USP10 suppresses tumor progression by inhibiting mTOR activation in hepatocellular carcinoma
USP10 suppresses tumor progression by inhibiting mTOR activation in hepatocellular carcinoma
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USP10 通过抑制肝细胞癌中 mTOR 的激活来抑制肿瘤进展
DOI：
10.1016/j.canlet.2018.07.032
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发表时间：
2018-01-01
期刊：
影响因子：
9.7
通讯作者：
Tan, Guang
中科院分区：
文献类型：
--
作者：
Lu, Chang;Ning, Zhen;Tan, Guang
去泛素化途径的失调与癌症如肝细胞癌（HCC）的不良预后相关。雷帕霉素的哺乳动物靶点mTOR已成为HCC中有吸引力的癌症治疗靶点。然而，去泛素化通路的异常表达是否以及如何调节mTOR通路仍然是一个谜。在这里，我们报告说，泛素特异性蛋白酶10（USP 10）作为一种肿瘤抑制因子，通过稳定肝癌细胞中的PTEN和AMPK α来抑制mTOR通路。在机制上，USP10通过抑制它们的多聚泛素化而相互作用并稳定PTEN和AMPK α。这种稳定反过来抑制AKT磷酸化和mTOR复合物1（mT0RC 1）活化。在人肝癌中，USP10表达在三个独立的HCC队列的HCC肿瘤组织中下调，USP10的低表达将产生不良预后结果。总的来说，我们的研究结果揭示了一种未描述的机制，其中USP 10作为肿瘤抑制因子，通过稳定HCC细胞中的AMPKa和PTEN来负调节mTORC 1活化和AKT磷酸化。本研究为临床上以mTOR信号通路为导向的靶向治疗奠定了理论基础。
Dysregulation of deubiquitination pathway is associated with poor prognosis in cancers such as hepatocellular carcinoma (HCC). The mammalian target of rapamycin, mTOR, has become an attractive cancer therapeutic target in HCC. However, whether and how aberrant expression of deubiquitination pathway regulates mTOR pathway has remained elusive. Here we report that ubiquitin-specific protease 10 (USP10) functions as a tumor suppressor which inhibits mTOR pathway by stabilizing PTEN and AMPK alpha in HCC cells. Mechanistically, USP10 interacts and stabilizes PTEN and AMPK alpha by inhibiting their polyubiquitylation. This stabilization in turn inhibits AKT phosphorylation and mTOR Complexl (mTORC1) activation. In human liver cancer, USP10 expression is downregulated in HCC tumor tissues across three independent HCC cohorts, and lower-expression of USP10 will generate poor prognosis outcome. Collectively, our results uncover an undescribed mechanism where USP10, as a tumor suppressor, negatively regulates mTORC1 activation and AKT phosphorylation by stabilizing AMPKa and PTEN in HCC cells. This study sheds light on the theoretical basis of mTOR signaling pathwayoriented targeting treatment in clinic.