USP22 Facilitates Gastric Cancer Progression via Hippo/YAP axis

Previous studies demonstrated that the dysregulation of the Hippo pathway and hyperactivation of the YAP/TEAD transcriptional axis played important roles in GC progression, although the underlying mechanisms remain incompletely understood. Our study demonstrated that the deubiquitinase USP22 plays a pivotal role in regulating the Hippo pathway in GC, where its inhibition markedly suppresses YAP/TEAD activity and tumor progression.

Mechanistically, USP22 interacts with YAP and inhibits its K48-linked polyubiquitination, thereby enhancing YAP protein stability and Hippo/YAP axis activity in GC. Intriguingly, YAP can transcriptionally upregulate USP22 by binding to its promoter region, establishing a positive feedback loop that promotes gastric cancer progression. Collectively, our findings reveal a reciprocal activation mechanism between USP22 and the Hippo pathway in gastric tumorigenesis, identifying USP22 as a promising novel therapeutic target.