Cullin-5, a ubiquitin ligase scaffold protein, is significantly underexpressed in endometrial adenocarcinomas and is a target of miR-182.
Cullin-5, a ubiquitin ligase scaffold protein, is significantly underexpressed in endometrial adenocarcinomas and is a target of miR-182.
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DOI：
10.3892/or.2016.4605
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发表时间：
2016-04
期刊：
影响因子：
4.2
通讯作者：
Leslie KK
中科院分区：
文献类型：
--
作者：
Devor EJ;Schickling BM;Reyes HD;Warrier A;Lindsay B;Goodheart MJ;Santillan DA;Leslie KK
Cullin-5(CUL5)是cullin环E3泛素连接酶家族的成员之一，它的表达变化与乳腺癌、宫颈癌和肝细胞癌等多种癌症有关。在本研究中，我们发现CUL5在子宫内膜样腺癌和浆液性子宫内膜腺癌中的表达均显著降低，其中侵袭性较强的浆液性子宫内膜腺癌的表达降低幅度(−为4.3倍)高于侵袭性较弱的子宫内膜样腺癌(−为2.9倍)。Ishikawa H子宫内膜癌细胞中CUL5mRNA和蛋白的过表达导致细胞增殖下降，并导致CUL5环E3连接酶下游客户JAK2和Fas-L的减少。最后，我们首次证明了CUL5是miR-182的直接靶点，我们先前发现miR-182在子宫内膜腺癌中显著过表达，我们提供的证据表明，miR-182表达的增加至少部分是其上游启动子去甲基化的结果。这些数据表明，miR-182的表达在表观遗传上增加，导致CUL5的表达减少，细胞增殖增加。级联反应的最后一步可能是通过减少促进生长的CUL5泛素连接酶客户的泛素化来发挥作用。这一级联反应提供了一系列潜在的干预步骤，包括表观遗传修饰、miRNA和/或基因靶向和泛素化。
Altered expression of cullin-5 (CUL5), a member of the cullin-RING E3 ubiquitin ligase family, has been implicated in a number of types of cancers including breast, cervical and hepatocellular cancers. In the present study, we found that CUL5 expression was significantly decreased in both endometrioid and serous endometrial adenocarcinomas with the more aggressive serous type displaying a higher reduction (−4.3-fold) than the less aggressive endometrioid type (−2.9-fold). Overexpression of CUL5 mRNA and protein in Ishikawa H endometrial cancer cells resulted in decreased cell proliferation and in a reduction in CUL5-RING E3 ligase downstream clients JAK2 and FAS-L. Finally, we demonstrated for the first time that CUL5 is a direct target of miR-182 that we previously showed to be significantly overexpressed in endometrial adenocarcinomas and we provided evidence that increased miR-182 expression is, at least in part, a result of demethylation of its upstream promoter. These data suggest a cascade in which miR-182 expression is epigenetically increased leading to decreased CUL5 expression and increased cellular proliferation. The final step in the cascade may be operating through a decrease in ubiquitination of pro-growth CUL5 ubiquitin ligase clients. This cascade offers a series of potential interventional steps involving epigenetic modification, miRNA and/or gene targeting and ubiquitination.