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Relationship: 1715
Title
Histone deacetylase inhibition leads to Cell cycle, disrupted
Upstream event
Downstream event
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 | non-adjacent | High | Moderate | Shihori Tanabe (send email) | Open for citation & comment | WPHA/WNT Endorsed |
Taxonomic Applicability
Sex Applicability
Sex | Evidence |
---|---|
Unspecific | High |
Life Stage Applicability
Term | Evidence |
---|---|
Not Otherwise Specified | High |
Key Event Relationship Description
HDAC inhibition leads to cell cycle arrest including G1/S phase arrest [Falkenberg and Johnstone, 2014]. The HDAC inhibition-induced cell cycle arrest is mediated by transcriptional changes of the CDK inhibitors such as p21 [Falkenberg and Johnstone, 2014].
Evidence Collection Strategy
Evidence Supporting this KER
Biological Plausibility
The knockdown of HDACs may induce antitumor effects such as cell cycle arrest and inhibition of proliferation [Falkenberg and Johnstone, 2014]. In leukemia, an oncogenic fusion protein recruits a variety of proteins including HDACs to repress cell cycle inhibitors, which suggests that HDAC inhibition leads to cell cycle dysregulation [Falkenberg and Johnstone, 2014].
Empirical Evidence
- 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 et al., 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 et al., 2000]. Apicidin induced hyperacetylation of histone H4, up-regulation of p21, and G0/G1 cell cycle arrest in HeLa cells [Han et al., 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 et al., 2002].
- G1/S transition blockade was observed in methoxyacetic acid (MAA)-treated prostate cancer cells [Parajuli et al., 2014].
- The change in the amounts of cells in the G1 phase and S phase of the cell cycle was detected in mouse HDAC1 knock-out fibroblast lines [Zupkovitz et al., 2010].
- MAA, an HDI, induced cell cycle arrest and up-regulation of p21 expression and inhibited prostate cancer cell growth [Parajuli et al., 2014].
Uncertainties and Inconsistencies
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 et al., 2014].
Known modulating factors
Quantitative Understanding of the Linkage
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 et al., 2014]. Almost 80% of the cells were arrested in the G1 phase upon stimulation of MAA, whereas approximately 40 to 60 % of the cells were in the G1 phase without MAA treatment [Parajuli et al., 2014].
Response-response Relationship
Time-scale
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 et al., 2014].
Known Feedforward/Feedback loops influencing this KER
Domain of Applicability
MAA induced G1 cell cycle arrest in human prostate cancer cells (Homo sapiens) [Parajuli et al., 2014].
Apicidin induced G1 cell cycle arrest in HeLa cells (Homo sapiens) [Han et al., 2000].
The change in the amounts of cells in the G1 phase and S phase of the cell cycle was detected in mouse HDAC1 knock-out fibroblast lines (Mus musculus) [Zupkovitz et al., 2010].
Loss of HDAC1 in mouse embryonic stem (ES) cells results in 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 et al., 2002].
References
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
Glaser, K.B. 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, J.W. 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, K.R. 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