Upstream eventSnail, Zeb, Twist activation
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 in 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
- Zeb1 activation leads to EMT via Prex1 activation in NCH421k, NCH441, and NCH644 human glioblastoma model cells (Homo sapiens) (Rosmaninho et al., 2018).
- Zeb1 siRNA induced the suppression of EMT in SGC-7901 human gastric cancer cell line (Homo sapiens) (Xue et al., 2019).
- Snail induces EMT in SAS and HSC-4 human head and neck squamous cancer cells (Homo sapiens) (Ota et al., 2016).
- Snail induces EMT in B16-F10 murine melanoma cells (Mus musculus) (Kudo-Saito, Shirako, Takeuchi, & Kawakami, 2009; Y. Wang, Shi, Chai, Ying, & Zhou, 2013).
- Twist1 is related to EMT in MCF-7 and MDA-MB-231 human breast cancer cell lines (Homo sapiens) (Menendez-Menendez et al., 2019).Hu et al., 2019).
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. 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. doi:10.4161/19336918.2014.969998
Hu, B., Cheng, J. W., Hu, J. W., Li, H., Ma, X. L., Tang, W. G., . . . Yang, X. R. (2019). KPNA3 Confers Sorafenib Resistance to Advanced Hepatocellular Carcinoma via TWIST Regulated Epithelial-Mesenchymal Transition. Journal of Cancer, 10(17), 3914-3925. doi:10.7150/jca.31448
Kudo-Saito, C., Shirako, H., Takeuchi, T., & Kawakami, Y. (2009). Cancer Metastasis Is Accelerated through Immunosuppression during Snail-Induced EMT of Cancer Cells. Cancer Cell, 15(3), 195-206. doi:https://doi.org/10.1016/j.ccr.2009.01.023
Li, C., & Balazsi, G. (2018). A landscape view on the interplay between EMT and cancer metastasis. NPJ Syst Biol Appl, 4, 34. 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. doi:10.1038/s41467-019-09865-9
Menendez-Menendez, J., Hermida-Prado, F., Granda-Diaz, R., Gonzalez, A., Garcia-Pedrero, J. M., Del-Rio-Ibisate, N., . . . Martinez-Campa, C. (2019). Deciphering the Molecular Basis of Melatonin Protective Effects on Breast Cells Treated with Doxorubicin: TWIST1 a Transcription Factor Involved in EMT and Metastasis, a Novel Target of Melatonin. Cancers (Basel), 11(7). doi:10.3390/cancers11071011
Ota, I., Masui, T., Kurihara, M., Yook, J. I., Mikami, S., Kimura, T., . . . Kitahara, T. (2016). Snail-induced EMT promotes cancer stem cell-like properties in head and neck cancer cells. Oncol Rep, 35(1), 261-266. doi:10.3892/or.2015.4348
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. 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. doi:10.3390/cancers7030867
Rosmaninho, P., Mükusch, S., Piscopo, V., Teixeira, V., Raposo, A. A., Warta, R., . . . Castro, D. S. (2018). Zeb1 potentiates genome-wide gene transcription with Lef1 to promote glioblastoma cell invasion. The EMBO Journal, 37(15), e97115. doi:10.15252/embj.201797115
Wang, Y., Shi, J., Chai, K., Ying, X., & Zhou, B. P. (2013). The Role of Snail in EMT and Tumorigenesis. Current cancer drug targets, 13(9), 963-972. Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/24168186
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). doi:10.3390/cancers11020148
Xue, Y., Zhang, L., Zhu, Y., Ke, X., Wang, Q., & Min, H. (2019). Regulation of Proliferation and Epithelial-to-Mesenchymal Transition (EMT) of Gastric Cancer by ZEB1 via Modulating Wnt5a and Related Mechanisms. Medical science monitor : international medical journal of experimental and clinical research, 25, 1663-1670. doi:10.12659/MSM.912338