Inhibition of USP11 sensitizes gastric cancer to chemotherapy via suppressing RhoA and Ras-mediated signaling pathways

Abstract

Background: The poor outcomes in advanced gastric cancer (GC) necessitate alternative therapeutic strategy. Ubiquitin-specific protease 11 (USP11) has recently garnered attention as a therapeutic target in cancer because of its important regulatory role in cancer cell functions. Here, we revealed the expression, function and underlying molecular interactions of USP11 in gastric cancer.

Methods: The expression of USP11 was analyzed using immunohistochemistry and ELISA. The loss-of function and gain-of function analysis of USP11 was performed using siRNA knockdown and plasmid overexpression approaches. The downstream molecules regulated by USP11 were determined using immunoblotting analysis.

Results: USP11 was upregulated in ∼80% of gastric cancer patients, and the upregulation was associated with HER3 overexpression. In addition, USP11 level was not regulated by HER3 and vice versa. Functional studies demonstrated that USP11 overexpression promoted gastric cancer growth and migration, and alleviated toxicity-induced by chemotherapeutic drug. In contrast, USP11 depletion significantly inhibited gastric cancer growth, migration and survival, and augmented chemotherapeutic drug's efficacy. Gastric cancer cells with higher USP11 levels were more sensitive to USP11 inhibitions than cells with lower USP11 levels. Mechanism studies showed that USP11 depletion suppressed migration via RhoA-mediated pathway and inhibited growth and survival likely via Ras-mediated pathway.

Conclusions: Our work highlights the important role of USP11 in gastric cancer and therapeutic value of inhibiting USP11 to sensitize gastric cancer to chemotherapy.

Keywords: Chemotherapy; Gastric cancer; Ras; RhoA; USP11.