Tumor and Stem Cell Biology Diverse Targets of b-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 are 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) indicated that EMT induces a switch from the b-catenin/E-cadherin/Sox15 complex to the b-catenin/Twist1/TCF4 complex, the latter of which then binds to CSC-related gene promoters. Tandem coimmunoprecipitation and re-ChIP experiments with epithelial-type cells further revealed that Sox15 associates with the b-catenin/E-cadherin complex, which then binds to the proximal promoter region of CASP3. Through this mechanism, Twist1 cleavage is triggered to regulate a b-catenin–elicited promotion of the CSC phenotype. During EMT, we documented that Twist1 binding to b-catenin enhanced the transcriptional activity of the b-catenin/TCF4 complex, including by binding to the proximal promoter region of ABCG2, a CSC marker. In terms of clinical application, our definition of a five-gene CSC signature (nuclear b-catenin/ nuclear Twist1/E-cadherin/Sox15/CD133) may provide a useful prognostic marker for human lung cancer. Cancer Res; 75(16); 3398–410. 2015 AACR.