USP22 maintains gastric cancer stem cell stemness and promotes gastric cancer progression by stabilizing BMI1 protein.

Increased ubiquitin-specific protease 22 (USP22) has been associated with poor prognosis in several cancers including gastric cancer. However, the role of USP22 in gastric tumorigenesis is still unclear. Gastric cancer stem cells have been identified and shown to correlate with gastric cancer initiation and metastasis. In this study, we found that silencing of USP22 inhibited proliferation of gastric cancer cells and suppressed the cancer stem cell spheroid formation in serum-free culture. Furthermore, cancer stem cell markers, such as CD133, SOX2, OCT4 and NANOG were down-regulated. Additionally, knockdown of USP22 inhibited gastric cancer xenografts growth. Our analysis of TCGA database indicated that BMI1 overexpression may predict gastric cancer patient survival, and TAT-BMI1 proteins reversed the USP22 knockdown-mediated decreased in cancer stem cell properties, and elevated the expression of stemness-associated genes. Furthermore, we found that overexpression of USP22 stabilized the BMI1 protein in gastric cancer cells. Taken together, our study demonstrates that USP22 is indispensable for gastric cancer stem cell self-renewal through stabilization of BMI1. These results may provide novel approaches to the theranostics of gastric cancer in the near future.