API

Relationship: 1716

Title

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Histone deacetylase inhibition leads to Apoptosis

Upstream event

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Histone deacetylase inhibition

Downstream event

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Apoptosis

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 Moderate Moderate

Taxonomic Applicability

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Term Scientific Term Evidence Link
Homo sapiens Homo sapiens High NCBI
Mus musculus Mus musculus High 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 death through the apoptotic pathways [Falkenberg and Johnstone, 2014]. Intrinsic apoptosis pathway requires BH3-only proteins, and BCL-2 protein overexpression inhibits apoptosis [Falkenberg and Johnstone, 2014]. Administration of methoxyacetic acid (MAA), a 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 Supporting this KER

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Biological Plausibility

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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].

Empirical Evidence

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  • MAA-induced spermatocyte death is associated with histone acetylation increase [Wade et al., 2008].
  • The HDAC inhibition induced apoptosis markers such as BAK overexpression and suppression of phosphorylated AKT [Henderson et al., 2016].
  • The administration of MAA can cause apoptosis in the germ cells of adult male rats [Brinkworth et al., 1995].

Uncertainties and Inconsistencies

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It is uncertain through which pathway the HDAC inhibition induces apoptosis.

Quantitative Understanding of the Linkage

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MAA (5 mM) induced apoptosis in prostate cancer cell lines, LNCaP, C4-2B, PC-3 and DU-145, in which apoptotic nucleosomes were calculated as absorbance at 405 nm – absorbance at 490 nm [Parajuli et al., 2014].

Response-response Relationship

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Time-scale

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MAA (5 mM) decreased protein expression of BIRC2 and activated caspases 7 and 3 within 72 hrs [Parajuli et al., 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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・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, a 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].

References

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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