AP-1-mediated chromatin looping regulates ZEB2 transcription: new insights into TNFα-induced epithelial-mesenchymal transition in triple-negative breast cancer.
AP-1-mediated chromatin looping regulates ZEB2 transcription: new insights into TNFα-induced epithelial-mesenchymal transition in triple-negative breast cancer.
复制标题
AP-1介导的染色质循环调节Zeb2转录：三阴性乳腺癌中TNFα诱导的上皮间质转变的新见解。
DOI：
10.18632/oncotarget.3158
复制
发表时间：
2015-04-10
期刊：
影响因子：
--
通讯作者：
Dahlman-Wright K
中科院分区：
文献类型：
--
作者：
Qiao Y;Shiue CN;Zhu J;Zhuang T;Jonsson P;Wright AP;Zhao C;Dahlman-Wright K
三阴性乳腺癌（TNBC）中恶性细胞行为的分子决定因素知之甚少。最近的研究表明，上皮间质转化（EMT）的调节剂是TNBC的潜在治疗靶点。在这项研究中，我们证明了炎性细胞因子TNFα通过激活AP-1信号传导诱导TNBC细胞中的EMT，随后诱导EMT调节因子ZEB 2的表达。我们还发现，TNFα激活PI 3 K/Akt和MAPK/ERK途径，它们作用于AP-1的上游。我们进一步详细研究了AP-1对ZEB 2表达的调控。我们发现，两个ZEB 2转录来自不同的启动子都表达在乳腺癌细胞系和乳腺肿瘤样本。使用染色体构象捕获分析，我们证明，AP-1，当被TNFα激活时，结合到ZEB 2基因的启动子1b中的一个位点，在那里它调节启动子1b和1a的表达，后者通过介导长距离染色质相互作用。总的来说，这项工作为TNBC中炎症诱导的转移潜力提供了一种合理的机制，涉及一种控制ZEB 2亚型表达的新的调节机制。
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.
登录
查看更多内容
影响因子：
64.8
作者：
Jin, Fulai;Li, Yan;Dixon, Jesse R.;Selvaraj, Siddarth;Ye, Zhen;Lee, Ah Young;Yen, Chia-An;Schmitt, Anthony D.;Espinoza, Celso A.;Ren, Bing
通讯作者：
Ren, Bing
影响因子：
64.8
作者：
Sanyal, Amartya;Lajoie, Bryan R.;Jain, Gaurav;Dekker, Job
通讯作者：
Dekker, Job
影响因子：
14.9
作者：
Gong F;Sun L;Wang Z;Shi J;Li W;Wang S;Han X;Sun Y
通讯作者：
Sun Y
影响因子：
3.3
作者：
Medici, Damian;Hay, Elizabeth D.;Olsen, Bjorn R.
通讯作者：
Olsen, Bjorn R.
影响因子：
3.8
作者：
Pal, Sumanta Kumar;Childs, Barrett H.;Pegram, Mark
通讯作者：
Pegram, Mark