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

• Published in: Cancer research (Chicago, Ill.) Vol. 75; no. 16; pp. 3398 - 3410
• Main Authors: Chang, Yi-Wen, Su, Ying-Jhen, Hsiao, Michael, Wei, Kuo-Chen, Lin, Wei-Hsin, Liang, Chi-Lung, Chen, Shin-Cheh, Lee, Jia-Lin
• Format: Journal Article
• Language: English
• Published: United States 15.08.2015
• Subjects: AC133 Antigen; Animals; Antigens, CD - genetics; Antigens, CD - metabolism; beta Catenin - genetics; beta Catenin - metabolism; Blotting, Western; Cadherins - genetics; Cadherins - metabolism; Cell Line, Tumor; Epithelial-Mesenchymal Transition - genetics; Gene Expression Profiling; Gene Expression Regulation, Neoplastic; Glycoproteins - genetics; Glycoproteins - metabolism; HEK293 Cells; Humans; Immunohistochemistry; Lung Neoplasms - genetics; Lung Neoplasms - metabolism; Lung Neoplasms - pathology; Mice, SCID; Neoplasm Recurrence, Local; Neoplastic Stem Cells - metabolism; Nuclear Proteins - genetics; Nuclear Proteins - metabolism; Oligonucleotide Array Sequence Analysis; Peptides - genetics; Peptides - metabolism; Protein Binding; SOX Transcription Factors - genetics; SOX Transcription Factors - metabolism; Transplantation, Heterologous; Twist-Related Protein 1 - genetics; Twist-Related Protein 1 - metabolism; Wnt Signaling Pathway - genetics
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/0008-5472.CAN-14-3265

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 high-throughput sequencing (ChIP-seq) indicated that EMT induces a switch from the β-catenin/E-cadherin/Sox15 complex to the β-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 β-catenin/E-cadherin complex, which then binds to the proximal promoter region of CASP3. Through this mechanism, Twist1 cleavage is triggered to regulate a β-catenin-elicited promotion of the CSC phenotype. During EMT, we documented that Twist1 binding to β-catenin enhanced the transcriptional activity of the β-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 β-catenin(High)/nuclear Twist1(High)/E-cadherin(Low)/Sox15(Low)/CD133(High)) may provide a useful prognostic marker for human lung cancer.