FBXW7 negatively regulates ENO1 expression and function in colorectal cancer.
FBXW7 negatively regulates ENO1 expression and function in colorectal cancer.
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FBXW7 负向调节结直肠癌中 ENO1 的表达和功能。
DOI：
10.1038/labinvest.2015.71
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发表时间：
2015-09
期刊：
影响因子：
--
通讯作者：
Zhang P
中科院分区：
文献类型：
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作者：
Zhan P;Wang Y;Zhao S;Liu C;Wang Y;Wen M;Mao JH;Wei G;Zhang P
FBXW 7（F-box and WD 40 domain protein 7）是一种在人类癌症中经常失活的肿瘤抑制因子。FBXW 7发挥抗肿瘤活性的精确分子机制仍在深入研究中，并被认为部分与FBXW 7介导的关键癌症相关蛋白的破坏有关。烯醇化酶1（ENO 1）具有致癌活性，除了在糖酵解中起关键作用外，还经常在各种人类癌症中过表达。然而，ENO 1表达的详细调控机制仍不清楚。在这里，我们表明，通过二维蛋白质电泳和质谱分析（2DE-MS），在FBXW 7耗尽HCT 116细胞中确定了ENO 1的表达升高。随后的蛋白质印迹和免疫组织化学分析证实，在几种细胞和结肠癌组织中，ENO 1表达与FBXW 7表达相关。此外，我们表明FBXW 7物理结合到ENO 1和目标ENO 1的泛素介导的降解。在功能上，我们发现FBXW 7抑制ENO 1诱导的基因表达，乳酸产生，细胞增殖和迁移。这些结果表明，ENO 1是FBXW 7的一种新底物，FBXW 7可以在翻译后水平负调控其活性。我们的工作提供了一个新的分子洞察FBXW 7通过调控ENO 1的肿瘤抑制。
FBXW7 (F-box and WD40 domain protein 7) is a tumor suppressor frequently inactivated in human cancers. The precise molecular mechanisms by which FBXW7 exerts antitumor activity remain under intensive investigation and are thought to relate in part to FBXW7-mediated destruction of key cancer-relevant proteins. Enolase 1 (ENO1) possesses oncogenic activity and is often overexpressed in various human cancers, besides its critical role in glycolysis. However, the detailed regulatory mechanisms of ENO1 expression remain unclear. Here we show that the elevated expression of ENO1 was identified in FBXW7-depletion HCT116 cells through two-dimensional protein electrophoresis and mass spectrometry assays (2DE-MS). Subsequent western blotting and immunohistochemical assays confirmed that ENO1 expression reversely correlates with FBXW7 expression in several cells and colon cancer tissues. Furthermore, we show that FBXW7 physically binds to ENO1 and targets ENO1 for ubiquitin-mediated degradation. Functionally, we found that FBXW7 suppresses the ENO1-induced gene expression, lactate production, cell proliferation and migration. These findings suggest that ENO1 is a novel substrate of FBXW7, and its activity can be negatively regulated by FBXW7 at the posttranslational level. Our work provides a novel molecular insight into FBXW7-directed tumor suppression through regulation of ENO1.