The deubiquitinase USP10 restores PTEN activity and inhibits non-small cell lung cancer cell proliferation

He，Yuanming1,2; Jiang，Shuoyi1,2; Mao，Chenyu3; Zheng，Hui4; Cao，Biyin2; Zhang，Zubin2; Zhao，Jun5; Zeng，Yuanying6; Mao，Xinliang1,2

2021-09-01

10.1016/j.jbc.2021.101088

JOURNAL OF BIOLOGICAL CHEMISTRY   影响因子和分区

0021-9258

1083-351X

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.

SCI ; EI

英语

NI论文

其他

WOS:000706409200013

20213810901486

Biological organs ; Cell culture ; Cell proliferation ; Chromosomes ; Diseases ; Phosphatases ; Restoration

Bioengineering and Biology:461 ; Chemical Products Generally:804

BIOLOGY & BIOCHEMISTRY

2-s2.0-85114854668

Scopus

1.The Guangzhou Institute of Cardiovascular Diseases,Guangdong Key Laboratory of Vascular Diseases,State Key Laboratory of Respiratory Diseases,The Second Affiliated Hospital,Guangdong Key Laboratory of Protein Modification and Degradation,School of Basic Medical Sciences,Guangzhou Medical University,Guangzhou,China
2.Department of Pharmacology,College of Pharmaceutical Sciences,Soochow University,Suzhou,Jiangsu,China
3.School of Medicine,Southern University of Science and Technology,Shenzhen,Guangdong,China
4.Institute of Biomedical Sciences,Soochow University,Suzhou,Jiangsu,China
5.Department of Thoracic Surgery,The First Affiliated Hospital of Soochow University,Suzhou,China
6.Department of Oncology,Suzhou Municipal Hospital,Suzhou,China

He，Yuanming,Jiang，Shuoyi,Mao，Chenyu,et al. The deubiquitinase USP10 restores PTEN activity and inhibits non-small cell lung cancer cell proliferation[J]. JOURNAL OF BIOLOGICAL CHEMISTRY,2021,297(3).

He，Yuanming.,Jiang，Shuoyi.,Mao，Chenyu.,Zheng，Hui.,Cao，Biyin.,...&Mao，Xinliang.(2021).The deubiquitinase USP10 restores PTEN activity and inhibits non-small cell lung cancer cell proliferation.JOURNAL OF BIOLOGICAL CHEMISTRY,297(3).

He，Yuanming,et al."The deubiquitinase USP10 restores PTEN activity and inhibits non-small cell lung cancer cell proliferation".JOURNAL OF BIOLOGICAL CHEMISTRY 297.3(2021).