API

Relationship: 1715

Title

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Histone deacetylase inhibition leads to Cell cycle, disrupted

Upstream event

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Histone deacetylase inhibition

Downstream event

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Cell cycle, disrupted

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 atrophy non-adjacent High Moderate

Taxonomic Applicability

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Term Scientific Term Evidence Link
Homo sapiens Homo sapiens High NCBI
Mus musculus Mus musculus Moderate 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 cell cycle arrest including G1/S phase arrest [Falkenberg, 2014]. The HDAC inhibition-induced cell cycle arrest is the mediated by transcriptional changes of the CDK inhibitors such as p21 [Falkenberg, 2014].

Evidence Supporting this KER

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Biological Plausibility

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The knockdown of HDACs may induce antitumor effects such as cell cycle arrest and inhibition of proliferation [Falkenberg, 2014]. In leukemia, an oncogenic fusion protein recruits the variety of the proteins including HDACs to repress the cell cycle inhibitors, which suggests that the HDAC inhibition leads to cell cycle dysregulation [Falkenberg, 2014].

Empirical Evidence

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  • HDAC inhibition with SAHA, TSA and MS-27-275 induced acetylation of histone H4, up-regulation of cyclin-dependent kinase inhibitor p21, and inhibition of proliferation in human bladder carcinoma cells [Glaser, 2003].
  • Apicidin [cyclo(N-O-methyl-L-tryptophanyl-L-isoleucinyl-D-pipecolinyl-L-2-amino-8-oxodecanoyl)], a fungal metabolite HDI, inhibits proliferation of tumor cells via p21 induction [Han, 2000]. Apicidin induced hyperacetylation of histone H4, up-regulation of p21, and G0/G1 cell cycle arrest in HeLa cells [Han, 2000].
  • Falkenberg and Johnstone (2014) nicely reviewed that HDAC inhibition leads to cell cycle arrest in which G1/S phase arrest occurs via up-regulation of p21.
  • Loss of HDAC1 in mouse embryonic stem (ES) cells has demonstrated the acetylation of histones H3 and H4, up-regulation of cyclin-dependent kinase inhibitors p21WAF1/CIP1 and p27KIP1 and inhibition of proliferation [Lagger, 2002].
  • G1/S transition blockade was observed in MAA-treated prostate cancer cells [Parajuli, 2014].
  • The change in the amounts of cells in G1 phase and S phase of cell cycle was detected in mouse HDAC1 knock out fibroblast lines [Zupkovitz, 2010]. 
  • MAA, a HDI, induced cell cycle arrest and up-regulation of p21 expression, and inhibited prostate cancer cell growth [Parajuli, 2014].

Uncertainties and Inconsistencies

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The involvement of p53/p63/p73 in up-regulation of p21 induced by HDAC inhibition is not fully elucidated, where time course of the p21 and p53/p63/p73 mRNA expression has demonstrated the cell-line specific differences in the responses in 4 human prostate cancer cell lines LNCaP, C4-2B, PC-3 and DU-145 [Parajuli, 2014].

Quantitative Understanding of the Linkage

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MAA (20 mM) induced G1 cell cycle arrest upon the treatment for 24 hrs in LNCaP, C4-2B, PC-3 and DU-145 human prostate cancer cell lines [Parajuli, 2014]. Almost 80% of the cells were arrested in G1 phase upon stimulation of MAA, whereas approximately 40 to 60 % of the cells were in G1 phase without MAA treatment [Parajuli, 2014].

Response-response Relationship

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Time-scale

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MAA (5 mM) induced p21 up-regulation in 12 to 72 hrs in LNCaP, C4-2B, PC-3 and DU-145 human prostate cancer cell lines [Parajuli, 2014].

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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MAA induced G1 cell cycle arrest in human prostate cancer cells (Homo sapiens) [Parajuli, 2014].

Apicidin induced G1 cell cycle arrest in HeLa cells (Homo sapiens) [Han, 2000].

The change in the amounts of cells in G1 phase and S phase of cell cycle was detected in mouse HDAC1 knock out fibroblast lines (Mus musculus) [Zupkovitz, 2010].

Loss of HDAC1 in mouse embryonic stem (ES) cells has demonstrated the acetylation of histones H3 and H4, up-regulation of cyclin-dependent kinase inhibitors p21WAF1/CIP1 and p27KIP1 and inhibition of proliferation (Mus musculus) [Lagger, 2002].

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

Han JW et al. (2000) Apicidin, a histone deacetylase inhibitor, inhibits proliferation of tumor cells via induction of p21WAF1/Cip1 and gelsolin. Cancer Res 60:6068-6074

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

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

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