2002].
  • HDIs induce expression of p21 via Sp1 binding sites in the p21 promoter [Gartel, 2002].
  • HDIs such as SAHA, TSA and MS-275 up-regulates p21 gene expression in T24 bladder carcinoma cells, which also suggests that HDAC inhibition leads to p21 up-regulation [Glaser, 2003].
  • Cyclin-dependent kinase (CDK) inhibitor p21 is up-regulated in HDAC1-deficient embryonic stem (ES) cells [Lagger, 2002].
  • In HDAC1-/- mouse embryonic fibroblasts, p21 level increase is observed, which indicates that HDAC suppression leads to p21 up-regulation [Zupkovitz, 2010].
  • Loss of HDAC1 in ES cells decreased proliferation and cyclin A- and cyclin E-associated kinase activity in the HDAC1 mutant cells [Lagger, 2002].

Uncertainties and Inconsistencies

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The HDAC inhibition-induced p21 up-regulation seems to contain several pathway cross-talks. The HDAC inhibition with sodium butyrate increases p53-dependent up-regulation of p21 [Saldanha, 2014]. The HDAC inhibition with 2-MAA induced p53 acetylation [Dayan, 2014]. HDAC inhibition with ST2783 induced acetylation of p53 [Zuco, 2011].

Quantitative Understanding of the Linkage

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Response-response Relationship

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The exposure of 2-MAA (3, 10, 30 mM) on limbs for 3 hrs dose-dependently increased p21 mRNA level [Dayan, 2014]. The 2-MAA (3, 10, and 30 mM) dose-dependently induced acetylation on histone 3 lysine 9 (H3K9Ac) and histone 4 lysine 12 (H4K12Ac) at 1, 3, 6 and 24hr [Dayan, 2014]. The expression of p21 in A431 lung carcinoma cells and H1975 skin carcinoma cells stimulated with gefitinib loaded poly (lactic-co-glycolic acid) (PLGA) nanoparticles (GNPs) was increased in more than 3-fold compared to the cells without treatment [Kaur, 2013]. GNPs hyperacetylate histone H3 via histone acetyltransferases p300/CBP [Kaur, 2013].

Time-scale

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Time course for histone H4 hyperacetylation in response to in repeated doses of TSA every 8 hrs showed that histone hyperacetylation was peaked in 12 hrs in 8-fold increase and showed 5-fold increase in 24 hrs compared to control [Wu JT].

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 exposure of 2-MAA on mouse limbs in vitro induced histone hyperacetylation and p21 expression increase (Mus musculus) [Dayan, 2014]. HDAC-deficient embryonic stem cells demonstrated up-regulation of p21 in mice (Mus musculus) [Lagger, 2002]. HDAC inhibitor, AR-42 induced histone hyperacetylation and p21 up-regulation in human pancreatic cancer cells (Homo sapiens) [Henderson, 2016].

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 13:673-691

Glaser KB et al. (2003) Gene expression profiling of multiple histone deacetylase (HDAC) inhibitors: defining a common gene set produced by HDAC inhibition in T24 and MDA carcinoma cell lines. Mol Cancer Ther 2:151-163

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

Parajuli KR et al. (2014) Methoxyacetic acid suppresses prostate cancer cell growth by inducing growth arrest and apoptosis. Am J Clin Exp Urol 2:300-312

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 101:254-261

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

Gartel AL and Tyner AL (2002) The role of the cyclin-dependent kinase inhibitor p21 in apoptosis. Mol Cancer Ther 1: 639-649

Glaser KB et al. (2003) Gene expression profiling of multiple histone deacetylase (HDAC) inhibitors: defining a common gene set produced by HDAC inhibition in T24 and MDA carcinoma cell lines. Mol Cancer Ther 2:151-163

Zupkovitz G et al. (2010) The cyclin-dependent kinase inhibitor p21 is a crucial target for histone deacetylase 1 as a regulator of cellular proliferation. Mol Cell Biol 30:1171-1181

Saldanha SN et al. (2014) Molecular mechanisms for inhibition of colon cancer cells by combined epigenetic-modulating epigallocatechin gallate and sodium butyrate. Exp Cell Res 324:40-53

Zuco V et al. (2011) Synergistic antitumor effects of novel HDAC inhibitors and paclitaxel in vitro and in vivo. PLoS One 6:e29085

Kaur J and Tikoo K. (2013) p300/CBP dependent hyperacetylation of histone potentials anticancer activity of gefitinib nanoparticles. Biochimica et Biophysica Acta 1833:1028-1040

Wu JT et al. (2001) Transient vs prolonged histone hyper acetylation: effects on colon cancer cell growth, differentiation, and apoptosis. Am J Physiol Gastrointest Liver Physiol 280:G482-G490