NAT10-Mediated N4-Acetylcytidine Modification of GRB7 Promotes the Progression of Gastric Cancer.

Abstract

Gastric cancer (GC) is a highly prevalent malignancy with significant morbidity and mortality rates. N4-acetylcytidine (ac4C), an emerging RNA modification, has been implicated in tumorigenesis of GC. NAT10, an enzyme responsible for ac4C modification, has garnered attention for its potential role in cancer progression. This study investigates the role of NAT10 in GC. We analyzed NAT10 expression in GC tissues and cell lines using Rt-qPCR, immunohistochemistry and Western blotting. Functional studies were conducted using shRNA and overexpression models in vitro and in vivo. The molecular mechanisms underlying NAT10-mediated GRB7 regulation were elucidated through ac4C modification assays. Our findings revealed that NAT10 is overexpressed in GC tissues and cells and predicted poor prognosis of GC patients. Inhibition of NAT10 suppressed the proliferation, migration, and invasion of GC cells. Mechanistically, NAT10-mediated ac4C modification enhanced expression of GRB7 by promoting its mRNA stability. Overexpression of GRB7 antagonized the effects of NAT10 shRNA and promoted the malignant behaviors of GC. In vivo studies showed that NAT10 knockdown reduced tumor growth. Collectively, our study highlights the crucial roles of NAT10 and ac4C modification in GC progression through the regulation of GRB7. Therefore, targeting NAT10/GRB7 axis may be a novel strategy for GC.