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 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 ?-catenin/E-cadherin/Sox15 complex to the ?-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 ?-catenin/E-cadherin complex, which then binds to the proximal promoter region of CASP3. Through this mechanism, Twist1 cleavage is triggered to regulate a ?-catenin-elicited promotion of the CSC phenotype. During EMT, we documented that Twist1 binding to ?-catenin enhanced the transcriptional activity of the ?-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 ?-catenin(High)/nuclear Twist1(High)/E-cadherin(Low)/Sox15(Low)/CD133(High)) may provide a useful prognostic marker for human lung cancer.
Mesh Terms:
AC133 Antigen, Animals, Antigens, CD, Blotting, Western, Cadherins, Cell Line, Tumor, Epithelial-Mesenchymal Transition, Gene Expression Profiling, Gene Expression Regulation, Neoplastic, Glycoproteins, HEK293 Cells, Humans, Immunohistochemistry, Lung Neoplasms, Mice, SCID, Neoplasm Recurrence, Local, Neoplastic Stem Cells, Nuclear Proteins, Oligonucleotide Array Sequence Analysis, Peptides, Protein Binding, SOX Transcription Factors, Transplantation, Heterologous, Twist-Related Protein 1, Wnt Signaling Pathway, beta Catenin
AC133 Antigen, Animals, Antigens, CD, Blotting, Western, Cadherins, Cell Line, Tumor, Epithelial-Mesenchymal Transition, Gene Expression Profiling, Gene Expression Regulation, Neoplastic, Glycoproteins, HEK293 Cells, Humans, Immunohistochemistry, Lung Neoplasms, Mice, SCID, Neoplasm Recurrence, Local, Neoplastic Stem Cells, Nuclear Proteins, Oligonucleotide Array Sequence Analysis, Peptides, Protein Binding, SOX Transcription Factors, Transplantation, Heterologous, Twist-Related Protein 1, Wnt Signaling Pathway, beta Catenin
Cancer Res
Date: Aug. 15, 2015
PubMed ID: 26122848
View in: Pubmed Google Scholar
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