To the extent possible under law, AOP-Wiki has waived all copyright and related or neighboring rights to KER:1716

Relationship: 1716

Title

A descriptive phrase which clearly defines the two KEs being considered and the sequential relationship between them (i.e., which is upstream, and which is downstream). More help

Histone deacetylase inhibition leads to Apoptosis

Upstream event
The causing Key Event (KE) in a Key Event Relationship (KER). More help
Downstream event
The responding Key Event (KE) in a Key Event Relationship (KER). More help

Key Event Relationship Overview

The utility of AOPs for regulatory application is defined, to a large extent, by the confidence and precision with which they facilitate extrapolation of data measured at low levels of biological organisation to predicted outcomes at higher levels of organisation and the extent to which they can link biological effect measurements to their specific causes. Within the AOP framework, the predictive relationships that facilitate extrapolation are represented by the KERs. Consequently, the overall WoE for an AOP is a reflection in part, of the level of confidence in the underlying series of KERs it encompasses. Therefore, describing the KERs in an AOP involves assembling and organising the types of information and evidence that defines the scientific basis for inferring the probable change in, or state of, a downstream KE from the known or measured state of an upstream KE. More help

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

Taxonomic Applicability

Latin or common names of a species or broader taxonomic grouping (e.g., class, order, family) that help to define the biological applicability domain of the KER.In general, this will be dictated by the more restrictive of the two KEs being linked together by the KER.  More help
Term Scientific Term Evidence Link
Homo sapiens Homo sapiens High NCBI
Mus musculus Mus musculus High NCBI

Sex Applicability

An indication of the the relevant sex for this KER. More help
Sex Evidence
Unspecific High

Life Stage Applicability

An indication of the the relevant life stage(s) for this KER.  More help
Term Evidence
Not Otherwise Specified High

Key Event Relationship Description

Provides a concise overview of the information given below as well as addressing details that aren’t inherent in the description of the KEs themselves. More help

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

Include a description of the approach for identification and assembly of the evidence base for the KER.  For evidence identification, include, for example, a description of the sources and dates of information consulted including expert knowledge, databases searched and associated search terms/strings.  Include also a description of study screening criteria and methodology, study quality assessment considerations, the data extraction strategy and links to any repositories/databases of relevant references.Tabular summaries and links to relevant supporting documentation are encouraged, wherever possible. More help

Evidence Supporting this KER

Addresses the scientific evidence supporting KERs in an AOP setting the stage for overall assessment of the AOP. More help
Biological Plausibility
Addresses the biological rationale for a connection between KEupstream and KEdownstream.  This field can also incorporate additional mechanistic details that help inform the relationship between KEs, this is useful when it is not practical/pragmatic to represent these details as separate KEs due to the difficulty or relative infrequency with which it is likely to be measured.   More help

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
Addresses inconsistencies or uncertainties in the relationship including the identification of experimental details that may explain apparent deviations from the expected patterns of concordance. More help

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

Known modulating factors

This table captures specific information on the MF, its properties, how it affects the KER and respective references.1.) What is the modulating factor? Name the factor for which solid evidence exists that it influences this KER. Examples: age, sex, genotype, diet 2.) Details of this modulating factor. Specify which features of this MF are relevant for this KER. Examples: a specific age range or a specific biological age (defined by...); a specific gene mutation or variant, a specific nutrient (deficit or surplus); a sex-specific homone; a certain threshold value (e.g. serum levels of a chemical above...) 3.) Description of how this modulating factor affects this KER. Describe the provable modification of the KER (also quantitatively, if known). Examples: increase or decrease of the magnitude of effect (by a factor of...); change of the time-course of the effect (onset delay by...); alteration of the probability of the effect; increase or decrease of the sensitivity of the downstream effect (by a factor of...) 4.) Provision of supporting scientific evidence for an effect of this MF on this KER. Give a list of references.  More help
Response-response Relationship
Provides sources of data that define the response-response relationships between the KEs.  More help
Time-scale
Information regarding the approximate time-scale of the changes in KEdownstream relative to changes in KEupstream (i.e., do effects on KEdownstream lag those on KEupstream by seconds, minutes, hours, or days?). More help

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
Define whether there are known positive or negative feedback mechanisms involved and what is understood about their time-course and homeostatic limits. More help

Domain of Applicability

A free-text section of the KER description that the developers can use to explain their rationale for the taxonomic, life stage, or sex applicability structured terms. More help

・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].

References

List of the literature that was cited for this KER description. More help

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