PSMA1 Mediates Tumor Progression And Poor Prognosis Of Gastric Carcinoma By Deubiquitinating And Stabilizing TAZ

Background: Gastric cancer(GC)was the fifth most common malignancy and the third leading cause of cancer-related deaths worldwide.The deubiquitinating enzyme family in tumor progression play important role in intracellular protein degradation.The proteasome subunit alpha type 1(PSMA1)was identified as a new deubiquitinase,and has been reported to act as an oncogene in several human cancers.At present,many studies have focused on the mechanism of deubiquitination enzyme in gastric cancer.However,the functional significance and mechanism of PSMA1 in gastric cancer progression remained unclear.Methods: The expression of PSMA1 in normal gastric mucosal epithelial cells and different gastric cancer cells was examined by western blot(WB)analysis.Immunohistochemistry(IHC)was used to verify PSMA1 expression in different stages of gastric mucosa cancerous,gastric cancer tissue and normal tissue.Kaplan-Meier plotter was used to analyze the correlation between PSMA1 expression and survival prognosis of patients with gastric cancer.To further explore the role of PSMA1 and its downstream mechanism,we performed a mass spectrometry analysis.Herein,we reported transcriptional co-activator with PDZ-binding motif(TAZ)as a critical target of PSMA1.The relationship between PSMA1 and TAZ was verified by protein halflife experiment and co-immunoprecipitation experiment(Co-IP).Constructing PSMA1 knockout and overexpression models of gastric cancer cells to verify its biological function in GC.Xenograft mouse model was established to detect the role of PSMA1 in promoting the proliferation.The data were statistically analyzed with the SPSS software package(SPSS,IL,USA)and Graph Pad Prism software(Graph Pad,CA,USA).Results: We found that PSMA1 was upregulated in GC tissue compare to normal tissue,and the expression level increased with the progression stage of gastric cancer.PSMA1 was proved to play an important role in promoting the proliferation,migration and invasion in GC cells.Mechanistically,PSMA1 directly interacted with and stabilized TAZ via deubiquitination in GC.Furthermore,we found that TAZ was the essential mediator of PSMA1-modμlated oncogenic activity in vitro and in vivo.Examination of clinical samples confirmed that elevated mediators of PSMA1,concomitant with increased TAZ abundance,correlate with human GC progression.Conclusion: These data suggested that PSMA1 promotes GC progression and proliferation by deubiquitinating TAZ.Due to the lack of specific targets for gastric cancer,this study is expected to provide new ideas for the prevention and treatment of gastric cancer in future.