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Histone deacetylase inhibition leads to Cell cycle, disrupted
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||Brendan Ferreri-Hanberry (send email)||Open for citation & comment||EAGMST Under Review|
Life Stage Applicability
|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 the mediated by transcriptional changes of the CDK inhibitors such as p21 [Falkenberg and Johnstone, 2014].
Evidence Supporting this KER
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].
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].
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 modulating factors
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 G1 phase and S phase of 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].
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