Tumor-promoting action of ubiquitin protease 43 in gastric cancer progression through deubiquitination and stabilization of stress-inducible phosphoprotein 1

Abstract

Gastric cancer (GC) is the 5th most common cancer over the world. Ubiquitin protease 43 (UBP43) is a multifunctional protein with deubiquitinase activities. Abnormal expression of UBP43 has been reported in numerous types of malignancies. Bioinformatic analysis was performed to identify the differentially expressed genes (Fold change ≥2 or ≤ −2 and p < 0.01) in GC from the datasets downloaded from Gene Expression Omnibus and Gene Expression Profiling Interactive Analysis databases, which showed that UBP43 and stress-inducible phosphoprotein 1 (STIP1) were up-regulated in both datasets. Online databases displayed the binding of UBP43 to STIP1 and the positive correlation between the two proteins. This study aims to explore: the role of UBP43 in cell proliferation and apoptosis in GC; the relationship between UBP43 and STIP1; and whether UBP43 exerts its function via STIP1 in GC. Knockdown/overexpression stable GC cell lines were generated by transducing lentivirus carrying coding sequence/short hairpin RNA of UBP43 and puromycin selection. GC patients with higher expressions of UBP43 had poor prognosis. Loss-/gain-of-function experiments revealed that pro-proliferative and anti-apoptotic abilities of UBP43 in GC cells and xenografts. UBP43 could interact with STIP1, inhibit its ubiquitination, and promote its protein stability, thereby enhancing STIP1 expression. Moreover, STIP1 knockdown reversed the pro-proliferative ability of UBP43 in GC cells. Our study uncovers that the pro-proliferative role of UBP43 in GC development is STIP1-dependent and indicates that UBP43 may act as a potent therapeutic target in GC treatment.