WDR79 promotes the proliferation of non-small cell lung cancer cells via USP7-mediated regulation of the Mdm2-p53 pathway.
WDR79 promotes the proliferation of non-small cell lung cancer cells via USP7-mediated regulation of the Mdm2-p53 pathway.
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WDR79 通过 USP7 介导的 Mdm2-p53 通路调节促进非小细胞肺癌细胞增殖
DOI：
10.1038/cddis.2017.162
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发表时间：
2017-04-13
影响因子：
9
通讯作者：
Ye M
中科院分区：
文献类型：
--
作者：
Sun Y;Cao L;Sheng X;Chen J;Zhou Y;Yang C;Deng T;Ma H;Feng P;Liu J;Tan W;Ye M
WD重复序列蛋白79（WD repeat protein 79，WDR 79）是WD重复序列蛋白家族的一员，在端粒酶组装、Cajal小体形成和DNA双链断裂修复过程中起支架蛋白的作用。我们之前已经表明，WDR 79经常在非小细胞肺癌（NSCLC）的细胞系和组织中过表达，并加速NSCLC中的细胞增殖。然而，WDR 79在NSCLC细胞增殖中的作用的详细机制仍不清楚。在这里，我们报告了WDR 79和USP 7之间的分子相互作用的发现，并显示其在连接Mdm 2-p53通路的NSCLC细胞增殖的功能意义。我们发现WDR 79在NSCLC细胞核中与USP 7共定位并相互作用。这一事件反过来又减少了Mdm 2和p53的泛素化，从而增加了这两种蛋白质的稳定性并延长了它们的半衰期。我们进一步发现WDR 79的功能效应依赖于USP 7，因为USP 7的敲低导致它们的减弱。最后，我们通过USP 7证明了WDR 79促进NSCLC细胞的增殖。综上所述，我们的研究结果揭示了WDR 79的一种新的分子功能，并可能为NSCLC带来广泛适用和创新的治疗途径。
WD repeat protein 79 (WDR79) is a member of the WD-repeat protein family and functions as a scaffold protein during telomerase assembly, Cajal body formation and DNA double strand break repair. We have previously shown that WDR79 is frequently overexpressed in cell lines and tissues derived from non-small cell lung cancer (NSCLC) and it accelerates cell proliferation in NSCLC. However, the detailed mechanism underlying the role of WDR79 in the proliferation of NSCLC cells remains unclear. Here, we report the discovery of a molecular interaction between WDR79 and USP7 and show its functional significance in linking the Mdm2-p53 pathway to the proliferation of NSCLC cells. We found that WDR79 colocalized and interacted with USP7 in the nucleus of NSCLC cells. This event, in turn, reduced the ubiquitination of Mdm2 and p53, thereby increasing the stability and extending the half-life of the two proteins. We further found that the functional effects of WDR79 depended upon USP7, because the knockdown of USP7 resulted in their attenuation. Finally, we demonstrated that WDR79 promoted the proliferation of NSCLC cells via USP7. Taken together, our findings reveal a novel molecular function of WDR79 and may lead to broadly applicable and innovative therapeutic avenues for NSCLC.