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Relationship: 1714

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 p21 (CDKN1A) expression, increase

Upstream event

The causing Key Event (KE) in a Key Event Relationship (KER). More help

Histone deacetylase inhibition

Downstream event

The responding Key Event (KE) in a Key Event Relationship (KER). More help

p21 (CDKN1A) expression, increase

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

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 induction of the p21 through chromosomal hyperacetylation on promoter regions of cell cycle regulatory genes [Falkenberg, 2014]. The HDAC inhibitors, suberoylanilide hydroxamic acid (SAHA), trichostatin A (TSA), and MS-27-275 induced histone hyperacetylation and p21 up-regulation [Glaser, 2003].

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

In human pancreatic cancer cell lines, p21 up-regulation and histone H3 hyperacetylation by HDAC inhibitor AR-42 were observed [Henderson, 2016]. Furthermore, the oral administration of AR-42 at 50 mg/kg resulted in suppression of tumor in the pancreatic cancer cell xenograft and transgenic KP^fl/flC (LSL-Kras^G12D; Trp53^flox/flox; Pdx-1-Cre) mouse model [Henderson, 2016].

Empirical Evidence

Provides specific (citable) evidence that supports the idea of a change in the upstream KE (KEupstream) leading to, or being associated with, a subsequent change in the downstream KE (KEdownstream), assuming the perturbation of KEupstream is sufficient. More help

HDAC inhibitor, methoxyacetic acid (MAA), up-regulated p21 mRNA level and acetylation of histone H3 and H4 [Parajuli, 2014].
The expression of p21 was up-regulated with 10 mM of MAA [Dayan, 2014].
HDIs-induced G₁/S phase arrest occurs primarily through transcriptional changes in cell cycle regulatory genes, such as induction of the CDK inhibitors p21 (CDKN1A), p15^INK4B(CDKN2B), p19^INK4D (CDKN2D) and p57 (CDKN1C) [Falkenberg, 2014].
HDAC1-deficient embryonic stem cells showed decrease in cyclin-associated kinase activities and increase in p21^WAF1/CIP1 [Lagger, 2002]. Expression of p21 is up-regulated in HDAC1-null embryos [Lagger, 2002].
HDIs induce expression of p21 via Sp1 binding sites in the p21 promoter [Gartel, 2002].
HDIs such as SAHA, TSA and MS-275 up-regulates p21 gene expression in T24 bladder carcinoma cells, which also suggests that HDAC inhibition leads to p21 up-regulation [Glaser, 2003].
Cyclin-dependent kinase (CDK) inhibitor p21 is up-regulated in HDAC1-deficient embryonic stem (ES) cells [Lagger, 2002].
In HDAC1^-/- mouse embryonic fibroblasts, p21 level increase is observed, which indicates that HDAC suppression leads to p21 up-regulation [Zupkovitz, 2010].
Loss of HDAC1 in ES cells decreased proliferation and cyclin A- and cyclin E-associated kinase activity in the HDAC1 mutant cells [Lagger, 2002].

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

The HDAC inhibition-induced p21 up-regulation seems to contain several pathway cross-talks. The HDAC inhibition with sodium butyrate increases p53-dependent up-regulation of p21 [Saldanha, 2014]. The HDAC inhibition with 2-MAA induced p53 acetylation [Dayan, 2014]. HDAC inhibition with ST2783 induced acetylation of p53 [Zuco, 2011].

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

Quantitative Understanding of the Linkage

Captures information that helps to define how much change in the upstream KE, and/or for how long, is needed to elicit a detectable and defined change in the downstream KE. More help

Response-response Relationship

Provides sources of data that define the response-response relationships between the KEs. More help

The exposure of 2-MAA (3, 10, 30 mM) on limbs for 3 hrs dose-dependently increased p21 mRNA level [Dayan, 2014]. The 2-MAA (3, 10, and 30 mM) dose-dependently induced acetylation on histone 3 lysine 9 (H3K9Ac) and histone 4 lysine 12 (H4K12Ac) at 1, 3, 6 and 24hr [Dayan, 2014]. The expression of p21 in A431 lung carcinoma cells and H1975 skin carcinoma cells stimulated with gefitinib loaded poly (lactic-co-glycolic acid) (PLGA) nanoparticles (GNPs) was increased in more than 3-fold compared to the cells without treatment [Kaur, 2013]. GNPs hyperacetylate histone H3 via histone acetyltransferases p300/CBP [Kaur, 2013].

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

Time course for histone H4 hyperacetylation in response to in repeated doses of TSA every 8 hrs showed that histone hyperacetylation was peaked in 12 hrs in 8-fold increase and showed 5-fold increase in 24 hrs compared to control [Wu JT].

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

The exposure of 2-MAA on mouse limbs in vitro induced histone hyperacetylation and p21 expression increase (Mus musculus) [Dayan, 2014]. HDAC-deficient embryonic stem cells demonstrated up-regulation of p21 in mice (Mus musculus) [Lagger, 2002]. HDAC inhibitor, AR-42 induced histone hyperacetylation and p21 up-regulation in human pancreatic cancer cells (Homo sapiens) [Henderson, 2016].

References

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

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

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

Henderson SE 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 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

Dayan C and Hales BF. (2014) Effects of Ethylene glycol monomethyl ether and its metabolite, 2-methoxyacetic acid, on organogenesis stage mouse limbs in vitro. Birth Defects Res 101:254-261

Lagger G et al. (2002) Essential function of histone deacetylase 1 in proliferation control and CDK inhibitor repression. EMBO J 21:2672-2681

Gartel AL and Tyner AL (2002) The role of the cyclin-dependent kinase inhibitor p21 in apoptosis. Mol Cancer Ther 1: 639-649

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

Saldanha SN et al. (2014) Molecular mechanisms for inhibition of colon cancer cells by combined epigenetic-modulating epigallocatechin gallate and sodium butyrate. Exp Cell Res 324:40-53

Zuco V et al. (2011) Synergistic antitumor effects of novel HDAC inhibitors and paclitaxel in vitro and in vivo. PLoS One 6:e29085

Kaur J and Tikoo K. (2013) p300/CBP dependent hyperacetylation of histone potentials anticancer activity of gefitinib nanoparticles. Biochimica et Biophysica Acta 1833:1028-1040

Wu JT et al. (2001) Transient vs prolonged histone hyper acetylation: effects on colon cancer cell growth, differentiation, and apoptosis. Am J Physiol Gastrointest Liver Physiol 280:G482-G490