Dataset Information

USP1 Maintains the Survival of Liver Circulating Tumor Cells by Deubiquitinating and Stabilizing TBLR1.

ABSTRACT: The prognosis of hepatocellular carcinoma (HCC) is closely associated with the occurrence of distant metastases, which is likely due to circulating tumor cells (CTCs). However, the low number of CTCs is the main obstacle limiting research of the mechanism of CTC metastasis. Here, We evaluated the role of ubiquitin-specific protease 1 (USP1) in promoting CTC survival during blood-borne metastases. We observed that USP1 was frequently upregulated in CTCs and correlated with metastasis and a reduced overall survival rate of patients. Additionally, genetic knockout of USP1 the survival rate of CTCs. Further analyses showed that USP1 mediates oncogenic activity by deubiquitinating and stabilizing transducin ?-like 1 X-linked receptor 1 (TBLR1), which plays essential roles in regulating Wnt signaling. These results demonstrated that USP1 may act as an essential factor in promoting the survival of CTCs and suggest that inhibition of USP1 is a potential strategy for HCC treatment.

SUBMITTER: Li Y

PROVIDER: S-EPMC7545832 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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USP1 Maintains the Survival of Liver Circulating Tumor Cells by Deubiquitinating and Stabilizing TBLR1.

Li Yuancheng Y Xu Yang Y Gao Chao C Sun Yunfan Y Zhou Kaiqian K Wang Pengxiang P Cheng Jianweng J Guo Wei W Ya Cao C Fan Jia J Yang Xinrong X

Frontiers in oncology 20200925

The prognosis of hepatocellular carcinoma (HCC) is closely associated with the occurrence of distant metastases, which is likely due to circulating tumor cells (CTCs). However, the low number of CTCs is the main obstacle limiting research of the mechanism of CTC metastasis. Here, We evaluated the role of ubiquitin-specific protease 1 (USP1) in promoting CTC survival during blood-borne metastases. We observed that USP1 was frequently upregulated in CTCs and correlated with metastasis and a reduce ...[more]

PMID: 33102219

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Project description:BackgroundP53 pathway inactivation plays an important role in the process of breast cancer tumorigenesis. Post-translational protein modification abnormalities have been confirmed to be an important mechanism underlying inactivation of p53. Numerous deubiquitinating enzymes are aberrantly expressed in breast cancer, and a few deubiquitination enzymes can deubiquitinate and stabilize p53. Here, we report that ovarian tumor (OTU) deubiquitinase 3 (OTUD3) is a deubiquitylase of p53 in breast carcinoma (BC).MethodsCorrelations between the mRNA expression levels of OTUD3, TP53 and PTEN and the prognosis of BC were assessed with the Kaplan-Meier Plotter tool. OTUD3 protein expression in 80 pairs of specimens in our cohort was examined by immunohistochemistry and western blotting. The relationship among OTUD3, p53, and p21 proteins was analyzed. Half-life analysis and ubiquitylation assay were performed to elucidate the molecular mechanism by which OTUD3 stabilizes p53. The interaction between OTUD3 and p53 in BC cells was verified by a co-immunoprecipitation assay and GST pulldown experiments. MTS assay for proliferation detection, detection of apoptosis induced by cisplatin and colony formation assay were employed to investigate the functional effects of OTUD3 on breast cancer cells.ResultsOTUD3 downregulation is correlated with a poor prognosis in BC patients. OTUD3 expression is decreased in breast cancer tissues and not associated with the histological grade. OTUD3 also inhibits cell proliferation and clone formation and increases the sensitivity of BC cells to apoptosis induced by chemotherapy drugs. Reduced OTUD3 expression accompanied by decreased p53 abundance is correlated with human breast cancer progression. Ectopic expression of wild-type OTUD3, but not its catalytically inactive mutant, stabilizes and activates p53. Mechanistically, OTUD3 interacts directly with p53 through the amino-terminal OTU region. Finally, OTUD3 protects p53 from murine double minute 2 (Mdm2)-mediated ubiquitination and degradation, enabling the deubiquitination of p53 in BC cells.ConclusionsIn summary, we found that OTUD3 may be a potential therapeutic target for restoring p53 function in breast cancer cells and suggest that the OTUD3-p53 signaling axis may play a critical role in tumor suppression.

Dataset Information

USP1 Maintains the Survival of Liver Circulating Tumor Cells by Deubiquitinating and Stabilizing TBLR1.

Publications

USP1 Maintains the Survival of Liver Circulating Tumor Cells by Deubiquitinating and Stabilizing TBLR1.

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