Journal
CANCER RESEARCH
Volume 75, Issue 16, Pages 3398-3410Publisher
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/0008-5472.CAN-14-3265
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Funding
- Ministry of Science and Technology, Taiwan [103-2314-B-007-001]
- National Health Research Institutes, Taiwan [NHRI-EX101-10018BC]
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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 beta-catenin/E-cadherin/Sox15 complex to the beta-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 beta-catenin/E-cadherin complex, which then binds to the proximal promoter region of CASP3. Through this mechanism, Twist1 cleavage is triggered to regulate a beta-catenin-elicited promotion of the CSC phenotype. During EMT, we documented that Twist1 binding to beta-catenin enhanced the transcriptional activity of the beta-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 beta-catenin(High)/nuclear Twist1(High)/E-cadherin(Low)/Sox15(Low)/CD133(High)) may provide a useful prognostic marker for human lung cancer. (C) 2015 AACR.
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