USP49 mediates tumor progression and poor prognosis through a YAP1-dependent feedback loop in gastric cancer.

The importance of the Hippo-Yes-associated protein 1 (YAP1) pathway in gastric carcinogenesis and metastasis has attracted considerable research attention; however, the regulatory network of YAP1 in gastric cancer (GC) is not completely understood. In this study, ubiquitin-specific peptidase 49 (USP49) was identified as a novel deubiquitinase of YAP1, knockdown of USP49 inhibited the proliferation, metastasis, chemoresistance, and peritoneal metastasis of GC cells. Overexpression of USP49 showed opposing biological effects. Moreover, USP49 was transcriptionally activated by the YAP1/TEAD4 complex, which formed a positive feedback loop with YAP1 to promote the malignant progression of GC cells. Finally, we collected tissue samples and clinical follow-up information from 482 GC patients. The results showed that USP49 expression was high in GC cells and positively correlated with the expression of YAP1 and its target genes, connective tissue growth factor (CTGF) and cysteine-rich angiogenic inducer 61 (CYR61). Survival and Cox regression analysis showed that high USP49 expression was associated with poor prognosis and was an independent prognostic factor. Moreover, patients with high USP49 and YAP1 expression had extremely short overall survival. The findings of this study reveal that the aberrant activation of the USP49/YAP1 positive feedback loop plays a critical role in the malignant progression of GC, thus providing potential novel prognostic factors and therapeutic targets for GC.