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Histone deacetylase inhibition leads to Apoptosis
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||Moderate||Moderate||Brendan Ferreri-Hanberry (send email)||Open for citation & comment||WPHA/WNT Endorsed|
Life Stage Applicability
|Not Otherwise Specified||High|
Key Event Relationship Description
HDAC inhibition leads to cell death through the apoptotic pathways [Falkenberg and Johnstone, 2014]. The intrinsic apoptosis pathway requires BH3-only proteins, and BCL-2 protein overexpression inhibits apoptosis [Falkenberg and Johnstone, 2014]. Administration of methoxyacetic acid (MAA), an HDAC inhibitor, causes apoptosis with DNA ladder in male germ cells [Brinkworth et al., 1995]. MAA induces the apoptosis of spermatocytes at spermatogenic cycle stage IX-II [Brinkworth et al., 1995].
Evidence Collection Strategy
Evidence Supporting this KER
HDAC inhibition in cancer results in apoptosis with the up-regulation of pro-apoptotic B cell lymphoma 2 (BCL-2) family genes and down-regulation of pro-survival BCL-2 genes [Falkenberg, 2014]. The antitumor effect of HDAC inhibition includes cell death and apoptosis [Falkenberg and Johnstone, 2014].
Uncertainties and Inconsistencies
It is uncertain through which pathway the HDAC inhibition induces apoptosis.
Known modulating factors
MAA (5 mM) decreased protein expression of BIRC2 and activated caspases 7 and 3 within 72 hrs [Parajuli et al., 2014].
Known Feedforward/Feedback loops influencing this KER
Domain of Applicability
・AR-42 inhibited proliferation of human pancreatic cancer cells (Homo sapiens) [Henderson et al., 2016].
・MAA induced apoptosis in human prostate cancer cell lines. The apoptosis and proliferation inhibition induced by MAA, an HDAC inhibitor, was measured in human prostate cancer cell lines (Homo sapiens) [Parajuli et al., 2014].
・SAHA or TSA, which are HDAC inhibitors, reduced cell viability in NHDFs (Homo sapiens) [Glaser et al., 2003].
・The proliferation of the HDAC-/- ES cells was inhibited compared to HDAC+/+ ES cells (Homo sapiens) [Zupkovitz et al., 2010].
Brinkworth, M.H. et al. (1995), "Identification of male germ cells undergoing apoptosis in adult rats", J Reprod Fertil 105:25-33
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
Henderson, S.E. 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, 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
Wade, M.G. et al. (2008), "Methoxyacetic acid-induced spermatocyte death is associated with histone hyperacetylation in rats", Biol Reprod 78:822-831
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