OTUD7B deubiquitinates and stabilizes YAP1 to upregulate NUAK2 expression, thus accelerating gastric cancer procession

Abstract

Background

Gastric cancer (GC) is one of the most common malignancies worldwide. Ovarian tumor protein superfamily serves a crucial role in tumor growth progression, among them, ovarian tumor domain-containing 7B (OTUD7B) as a deubiquitinase (DUB) is frequently found in various cancers, but the role of OTUD7B in GC is poorly understood.

Aims

To clarify the effect of OTUD7B on GC progression.

Methods

Functional experiments were performed to detect the proliferation, migration and invasion of GC cells. Xenografts were used to measure the effects in vivo. Co-immunoprecipitation (Co-IP) and ubiquitination assays showed the interaction of OTUD7B and YAP1.

Results

OTUD7B was highly expressed in tumor tissues from GC patients, and high mRNA expression was strongly associated with poor prognosis, suggesting that OTUD7B was an independent prognostic factor. Moreover, OTUD7B overexpression promoted GC cell proliferation and metastasis both in vitro and in vivo, whereas OTUD7B knockdown exhibited opposing biological effects. Mechanically, OTUD7B promoted downstream target genes of YAP1 including NUAK2, Snail, Slug, CDK6, CTGF, and BIRC5. Importantly, OTUD7B enhanced the activation of YAP1 via deubiquitinating and stabilizing to upregulate NUAK2 expression.

Conclusions

OTUD7B is a novel DUB of the YAP1 pathway and accelerates GC progression. Therefore, OTUD7B may be a promising therapeutic target against GC.