Diverse Targets of -catenin during the Epithelial-Mesenchymal Transition Define Cancer Stem Cells and Predict Disease Relapse

Wnt signaling contributes to the reprogramming and maintenance of cancer stem cell (CSC) states that is activated by the epithelial-mesenchymal transition (EMT) program. However, the mechanistic relationship between the EMT and Wnt pathway in CSCs remains unclear. Chromatin immunoprecipitation with high-throughput sequencing (ChIP-seq) indicated that EMT induces a switch from the -catenin/E-cadherin/Sox15 complex to the -catenin/Twist1/TCF4 complex, which then binds to CSC-related gene promoters. In tandem co-IP and re-ChIP experiments using epithelial-type cells, Sox15 associated with the -catenin/E-cadherin complex and then bound to the proximal promoter region of CASP3, consequently resulting in Twist1 cleavage and negatively regulating the -cateninelicited promotion of the CSC phenotype. During the EMT, Twist1 in complex with -catenin enhanced -catenin/TCF4 transcriptional activity, which includes binding to the proximal promoter region of ABCG2, a marker of CSCs. For clinical application, the five-gene signature nuclear -cateninHigh/nuclear Twist1High/E-cadherinLow/Sox15Low/CD133High may be a valuable prognostic marker in patients with human lung cancer.

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Chang YW, Su YJ, Hsiao M, Wei KC, Lin WH, Liang CL, Chen SC, Lee JL