Diverse Targets of β-Catenin during the Epithelial-Mesenchymal Transition Define Cancer Stem Cells and Predict Disease Relapse
Diverse Targets of β-Catenin during the Epithelial-Mesenchymal Transition Define Cancer Stem Cells and Predict Disease Relapse
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DOI：
10.1158/0008-5472.can-14-3265
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发表时间：
2015-08-15
期刊：
影响因子：
11.2
通讯作者：
Lee, Jia-Lin
中科院分区：
文献类型：
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作者：
Chang, Yi-Wen;Su, Ying-Jhen;Lee, Jia-Lin
Wnt信号转导有助于由上皮-间充质转化（EMT）激活的癌症干细胞（CSC）状态的重编程和维持。然而，CSC中EMT和Wnt通路之间的机制关系尚不完全清楚。染色质免疫沉淀与高通量测序（ChIP-seq）表明，EMT诱导从β-catenin/E-cadherin/Sox 15复合物的β-catenin/Twist 1/TCF 4复合物，后者然后结合到CSC相关的基因启动子的开关。串联免疫共沉淀和再ChIP实验与上皮型细胞进一步揭示，Sox 15协会与β-连环蛋白/E-钙粘蛋白复合物，然后结合到近端启动子区CASP 3。通过这种机制，Twist 1切割被触发以调节β-连环蛋白引起的CSC表型的促进。在EMT过程中，我们记录了Twist 1与β-连环蛋白的结合增强了β-连环蛋白/TCF 4复合物的转录活性，包括与CSC标记物ABCG 2的近端启动子区域结合。在临床应用方面，我们定义的五基因CSC签名（核β-连环蛋白（高）/核Twist 1（高）/E-cadherin（低）/Sox 15（低）/CD 133（高））可能为人类肺癌提供有用的预后标志物。(C)2015年AACR。
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.