Department of Pathophysiology, Nanjing Medical University, Nanjing, China.
Department of Pathophysiology, Wuxi College of Medicine, Jiangnan University, Nanjing, Jiangsu, China.
J Cell Biochem. 2018 Feb;119(2):2418-2426. doi: 10.1002/jcb.26404. Epub 2017 Oct 17.
Malignant cancers are distinguished from more benign forms of cancers by enhanced ability to disseminate. A number of factors aid the migration and invasion of malignant cancer cells. Epithelial-to-mesenchymal transition (EMT), which greatly facilitates the dissemination of cancer cells, is characterized by the loss of epithelial markers and the acquisition of mesenchymal markers thereby rendering the cells more migratory and invasive. We have previously shown that the class III lysine deacetylase SIRT1 plays a critical role curbing the metastasis of ovarian cancer cells partly by blocking EMT. Here we investigated the mechanism by which SIRT1 regulates the transcription of Claudin 5 (CLDN5), an epithelial marker gene, in ovarian cancer cells. SIRT1 activation or over-expression up-regulated CLDN5 expression while SIRT1 inhibition or depletion down-regulated CLDN5 expression. SIRT1 interacted with and deacetylated Kruppel-like factor 4 (KLF4), a known transcriptional activator for CLDN5. Deacetylation by SIRT1 promoted nuclear accumulation of KLF4 and enhanced the binding of KLF4 to the CLDN5 promoter in the nucleus. SIRT1-mediated up-regulation of CLDN5 was abrogated in the absence of KLF4. In accordance, KLF4 depletion by siRNA rendered ovarian cancer cells more migratory and invasive despite of SIRT1 activation or over-expression. In conclusion, our data suggest that SIRT1 activates CLDN5 transcription by deacetylating and potentiating KLF4.
恶性癌症的特征是具有更强的扩散能力，与更良性的癌症形式区分开来。许多因素有助于恶性癌细胞的迁移和侵袭。上皮-间充质转化（EMT）极大地促进了癌细胞的扩散，其特征是上皮标志物的丧失和间充质标志物的获得，从而使细胞更具迁移和侵袭性。我们之前已经表明，III 类赖氨酸去乙酰化酶 SIRT1 通过阻断 EMT 在抑制卵巢癌细胞转移中起着关键作用。在这里，我们研究了 SIRT1 调节卵巢癌细胞中 Claudin 5（CLDN5）表达的机制，CLDN5 是一种上皮标志物基因。SIRT1 的激活或过表达上调了 CLDN5 的表达，而 SIRT1 的抑制或耗竭下调了 CLDN5 的表达。SIRT1 与 Kruppel 样因子 4（KLF4）相互作用并使其去乙酰化，KLF4 是 CLDN5 的已知转录激活因子。SIRT1 介导的去乙酰化促进了 KLF4 的核积累，并增强了 KLF4 与细胞核中 CLDN5 启动子的结合。在不存在 KLF4 的情况下，SIRT1 介导的 CLDN5 上调被阻断。相应地，尽管 SIRT1 被激活或过表达，siRNA 耗竭 KLF4 仍使卵巢癌细胞更具迁移和侵袭性。总之，我们的数据表明，SIRT1 通过去乙酰化和增强 KLF4 来激活 CLDN5 转录。
