Upstream eventSnail, Zeb, Twist activation
Epithelial-mesenchymal transition, induced
Key Event Relationship Overview
AOPs Referencing Relationship
|AOP Name||Adjacency||Weight of Evidence||Quantitative Understanding|
|Wnt ligand stimulation and Wnt signalling activation lead to cancer malignancy||adjacent||High||Moderate|
|Homo sapiens||Homo sapiens||High||NCBI|
Life Stage Applicability
|All life stages||High|
Key Event Relationship Description
EMT-related transcription factors including Snail, ZEB and Twist are up-regulated in cancer cells (Diaz, Vinas-Castells, & Garcia de Herreros, 2014). The transcription factors such as Snail, ZEB and Twist bind to E-cadherin (CDH1) promoter and inhibit the CDH1 transcription via the consensus E-boxes (5’-CACCTG-3’ or 5’-CAGGTG-3’), which leads to EMT (Diaz et al., 2014).
Evidence Supporting this KER
The transcription factors such as Snail, Zeb and Twist inhibit the CDH1 expression through their binding towards the promoter of CDH1, which leads to inhibition of cell adhesion and EMT (Diaz et al., 2014).
Histone deacetylase inhibitors affect on EMT-related transcription factors including ZEB, Twist and Snail (Wawruszak et al., 2019).
Snail and Zeb induces EMT and suppress E-cadherin (CDH1) (Batlle et al., 2000; Diaz et al., 2014; Peinado, Olmeda, & Cano, 2007).
Uncertainties and Inconsistencies
The EMT is induced different transcription factors other than Zeb, Twist and Snail, which includes E47 and KLF8 (Diaz et al., 2014).
Zeb, Twist and Snail may activate or inactivate different genes or molecules to induce phenomena related to EMT and other phenomena other than EMT (Li & Balazsi, 2018).
Quantitative Understanding of the Linkage
Snail (SNAI1) mRNA is methylated and N6-methyladenosine (m6A) in its coding region (CDS) and 3’ untranslated region (3’UTR) are significantly enriched during EMT progression (Lin et al., 2019). The m6A enrichment fold of SNAI1 mRNA in EMT cells is about 2.3-fold greater than in control cells (Lin et al., 2019).
Snail (SNAI1) transfection for 48 hours induce the repression of E-cadherin (CDH1) protein expression (Lin et al., 2019).
SNAI1 mRNA in polysome is up-regulated in EMT-undergoing HeLa cells treated with 10 ng/ml of TGF-beta for 3 days compared with control cells (Lin et al., 2019).
Known modulating factors
The decrease E-cadherin (CDH1), a cell adhesion molecule, is related to EMT (Diaz et al., 2014).
Methyltransferase-like 3 (METTL3) modulates methylation of Snail (SNAI1) mRNA and EMT (Lin et al., 2019).
Binding of beta-catenin to members of the TCF/LEF family transcription factors increase gene expression related to EMT such as Twist and decrease E-cadherin protein expression (Qualtrough, Rees, Speight, Williams, & Paraskeva, 2015).
Known Feedforward/Feedback loops influencing this KER
The inhibition of Hedgehog signaling pathway with cyclopamine reduces beta-catenin-TCF transcriptional activity, decreases the Twist expression, induces E-cadherin expression and inhibits EMT (Qualtrough et al., 2015).
Domain of Applicability
Batlle, E., Sancho, E., Francí, C., Domínguez, D., Monfar, M., Baulida, J., & García de Herreros, A. (2000). The transcription factor Snail is a repressor of E-cadherin gene expression in epithelial tumour cells. Nature Cell Biology, 2(2), 84-89. Retrieved from https://doi.org/10.1038/35000034. doi:10.1038/35000034
Diaz, V. M., Vinas-Castells, R., & Garcia de Herreros, A. (2014). Regulation of the protein stability of EMT transcription factors. Cell Adh Migr, 8(4), 418-428. Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/25482633. doi:10.4161/19336918.2014.969998
Li, C., & Balazsi, G. (2018). A landscape view on the interplay between EMT and cancer metastasis. NPJ Syst Biol Appl, 4, 34. Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/30155271. doi:10.1038/s41540-018-0068-x
Lin, X., Chai, G., Wu, Y., Li, J., Chen, F., Liu, J., . . . Wang, H. (2019). RNA m(6)A methylation regulates the epithelial mesenchymal transition of cancer cells and translation of Snail. Nat Commun, 10(1), 2065. Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/31061416. doi:10.1038/s41467-019-09865-9
Peinado, H., Olmeda, D., & Cano, A. (2007). Snail, Zeb and bHLH factors in tumour progression: an alliance against the epithelial phenotype? Nat Rev Cancer, 7(6), 415-428. Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/17508028. doi:10.1038/nrc2131
Qualtrough, D., Rees, P., Speight, B., Williams, A. C., & Paraskeva, C. (2015). The Hedgehog Inhibitor Cyclopamine Reduces beta-Catenin-Tcf Transcriptional Activity, Induces E-Cadherin Expression, and Reduces Invasion in Colorectal Cancer Cells. Cancers (Basel), 7(3), 1885-1899. Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/26393651. doi:10.3390/cancers7030867
Wawruszak, A., Kalafut, J., Okon, E., Czapinski, J., Halasa, M., Przybyszewska, A., . . . Stepulak, A. (2019). Histone Deacetylase Inhibitors and Phenotypical Transformation of Cancer Cells. Cancers (Basel), 11(2). Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/30691229. doi:10.3390/cancers11020148