Abstract
Wnt signaling contributes to the reprogramming and maintenance of cancer stem cell (CSC) states that are also activated by epithelial–mesenchymal transition (EMT). However, the mechanistic relationship between EMT and the Wnt pathway in CSC is not entirely clear. Chromatin immunoprecipitation with highthroughput sequencing (ChIP-seq) indicates that EMT induces a switch from the β-catenin/E-cadherin/Sox15 complex to the β-catenin/Twist1/TCF4 complex. Further tandem coimmunoprecipitation and re-ChIP experiments reveal that the β-catenin/E-cadherin/Sox15 complex in epithelial-type cells binds to the proximal promoter region of CASP3, whereas β-catenin/Twist1/TCF4 complex in mesenchymal-type cells targets to CSC-related gene, ABCG2. In detail, we demonstrate that nuclear E-cadherin, a component of the inhibitory complex, acts as a negative regulator in Wnt/β-catenin-elicited promotion of the CSC phenotype. E-cadherin reduces β-catenin/TCF4 transcriptional activity through abolishing the β-catenin/TCF4 interaction. During EMT, accumulating Twist1 enhances the transcriptional activity of the β-catenin/TCF4 complex by increasing the stabilization of β-catenin and nuclear translocation of TCF4. Nevertheless, its potent enhancer in the promotion of the CSC phenotype is counteracted by Caspase3-mediated Twist1 cleavage. In terms of clinical application, our definition of muti-gene CSC signatures (nuclear E-cadherinLow/nuclear β-cateninHigh/CD133High) (nuclear β-cateninHigh/ nuclear Twist1High/E-cadherinLow/Sox15Low/CD133High) may provide a useful prognostic marker for human lung cancer.