The deubiquitinase USP10 restores PTEN activity and inhibits non–small cell lung cancer cell proliferation
| Autor: | Yuanming He, Zubin Zhang, Yuanying Zeng, Xinliang Mao, Jun Zhao, Chenyu Mao, Hui Zheng, Shuoyi Jiang, Biyin Cao |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
Male
PTEN Lung Neoplasms Gene Expression medicine.disease_cause NSCLC PI3K phosphatidylinositol-3-kinase Biochemistry Deubiquitinating enzyme Tripartite Motif Proteins chemistry.chemical_compound NSCLC non–small cell lung cancer Cell Movement Carcinoma Non-Small-Cell Lung Tensin Dub deubiquitinase biology Deubiquitinating Enzymes TRIM25 tripartite motif containing 25 EdU 5-ethynyl-2′-deoxyuridine IP immunoprecipitation Middle Aged Gene Expression Regulation Neoplastic Female Signal transduction Ubiquitin Thiolesterase Research Article Signal Transduction Adult sgRNA single-guide RNA Ubiquitin-Protein Ligases IgG immunoglobulin G mTOR mammalian target of rapamycin CHX cycloheximide Cell Line Tumor medicine Humans MTT 3-(4 5-dimethylthylthiazol-2-yl)-2 5-diphenyltetrazoliumbromide IB immunoblotting Molecular Biology Protein kinase B PI3K/AKT/mTOR pathway Cell Proliferation PTEN phosphatase and tensin homolog deleted on chromosome 10 Phosphatidylinositol (3 4 5)-trisphosphate USP10 ubiquitin-specific protease 10 PTEN Phosphohydrolase Ubiquitination Cell Biology USP10 HEK293T human embryonic kidney 293T deubiquitinase chemistry PI(3 4 5)P3 phosphatidylinositol-3 4 5-trisphosphate K63-linked polyubiquitination Cancer research biology.protein Carcinogenesis Transcription Factors |
| Zdroj: | The Journal of Biological Chemistry |
| ISSN: | 1083-351X 0021-9258 |
| Popis: | The phosphatase and tensin homolog deleted on chromosome 10 (PTEN) protein is a key player in tumorigenesis of non–small cell lung cancer (NSCLC) and was recently found to be inactivated by tripartite motif containing 25 (TRIM25)–mediated K63-linked polyubiquitination. However, the deubiquitinase (Dub) coordinate TRIM25 in PTEN ubiquitination is still elusive. In the present study, we found that this K63-linked polyubiquitination could be ablated by the ubiquitin-specific protease 10 (USP10) in a screen against a panel of Dubs. We found using coimmununoprecipitation/immunoblotting that USP10 interacted with PTEN and reduced the K63-linked polyubiquitination of PTEN mediated by TRIM25 in NSCLC cells. Moreover, USP10, but not its inactive C424A deubiquitinating mutant or other Dubs, abolished PTEN from K63-linked polyubiquitination mediated by TRIM25. In contrast to TRIM25, USP10 restored PTEN phosphatase activity and reduced the production of the secondary messenger phosphatidylinositol-3,4,5-trisphosphate, thereby inhibiting AKT/mammalian target of rapamycin progrowth signaling transduction in NSCLC cells. Moreover, USP10 was downregulated in NSCLC cell lines and primary tissues, whereas TRIM25 was upregulated. Consistent with its molecular activity, re-expression of USP10 suppressed NSCLC cell proliferation and migration, whereas knockout of USP10 promoted NSCLC cell proliferation and migration. In conclusion, the present study demonstrates that USP10 coordinates TRIM25 to modulate PTEN activity. Specifically, USP10 activates PTEN by preventing its K63-linked polyubiquitination mediated by TRIM25 and suppresses the AKT/mammalian target of rapamycin signaling pathway, thereby inhibiting NSCLC proliferation, indicating that it may be a potential drug target for cancer treatment. |
| Databáze: | OpenAIRE |
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