Diverse targets of β-catenin during the epithelial-mesenchymal transition define cancer stem cells and predict disease relapse

Yi Wen Chang, Ying Jhen Su, Michael Hsiao, Kuo Chen Wei, Wei Hsin Lin, Chi Lung Liang, Shin Cheh Chen, Jia Lin Lee*

*Corresponding author for this work

Research output: Contribution to journalJournal Article peer-review

75 Scopus citations

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.

Original languageEnglish
Pages (from-to)3398-3410
Number of pages13
JournalCancer Research
Volume75
Issue number16
DOIs
StatePublished - 15 08 2015
Externally publishedYes

Bibliographical note

Publisher Copyright:
© 2015 American Association for Cancer Research.

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