Upstream eventHistone deacetylase inhibition
cell cycle, disrupted
Key Event Relationship Overview
AOPs Referencing Relationship
|AOP Name||Adjacency||Weight of Evidence||Quantitative Understanding|
|Histone deacetylase inhibition leading to testicular toxicity||non-adjacent||High||High|
|Homo sapiens||Homo sapiens||High||NCBI|
Life Stage Applicability
|Not Otherwise Specified||High|
Key Event Relationship Description
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
The knockdown of HDACs may induce antitumor effects such as cell cycle arrest and inhibition of proliferation [Falkenberg, 2014]. In leukemia, acute myloid leukaemia 1-ETO, oncogenic fusion protein, recruits the variety of the proteins including HDACs to form multiprotein complexes to repress the cell cycle inhibitors, which suggests that the HDAC inhibition leads to cell cycle dysregulation [Falkenberg, 2014].
- In HDAC1-/- fibroblast lines, increase in the amount of cells in G1 phase and decrease in the amount of cells in S phase were observed, which indicates the importance of HDAC inhibition in cell cycle regulation [Zupkovitz, 2010].
- 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].
- HDAC inhibition leads to cell cycle arrest, where G1/S phase arrest occurs via up-regulation of p21 [Falkenberg, 2014].
- 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].
Uncertainties and Inconsistencies
MAA, a HDI, induced cell cycle arrest and up-regulation of p21 expression, and inhibited prostate cancer cell growth [Parajuli, 2014]. 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
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].
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
Known Feedforward/Feedback loops influencing this KER
Domain of Applicability
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].
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
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
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