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AP-1-mediated chromatin looping regulates ZEB2 transcription: new insights into TNFα-induced epithelial–mesenchymal transition in triple-negative breast cancer

Yichun Qiao, Chiou-Nan Shiue, Jian Zhu, Ting Zhuang, Philip Jonsson, Anthony P.H. Wright, Chunyan Zhao _ and Karin Dahlman-Wright

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Oncotarget. 2015; 6:7804-7814. https://doi.org/10.18632/oncotarget.3158

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Abstract

Yichun Qiao1, Chiou-Nan Shiue2,3, Jian Zhu1, Ting Zhuang1, Philip Jonsson4, Anthony P.H. Wright2, Chunyan Zhao1, Karin Dahlman-Wright1,5

1Department of Biosciences and Nutrition, Novum, Karolinska Institutet, Huddinge, Sweden

2Clinical Research Center (KFC), Department of Laboratory Medicine, Karolinska Institutet, Huddinge, Sweden

3Department of Pediatrics, Hualien Tzu Chi Hospital, Buddist Tzu Chi Medical Foundation, Hualien, Taiwan

4Center for Nuclear Receptors and Cell Signaling, Department of Biology and Biochemistry, University of Houston, Houston, USA

5Science for Life Laboratory, Karolinska Institutet, Solna, Sweden

Correspondence to:

Chunyan Zhao, e-mail: chunyan.zhao@ki.se

Karin Dahlman-Wright, e-mail: karin.dahlman-wright@ki.se

Keywords: AP-1, triple-negative breast cancer, ZEB2, epithelial–mesenchymal transition, TNFα

Received: October 28, 2014     Accepted: January 16, 2015     Published: January 30, 2015

ABSTRACT

The molecular determinants of malignant cell behaviour in triple-negative breast cancer (TNBC) are poorly understood. Recent studies have shown that regulators of epithelial-mesenchymal transition (EMT) are potential therapeutic targets for TNBC. In this study, we demonstrate that the inflammatory cytokine TNFα induces EMT in TNBC cells via activation of AP-1 signaling and subsequently induces expression of the EMT regulator ZEB2. We also show that TNFα activates both the PI3K/Akt and MAPK/ERK pathways, which act upstream of AP-1. We further investigated in detail AP-1 regulation of ZEB2 expression. We show that two ZEB2 transcripts derived from distinct promoters are both expressed in breast cancer cell lines and breast tumor samples. Using the chromosome conformation capture assay, we demonstrate that AP-1, when activated by TNFα, binds to a site in promoter 1b of the ZEB2 gene where it regulates the expression of both promoter 1b and 1a, the latter via mediating long range chromatin interactions. Overall, this work provides a plausible mechanism for inflammation-induced metastatic potential in TNBC, involving a novel regulatory mechanism governing ZEB2 isoform expression.


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