API

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Relationship: 2970

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

Epigenetic modification process leads to Expression of factors ruling proliferation, modified

Upstream event
The causing Key Event (KE) in a Key Event Relationship (KER). More help
Epigenetic modification process
Downstream event
The responding Key Event (KE) in a Key Event Relationship (KER). More help
Expression of factors ruling proliferation, modified

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
Activation of uterine estrogen receptor-alfa leading to endometrial adenocarcinoma, via epigenetic modulation adjacent Barbara Viviani (send email) Under development: Not open for comment. Do not cite Under Review

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

Sex Applicability

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

Life Stage Applicability

An indication of the the relevant life stage(s) for this KER.  More help
Term Evidence
All life stages

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

Epigenetics, in general, can affect gene accessibility to several proteins involved in transcription and not only, such as methyl-CpG-binding proteins, with the final effect of modulating and altering gene transcription. Epigenetic modifications involve DNA methylation, histone modification and variants, and non-coding RNAs (Kobow et al., 2020). The main process that favors gene transcription is increased histone acetylation (Kobow et al., 2020). Whereas DNA methylation and non-coding RNAs are usually associated with transcription repression (Jones & Baylin, 2007). In particular, histone modifications have different effects based on the molecule that is added or removed (acetylation, phosphorylation, methylation). Generally, these modifications influence the binding of proteins (Fischle et al., 2005) and alter the contact between nucleosomes or histone and DNA (Grewal & Moazed, 2003). Indeed, histone acetylation of lysine, for example, is able to decrease the positive charge from lysine and therefore to favor a less-packed chromatin structure, therefore more accessible to transcription (Stephens et al., 2013). On the other hand, histone deacetylation favors a closed chromatin which is inaccessible to the transcription machinery. DNA methylation, instead, impede the binding of transcription factors to the DNA and also of transcription factors, since the methyl-CpG-binding proteins have a higher affinity for methylated cytosines in the promoter (Hark et al., 2000). Furthermore, these proteins are also able to recruit other proteins and form a complex with histone deacetylase activity, therefore reducing gene transcription (Boyes & Bird, 1991; Jin et al., 2005).

Finally, non-coding RNAs, like miRNAs, are able to modify the post-transcriptional gene expression, targeting the mRNAs (Bartel, 2004), but they are also involved in the recruitment of DNA methyltransferases (Poddar et al., 2017). lncRNAs are able to regulate gene expression of nearby genes (Mercer et al., 2009). Furthermore, they are able to recruit chromatin remodeling complexes to several loci (i.e., homebox loci) (Rinn et al., 2007).

It is important to underline that DNA methylation, histone modifications and non-coding RNAs cooperate to regulate gene expression. Also several miRNAs have been related to cancer: oncomiRs and tumor suppressive miRs (Esquela-Kerscher & Slack, 2006; Banno et al., 2014).

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

Aberrant DNA methylation in cancer cells involves the silencing of tumor suppressor (through the hypermethylation) while oncogenes are hypomethylated and therefore their transcription is promoted (Robbins and Cotran 2015). The transcription of the oncogenes/tumor suppressors can also be altered through histone modifications, altering the chromatin structure in correspondence of those genes. One example is p16, a tumor suppressor able to slow the progression from G1 to S phase of the cell cycle, its promoter is often hypermethylated, and therefore silenced, in several tumors, like cervical cancer (Kumar et al., 2015). In addition to local hypermethylation of onco-suppressors, the methylation changes can occur also globally throughout the genome, and sometime the reason why is the mutation of DNA methyltransferases (Baylin & Jones, 2011).

Several genes, such as homeobox genes (e.g. HOPX), have been found to be methylated in human endometrioid adenocarcinoma (Chen et al., 2015; Yamaguchi et al. 2009). HOPX methylation occurs at CpG islands in regions associated to the promoter and results in decreased expression (Yamaguchi et al. 2009). In particular, the modulation of HOPX in endometrioid adenocarcinoma is restricted to gland epithelium with the exclusion of stroma and is also detectable in human samples of normal endometrial tissue adjacent to the tumor (Yamaguchi et al. 2009). This observation suggests that methylation and downregulation of HOPX gene and protein may represent early changes leading to the initiation process. Other observations reporting hypermethylation of promoter regions for cancer related genes in normal endometrial tissue closely adjacent to the endometrial cancer (Kanaya et al. 2003; Arafa et al. 2008) point to a possible role of hypermethylation as an early event which prefigures cells transformation.

Dense methylation of HOPX associated with CpG region resulting in a reduced gene expression is evident also in endometrial cancer cell lines like Ishikawa, HEC-1A and HHUA (Yamaguchi et al. 2009).

Hypomethylated genes involved in the expression of factors ruling endometrial cells proliferation (e.g. PAX2) have been found in human cells obtained by patient specimens (Wu et al. 2005). Hypomethylation of PAX2 is distinctive of endometrioid Type I cancer and is absent in endometrial cells obtained by age-matched healthy subjects, where the promoter of PAX2 is methylated (Wu et al. 2005). In these cells methylated CpG binds methyl-CpG binding proteins associated with transcription repression complexes containing mSin3A/HDAC1 with histone deacetylase activity (Wu et al. 2005), suggesting a complex an epigenetic modulation of the promoter based on DNA methylation/histone deacetylation joint action. Accordingly, the repression complex is faintly associated to PAX promoter in cancer (Type I) endometrial cells (Wu et al. 2005). The release of the methylated/deacetylated status is a condition sine qua non to allow transcription of factors modulating endometrial cell proliferation (Wu et al. 2005).

The observation of an increased total histone H3 acetylation in human specimens from patient affected by endometrial carcinoma supports its relevance in this type of tumor (Dai et al. 2021). The increased acetylation in UA specimens has been linked to the increased expression of specific modulators, like ACLY, also expressed in endometrial cancer cell lines (Dai et al. 2021). Silencing of ACLY in these cells reduces histone acetylation at lysine in position 27 (H3K27) and 9 (H3K9) and at lysine position 27 in DOHOD promoter, a factor contributing to endometrial cancer cell proliferation (Dai et al. 2021 – see essentiality for details). Both H3K27 and H3K9 are associated with higher transcription and thus considered as active enhancer marks. Accordingly, ACLY silencing reduces DOHOD expression (Dai et al. 2021). As a human counterpart, DOHOD mRNA expression is directly correlated to ACLY mRNA expression in specimens from EC patients (Dai et al. 2021).

Trefoil factor 3 (TFF3) - The promoter sequence of TFF3 from -700bp to +50 bp, a region where four transcription factor binding sites for FOXA2, c-Jun, SP-1 and SOX5 respectively are located, contains 13 CpGs (Pandey et al. 2017). Hypomethylation of this region leading to increased TFF3 expression has been observed in different type of tumors (Okada et al. 2005; Vestergaard et al. 2010). The degree of promoter methylation correlates with endogenous TFF3 expression in the retinoblastoma cell lines (Philippeit et al. 2014).

Endometrial carcinoma is also associated with the up-regulation or down-regulation of several miRNAs and lncRNAs (Boren et al., 2008; Chung et al., 2009; Wu et al., 2009; Devor et al., 2011; Zhai et al., 2015). For example, HOTAIR, a lncRNA, is able to modulate cell proliferation in endometrial cancer by interacting with miRNAs and regulated proteins (Chiyomaru et al., 2014; Rajagopal et al., 2020 Zhou et al. 2018).

Within RIZ1 main functions, there is the induction of the arrest between G2 and M phase of the cell cycle, therefore it has been defined as tumor suppressor gene (He et al., 1998; Yang et al., 2017). This evidence has been obtained in breast, liver, microsatellite-unstable colon cancers, and glioma, within others (He et al., 1998; Zhang et al., 2015). In these tumors its promoter region is methylated, and therefore its transcription is silenced, leading to cell cycle progression (Mori et al., 2011). Regarding endometrial cancer, a link between RIZ1 low expression and tumor progression has been established (Yang et al., 2017).

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 studies providing insight into molecular mechanisms of epigenetic regulation have been essentially performed in tumoral cells, thus in cells with an already altered biochemical background compared to control cells and already prompted to uncontrolled proliferation. The relevance of the different background of endometrial cancer cells compared to normal is evident also in the epigenetic modulation, e.g. promoters of factors that rule cell proliferation like PAX2 are hypomethylated in human primary endometrial cancer (type I) cells but methylated in the normal counterpart (Wu et al.2005). Hypomethylation favours the increase of PAX2 transcription in cancer cells by 3h exposure to TAM or E2 but not in normal cells (Wu et al.2005). No dose or time-response were performed in normal cells (Wu et al.2005).

The collection of studies retrieved identify several factors ruling cell proliferation altered in uterine adenocarcinoma and ERa positive cancer cells. Essentiality linking epigenetic modulation (via different pathways) to the expression of these factors is supported. Nevertheless, for some of these studies (Dai et al. 2021; Yamaguchi et al, 2009; Zhou et al. 2018) empirical evidence supported by the exposure to E2 or TAM is lacking. A regulation of HOPX, ACLY/DOHOD, HOTAIR independent from E2 cannot be excluded.

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
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

References

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

Arafa M, Kridelka F, Mathias V, Vanbellinghen JF, Renard I, Foidart JM, Boniver J, Delvenne P. High frequency of RASSF1A and RARb2 gene promoter methylation in morphologically normal endometrium adjacent to endometrioid adenocarcinoma. Histopathology 2008;53:525–32

Banno, K., Iida, M., Yanokura, M., Kisu, I., Iwata, T., Tominaga, E., Tanaka, K., & Aoki, D. (2014). MicroRNA in cervical cancer: OncomiRs and tumor suppressor miRs in diagnosis and treatment. TheScientificWorldJournal, 2014, 178075. https://doi.org/10.1155/2014/178075

Bartel D. P. (2004). MicroRNAs: genomics, biogenesis, mechanism, and function. Cell, 116(2), 281–297. https://doi.org/10.1016/s0092-8674(04)00045-5

Baylin, S. B., & Jones, P. A. (2011). A decade of exploring the cancer epigenome - biological and translational implications. Nature reviews. Cancer, 11(10), 726–734. https://doi.org/10.1038/nrc3130

Baylin, S. B., & Ohm, J. E. (2006). Epigenetic gene silencing in cancer - a mechanism for early oncogenic pathway addiction?. Nature reviews. Cancer, 6(2), 107–116. https://doi.org/10.1038/nrc1799

Boyes J, Bird A. DNA methylation inhibits transcription indirectly via a methyl-CpG binding protein. Cell. 1991;64(6):1123–1134

Dai M, Yang B, Chen J, Liu F, Zhou Y, Zhou Y, Xu Q, Jiang S, Zhao S, Li X, Zhou X, Yang Q, Li J, Wang Y, Zhang Z, Teng Y. Nuclear-translocation of ACLY induced by obesity-related factors enhances pyrimidine metabolism through regulating histone acetylation in endometrial cancer. Cancer Lett. 2021 Aug 10;513:36-49. doi: 10.1016/j.canlet.2021.04.024. Epub 2021 May 13. PMID: 33991616.

Esquela-Kerscher, A., & Slack, F. J. (2006). Oncomirs - microRNAs with a role in cancer. Nature reviews. Cancer, 6(4), 259–269. https://doi.org/10.1038/nrc1840

Fischle W, Tseng BS, Dormann HL, Ueberheide BM, Garcia BA, Shabanowitz J, Allis CD. Regulation of HP1-chromatin binding by histone H3 methylation and phosphorylation. Nature. 2005;438(7071):1116–1122. doi: 10.1038/nature04219.

Grewal SIS, Moazed D. Heterochromatin and epigenetic control of gene expression. Science. 2003;301(5634):798–802. doi: 10.1126/science.1086887.

Hark AT, Schoenherr CJ, Katz DJ, Ingram RS, Levorse JM, Tilghman SM. CTCF mediates methylation-sensitive enhancer-blocking activity at the H19/Igf2 locus. Nature. 2000;405(6785):486–489. doi: 10.1038/35013106.

He, L., Yu, J. X., Liu, L., Buyse, I. M., Wang, M. S., Yang, Q. C., Nakagawara, A., Brodeur, G. M., Shi, Y. E., & Huang, S. (1998). RIZ1, but not the alternative RIZ2 product of the same gene, is underexpressed in breast cancer, and forced RIZ1 expression causes G2-M cell cycle arrest and/or apoptosis. Cancer research, 58(19), 4238–4244.

Jin S-G, Jiang C-L, Rauch T, Li H, Pfeifer GP. MBD3L2 interacts with MBD3 and components of the NuRD complex and can oppose MBD2-MeCP1-mediated methylation silencing. The Journal of Biological Chemistry. 2005;280(13):12700–12709. doi: 10.1074/jbc.M413492200.

Jones PA, Baylin SB. The epigenomics of cancer. Cell. 2007;128(4):683–692. doi: 10.1016/j.cell.2007.01.029.

Kanaya T, Kyo S, Maida Y, Yatabe N, Tanaka M, Nakamura M, Inoue M. Frequent hypermethylation of MLH1 promoter in normal endometrium of patients with endometrial cancers. Oncogene 2003; 22:2352–60

Kobow, K., Reid, C. A., van Vliet, E. A., Becker, A. J., Carvill, G. L., Goldman, A. M., Hirose, S., Lopes-Cendes, I., Khiari, H. M., Poduri, A., Johnson, M. R., & Henshall, D. C. (2020). Epigenetics explained: a topic "primer" for the epilepsy community by the ILAE Genetics/Epigenetics Task Force. Epileptic disorders : international epilepsy journal with videotape, 22(2), 127–141. https://doi.org/10.1684/epd.2020.1143

Kumar, V., Abbas, A. K., & Aster, J. C. (2015). Robbins and Cotran pathologic basis of disease (Ninth edition.). Elsevier/Saunders.

Mercer, T. R., Dinger, M. E., & Mattick, J. S. (2009). Long non-coding RNAs: insights into functions. Nature reviews. Genetics, 10(3), 155–159. https://doi.org/10.1038/nrg2521

Mori, N., Yoshinaga, K., Tomita, K., Ohwashi, M., Kondoh, T., Shimura, H., Wang, Y. H., Shiseki, M., Okada, M., & Motoji, T. (2011). Aberrant methylation of the RIZ1 gene in myelodysplastic syndrome and acute myeloid leukemia. Leukemia research, 35(4), 516–521. https://doi.org/10.1016/j.leukres.2010.08.002

Okada H, Kimura MT, Tan D, Fujiwara K, Igarashi J, Makuuchi M, Hui AM, Tsurumaru M, Nagase H. Frequent trefoil factor 3 (TFF3) overexpression and promoter hypomethylation in mouse and human hepatocellular carcinomas. Int J Oncol. 2005; 26:369-377.

Pandey V., Zhang M., Chong Q., You M., Rushdiana Raquib A., Pandey A. K., Liu D., Liu L., Ma L., Jha S., Wu Z., Zhu T., Lobie P. E. et al Hypomethylation associated enhanced transcription of trefoil factor-3 mediates tamoxifen-stimulated oncogenicity of ER+ endometrial carcinoma cells. Oncotarget. 2017; 8: 77268-77291. Retrieved from https://www.oncotarget.com/article/20461/

Philippeit C, Busch M, Dunker N. Epigenetic control of trefoil factor family (TFF) peptide expression in human retinoblastoma cell lines. Cell Physiol Biochem. 2014; 34:1001-1014.

Poddar, S., Kesharwani, D., & Datta, M. (2017). Interplay between the miRNome and the epigenetic machinery: Implications in health and disease. Journal of Cellular Physiology, 232(11), 2938–2945.

Rinn, J. L. et al. Functional demarcation of active and silent chromatin domains in human HOX loci by noncoding RNAs. Cell 129, 1311–1323 (2007).

Stephens, K. E., Miaskowski, C. A., Levine, J. D., Pullinger, C. R., & Aouizerat, B. E. (2013). Epigenetic regulation and measurement of epigenetic changes. Biological research for nursing, 15(4), 373–381. https://doi.org/10.1177/1099800412444785

Vestergaard EM, Nexo E, Torring N, Borre M, Orntoft TF, Sorensen KD. Promoter hypomethylation and upregulation of trefoil factors in prostate cancer. Int J Cancer. 2010; 127:1857-1865.

Wu, H., Chen, Y., Liang, J. et al. Hypomethylation-linked activation of PAX2 mediates tamoxifen-stimulated endometrial carcinogenesis. Nature 438, 981–987 (2005). https://doi.org/10.1038/nature04225

Yamaguchi, S., Asanoma, K., Takao, T., Kato, K., & Wake, N. (2009). Homeobox gene HOPX is epigenetically silenced in human uterine endometrial cancer and suppresses estrogen-stimulated proliferation of cancer cells by inhibiting serum response factor. International Journal of Cancer, 124(11), 2577-2588. https://doi.org/10.1002/ijc.24217

Yang, T., Ren, C., Jiang, A., Yu, Z., Li, G., Wang, G., & Zhang, Q. (2017). RIZ1 is regulated by estrogen and suppresses tumor progression in endometrial cancer. Biochemical and biophysical research communications, 489(2), 96–102. https://doi.org/10.1016/j.bbrc.2017.05.095

You, J. S., & Jones, P. A. (2012). Cancer genetics and epigenetics: two sides of the same coin?. Cancer cell, 22(1), 9–20. https://doi.org/10.1016/j.ccr.2012.06.008

Zhang, C., Zhu, Q., He, H., Jiang, L., Qiang, Q., Hu, L., Hu, G., Jiang, Y., Ding, X., & Lu, Y. (2015). RIZ1: a potential tumor suppressor in glioma. BMC cancer, 15, 990. https://doi.org/10.1186/s12885-015-2023-1

Zhou Y, Wang C, Mao L, Wang Y, Xia L, Zhao W, Shen J, and Chen J. Long noncoding RNA HOTAIR mediates the estrogen-induced metastasis of endometrial cancer cells via the miR-646/NPM1 axis. Am J Physiol Cell Physiol 314: C690–C701, 2018. doi:10.1152/ajpcell.00222.2017

Zierau O, Helle J, Schadyew S, Morgenroth Y, Bentler M, Hennig A, Chittur S, Tenniswood M, Kretzschmar G. Role of miR-203 in estrogen receptor-mediated signaling in the rat uterus and endometrial carcinoma. J Cell Biochem. 2018 Jul;119(7):5359-5372. doi: 10.1002/jcb.26675. Epub 2018 Mar 14. PMID: 29331043.