Diverse targets of β-catenin during the epithelial-mesenchymal transition define cancer stem cells and predict disease relapse
Journal
Cancer Research
Journal Volume
75
Journal Issue
16
Pages
3398-3410
Date Issued
2015
Author(s)
Abstract
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/Sox15Low/CD133High) may provide a useful prognostic marker for human lung cancer. ? 2015 American Association for Cancer Research.
SDGs
Other Subjects
beta catenin; breast cancer resistance protein; caspase 3; CD133 antigen; protein Sox15; T cell factor 4 protein; transcription factor; transcription factor Twist1; unclassified drug; uvomorulin; beta catenin; cadherin; CD133 antigen; glycoprotein; leukocyte antigen; nuclear protein; peptide; protein binding; SOX15 protein, human; transcription factor Sox; transcription factor Twist; TWIST1 protein, human; ABCG2 gene; animal experiment; animal model; Article; autocrine effect; cancer recurrence; cancer stem cell; carcinogenicity; CASP3 gene; controlled study; epithelial mesenchymal transition; female; human; human tissue; in vitro study; in vivo study; lung cancer; mouse; nonhuman; paracrine signaling; phenotype; prediction; priority journal; promoter region; protein cleavage; protein protein interaction; transcription regulation; animal; cancer stem cell; DNA microarray; epithelial mesenchymal transition; gene expression profiling; gene expression regulation; genetics; HEK293 cell line; immunohistochemistry; lung tumor; metabolism; pathology; SCID mouse; tumor cell line; tumor recurrence; Western blotting; Wnt signaling pathway; xenograft; Animals; Antigens, CD; beta Catenin; 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 Transcription Factor; Wnt Signaling Pathway
Publisher
American Association for Cancer Research Inc.
Type
journal article