Prefoldin 1 promotes EMT and lung cancer progression by suppressing cyclin A expression
Prefoldin 1 promotes EMT and lung cancer progression by suppressing cyclin A expression
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Prefoldin 1 通过抑制细胞周期蛋白 A 表达促进 EMT 和肺癌进展
DOI：
10.1038/onc.2016.257
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发表时间：
2017-02-16
期刊：
影响因子：
8
通讯作者：
Song, J.
中科院分区：
文献类型：
--
作者：
Wang, D.;Shi, W.;Song, J.
前折叠蛋白（Prefoldin，PFDN）是一种共分子伴侣蛋白，主要以其在细胞骨架组装过程中折叠肌动蛋白和微管蛋白单体的经典细胞质功能而闻名。在这里，我们报告了转化生长因子（TGF）-β 1介导的上皮间质转化（EMT）和人肺肿瘤组织中前折叠蛋白亚基1（PFDN 1）水平的显着增加。有趣的是，还检测到了PFDN 1的核定位。这些观察结果表明PFDN 1可能对于重要的新功能至关重要。PFDN 1的过表达诱导EMT和细胞侵袭。与此形成鲜明对比的是，敲低PFDN 1产生相反的效果。PFDN 1的过表达也被发现诱导肺肿瘤的生长和转移。进一步的实验表明，PFDN 1过表达抑制细胞周期蛋白A的表达。PFDN 1通过在转录起始位点直接与细胞周期蛋白A启动子相互作用来抑制细胞周期蛋白A的表达。引人注目的是，细胞周期蛋白A过表达消除了上述PFDN 1介导的对肺癌细胞行为的影响，而细胞周期蛋白A敲低单独诱导EMT，并增加细胞迁移和侵袭能力。本研究揭示TGF-β 1/PFDN 1/ cyclin A轴在肺癌细胞EMT诱导和转移过程中是必不可少的。
Prefoldin (PFDN) is a co-chaperone protein that is primarily known for its classic cytoplasmic functions in the folding of actin and tubulin monomers during cytoskeletal assembly. Here, we report a marked increase in prefoldin subunit 1 (PFDN1) levels during the transforming growth factor (TGF)-beta 1-mediated epithelial-mesenchymal transition (EMT) and in human lung tumor tissues. Interestingly, the nuclear localization of PFDN1 was also detected. These observations suggest that PFDN1 may be essential for important novel functions. Overexpression of PFDN1 induced EMT and cell invasion. In sharp contrast, knockdown of PFDN1 generated the opposite effects. Overexpression of PFDN1 was also found to induce lung tumor growth and metastasis. Further experiments showed that PFDN1 overexpression inhibits the expression of cyclin A. PFDN1 suppressed cyclin A expression by directly interacting with the cyclin A promoter at the transcriptional start site. Strikingly, cyclin A overexpression abolished the above PFDN1-mediated effects on the behavior of lung cancer cells, whereas cyclin A knockdown alone induced EMT and increased cell migration and invasion ability. This study reveals that the TGF-beta 1/ PFDN1/ cyclin A axis is essential for EMT induction and metastasis of lung cancer cells.