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

作者：Qiao Yichun; Shiue Chiou Nan; Zhu Jian; Zhuang Ting; Jonsson Philip; Wright Anthony P H; Zhao Chunyan^*; Dahlman Wright Karin

来源：Oncotarget, 2015, 6(10): 7804-7814.

DOI：10.18632/oncotarget.3158

• AP-1
• triple-negative breast cancer
• ZEB2
• epithelial-mesenchymal transition
• TNF alpha

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 TNF alpha induces EMT in TNBC cells via activation of AP-1 signaling and subsequently induces expression of the EMT regulator ZEB2. We also show that TNF alpha 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 TNF alpha, 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.

• 出版日期2015-4-10