Research Article
The deubiquitinase USP10 restores PTEN activity and inhibits non–small cell lung cancer cell proliferation

https://doi.org/10.1016/j.jbc.2021.101088Get rights and content
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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.

Keywords

PTEN
deubiquitinase
USP10
K63-linked polyubiquitination
NSCLC

Abbreviations

CHX
cycloheximide
Dub
deubiquitinase
EdU
5-ethynyl-2′-deoxyuridine
HEK293T
human embryonic kidney 293T
IB
immunoblotting
IgG
immunoglobulin G
IP
immunoprecipitation
mTOR
mammalian target of rapamycin
MTT
3-(4,5-dimethylthylthiazol-2-yl)-2,5-diphenyltetrazoliumbromide
NSCLC
non–small cell lung cancer
PI(3,4,5)P3
phosphatidylinositol-3,4,5-trisphosphate
PI3K
phosphatidylinositol-3-kinase
PTEN
phosphatase and tensin homolog deleted on chromosome 10
sgRNA
single-guide RNA
TRIM25
tripartite motif containing 25
USP10
ubiquitin-specific protease 10

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