期刊
CANCER LETTERS
卷 436, 期 -, 页码 139-148出版社
ELSEVIER IRELAND LTD
DOI: 10.1016/j.canlet.2018.07.032
关键词
HCC; USP10; Deubiquitination; mTOR
类别
资金
- National Key Research and Development Program of China [2016YFC0903302]
- National Natural Science Foundation of China [81502024, 81672440, 31701156]
- Innovation program of science and research from the DICP, CAS [DICP TMSR201601]
- 100 Talents Program of Chinese Academy of Sciences
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.
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