Ubiquitin-specific peptidase 46 (USP46) suppresses renal cell carcinoma tumorigenesis through AKT pathway inactivation
| Autor: | Wei Peng, Weidong Jiang, Zuwei Xu, Jinlun Fu, Yunfei Zhao, Gang Liu, Geng Huang, Zhihua Ye, Dingwen Gui, Yang Wang, Shuai Luo |
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| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
Carcinogenesis Biophysics Kaplan-Meier Estimate medicine.disease_cause Biochemistry 03 medical and health sciences 0302 clinical medicine Cell Movement Cell Line Tumor Endopeptidases medicine Humans Molecular Biology Protein kinase B Carcinoma Renal Cell PI3K/AKT/mTOR pathway Cell Proliferation Chemistry Akt/PKB signaling pathway Cell growth Cell migration Cell Biology Prognosis Kidney Neoplasms 030104 developmental biology HEK293 Cells 030220 oncology & carcinogenesis Cancer cell Cancer research Phosphorylation RNA Interference Proto-Oncogene Proteins c-akt Signal Transduction |
| Zdroj: | Biochemical and biophysical research communications. 519(4) |
| ISSN: | 1090-2104 |
| Popis: | USP46, a member of the ubiquitin-specific protease family, plays essential roles in cancer cell proliferation and metastasis and is used as a candidate target for cancer therapeutics. However, the effects of USP46 on renal cell carcinoma (RCC) and its underlying molecular mechanism remain unknown. In this study, the predictive and prognostic relevance of USP46 in RCC, patient-derived primary tissues, and normal liver tissues obtained from the TCGA dataset were analyzed for the USP46 mRNA levels or prognostic relevance. Gain-of-function or loss-of-function assays were used to evaluate the vital roles of USP46 in tumor cell proliferation and cell migration. As a result, the USP46 expression level in RCC is highly decreased compared to normal tissues, and the Kaplan-Meier curve showed that USP46 high expression patients had good prognoses. Functionally, the forced expression of USP46 significantly restrained tumor cell proliferation, colony formation, and cell migration. The shRNA mediated USP46 knockdown cells exhibited the opposite results. We further showed that ectopically expressed USP46 obviously inhibited the AKT signaling pathway in cancer cells, while USP46 depletion caused a dramatic increase in AKT activity reflected by phosphorylation in the serine and threonine residues of AKT or downstream p70S6K1. Importantly, MK2206, a specific AKT inhibitor, completely counteracted the effects on cell proliferation, cell migration, and AKT activity in the USP46 depletion cells. We thus revealed a novel mechanism of USP46 regulation in RCC, and our data indicate that USP46 is a tumor suppressor in RCC via AKT signaling pathway inactivation. |
| Databáze: | OpenAIRE |
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