title: AP-1-mediated chromatin looping regulates ZEB2 transcription: new insights into TNFα-induced epithelial-mesenchymal transition in triple-negative breast cancer.
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.
authors.affiliation: Department of Biosciences and Nutrition, Novum, Karolinska Institutet, Huddinge, Sweden.
authors.forename: Yichun
authors.initials: Y
authors.lastname: Qiao
authors.affiliation: Clinical Research Center (KFC), Department of Laboratory Medicine, Karolinska Institutet, Huddinge, Sweden.|Department of Pediatrics, Hualien Tzu Chi Hospital, Buddist Tzu Chi Medical Foundation, Hualien, Taiwan.
authors.forename: Chiou-Nan
authors.initials: CN
authors.lastname: Shiue
authors.affiliation: Department of Biosciences and Nutrition, Novum, Karolinska Institutet, Huddinge, Sweden.
authors.forename: Jian
authors.initials: J
authors.lastname: Zhu
authors.affiliation: Department of Biosciences and Nutrition, Novum, Karolinska Institutet, Huddinge, Sweden.
authors.forename: Ting
authors.initials: T
authors.lastname: Zhuang
authors.affiliation: Center for Nuclear Receptors and Cell Signaling, Department of Biology and Biochemistry, University of Houston, Houston, USA.
authors.forename: Philip
authors.initials: P
authors.lastname: Jonsson
authors.affiliation: Clinical Research Center (KFC), Department of Laboratory Medicine, Karolinska Institutet, Huddinge, Sweden.
authors.forename: Anthony P H
authors.initials: AP
authors.lastname: Wright
authors.affiliation: Department of Biosciences and Nutrition, Novum, Karolinska Institutet, Huddinge, Sweden.
authors.forename: Chunyan
authors.initials: C
authors.lastname: Zhao
authors.affiliation: Department of Biosciences and Nutrition, Novum, Karolinska Institutet, Huddinge, Sweden.|Science for Life Laboratory, Karolinska Institutet, Solna, Sweden.
authors.forename: Karin
authors.initials: K
authors.lastname: Dahlman-Wright
mesh_terms: D045744:Cell Line, Tumor; D002843:Chromatin / Q000235:genetics / Q000378:metabolism*; D058750:Epithelial-Mesenchymal Transition; D005260:Female; D018398:Homeodomain Proteins / Q000235:genetics* / Q000378:metabolism*; D006801:Humans; D011994:Recombinant Proteins / Q000494:pharmacology; D012097:Repressor Proteins / Q000235:genetics* / Q000378:metabolism*; D015398:Signal Transduction; D018808:Transcription Factor AP-1 / Q000235:genetics* / Q000378:metabolism; D014162:Transfection; D064726:Triple Negative Breast Neoplasms / Q000235:genetics* / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*; D000074165:Zinc Finger E-box Binding Homeobox 2
chemical_list: D002843:Chromatin; D018398:Homeodomain Proteins; D011994:Recombinant Proteins; D012097:Repressor Proteins; D018808:Transcription Factor AP-1; D014409:Tumor Necrosis Factor-alpha; C492363:ZEB2 protein, human; D000074165:Zinc Finger E-box Binding Homeobox 2
keywords: AP-1; TNFα; ZEB2; epithelial–mesenchymal transition; triple-negative breast cancer