Abstract
Epithelial-to-mesenchymal transition (EMT) is the first step in the development of the invasive and migratory properties of cancer metastasis. Since the transcriptional reprogramming of a number of genes occurs in EMT, the regulation of EMT transcription factors has been intensively investigated. EMT transcriptional factors are commonly classified by the direct or indirect repression of E-cadherin because one of hallmarks of EMT is the loss of E-cadherin. This facilitates the expression of genes for EMT, tumor invasion, and metastasis. The posttranslational modification of EMT transcriptional factors, such as Snail and Slug, directly regulates their functions, including their stability, nuclear localization, protein-protein interaction, and ubiquitination for the promotion or termination of EMT at the specific points. Here, we discuss how posttranslational modifications regulate gene expression in a dynamic and reversible manner by modifying upstream signaling pathways, focusing in particular on the posttranslational modifications of Snail, Slug, ZEB1, ZEB2, and TWIST1. This review demonstrates that EMT transcription factors regulate metastasis through their posttranslational modifications and that the flexibility and reversibility of EMT can be modified by phosphorylation.
Highlights
Cancer metastasis begins with the migration and invasion of cancer cells to the surrounding tissues and involves the loss of cell-cell adhesion
The transforming growth factor-β (TGF-β) signals crosstalk with Wnt, Notch, and receptor tyrosine kinase signals to induce the specific expression of epithelial-to-mesenchymal transition (EMT) transcription factor and its functions in cancer metastasis, depending on the cellular context [1]
This review provides an overview of how these core EMT transcription factors regulate metastasis via posttranslational modifications
Summary
Cancer metastasis begins with the migration and invasion of cancer cells to the surrounding tissues and involves the loss of cell-cell adhesion. O-GlcNAc modification stabilizes Snail to avoid the protein degradation and thereby increases its transcriptional repressor activity for CDH1 expression. The phosphorylation of residue S42 increases the transcriptional activity and enhances EMT, AKT1 may exert dual functions in Twist 1 and EMT The findings of these studies are proof of the flexible characteristics of Twist 1 in regulating the transition from epithelial-to-mesenchymal cells. Aurora A kinase promotes the transcriptional activation of Twist 1, as mentioned previously [40] In addition to this function, the phosphorylation of Twist at residues S123, T148, and S184 by Aurora A kinase increases the levels of Twist 1 protein, possibly by inhibiting its ubiquitination [40]. The stability of Twist 1 is directly associated with its functional activity in EMT, invasiveness, and cell plasticity
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