Transcriptional repression of E-cadherin in nickel-exposed lung epithelial cells mediated by loss of Sp1 binding at the promoter.
Transcriptional repression of E-cadherin in nickel-exposed lung epithelial cells mediated by loss of Sp1 binding at the promoter.
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DOI：
10.1002/mc.23364
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发表时间：
2022-01
影响因子：
4.6
通讯作者：
Cuddapah S
中科院分区：
文献类型：
--
作者：
Zhang X;Tanwar VS;Jose CC;Lee HW;Cuddapah S
通过促进细胞 - 细胞粘附，电子钙粘蛋白在上皮组织的稳定性中起着核心作用。 E-钙粘蛋白表达的丧失是上皮 - 间质转变（EMT）的标志，这是几种肺部疾病发病机理的主要事件。我们较早的研究表明，镍是一种普遍存在的环境毒性，通过持续下调人肺上皮细胞中的e-钙粘着蛋白的表达来诱导EMT，并且EMT仍然是不可逆的暴露后暴露。但是，尚不清楚通过镍暴露的持续E-钙粘蛋白下调的分子基础。在这里，我们的研究表明，转录因子SP1与编码基因CDH1的启动子的结合对于其表达至关重要。镍暴露会导致CDH1启动子处SP1结合的损失，从而导致其下调和EMT诱导。 CDH1启动子上SP1结合的损失与邻近SP1结合位点的Zeb1结合的增加有关。 Zeb1是一种由镍暴露的EMT主调节器持续上调，是CDH1的负调节剂。 CRISPR-Cas9介导的Zeb1敲除在CDH1启动子处恢复了SP1结合。此外，Zeb1基因敲除挽救了E-钙粘蛋白的表达并重新建立上皮表型。由于EMT与许多与镍相关的慢性炎症性肺部疾病有关，包括哮喘，纤维化和癌症以及转移，因此我们的发现为与镍发病机理相关的机制提供了新的见解。
E-cadherin plays a central role in the stability of epithelial tissues by facilitating cell-cell adhesion. Loss of E-cadherin expression is a hallmark of epithelial-mesenchymal transition (EMT), a major event in the pathogenesis of several lung diseases. Our earlier studies showed that nickel, a ubiquitous environmental toxicant, induced EMT by persistently downregulating E-cadherin expression in human lung epithelial cells and that the EMT remained irreversible post-exposure. However, the molecular basis of persistent E-cadherin downregulation by nickel exposure is not understood. Here, our studies show that the binding of transcription factor Sp1 to the promoter of E-cadherin encoding gene, CDH1, is essential for its expression. Nickel exposure caused a loss of Sp1 binding at the CDH1 promoter, resulting in its downregulation and EMT induction. Loss of Sp1 binding at the CDH1 promoter was associated with an increase in the binding of ZEB1 adjacent to the Sp1 binding site. ZEB1, an EMT master regulator persistently upregulated by nickel exposure, is a negative regulator of CDH1. CRISPR-Cas9-mediated knockout of ZEB1 restored Sp1 binding at the CDH1 promoter. Furthermore, ZEB1 knockout rescued E-cadherin expression and re-established the epithelial phenotype. Since EMT is associated with a number of nickel-exposure-associated chronic inflammatory lung diseases including asthma, fibrosis and cancer and metastasis, our findings provide new insights into the mechanisms associated with nickel pathogenesis.
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影响因子：
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作者：
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