Hsa_circ_0000479 promotes gastric cancer progression by inhibiting BTRC-mediated ubiquitination of G3BP1

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An increasing number of studies have shown that circular RNAs (circRNAs) are key regulators of cancer development and progression. RNA-binding proteins (RBPs) play critical roles in the regulation of biological activities, such as RNA synthesis, selective splicing, modification, translocation, and translation; therefore, research on the interactions of circRNAs with RBPs is key to identifying potential targets for cancer treatment. However, the biological roles and mechanisms of circRNAs in gastric cancer (GC) remain largely unknown. We identified differentially expressed circRNAs in GC by analysing Gene Expression Omnibus (GEO) datasets. Concurrently, in vitro functional assays and in vivo animal studies were performed to explore the biological role of circRNAs in GC. We performed western blotting (WB) of labelled proteins, salvage assays, mass spectrometry (MS), and RNA sequencing to investigate the mechanism of circRNAs in GC to explore their effects on GC cell proliferation and metastasis and to validate their potential value as therapeutic targets. Upregulated expression of cyclic RNA EPSTI1 (circEPSTI1; hsa_circ_0000479) was found in GC tissues and was associated with a poor clinical prognosis. hsa_circ_0000479 promotes the proliferation and migration of GC cells in vitro and in vivo. Notably, hsa_circ_0000479 interacts with Ras-GTPase-activated protein-binding protein 1 (G3BP1) in GC cells and inhibits the degradation of G3BP1 via the ubiquitin‒proteasome pathway, whereas hsa_circ_0000479 blocks the binding of G3BP1 to the E3 ligase BTRC. Mechanistic studies suggest that hsa_circ_0000479 promotes GC progression by competitively inhibiting the G3BP1 ubiquitination-mediated degradation facilitated by BTRC. Our results reveal the molecular mechanism by which hsa_circ_0000479 promotes GC progression through BTRC-mediated competitive binding to G3BP1 to inhibit its ubiquitination-mediated degradation, which provides a new theoretical basis for the targeted treatment of GC and elucidates the potential of hsa_circ_0000479-G3BP1-BTRC as a therapeutic target in GC. These findings provide a new direction for the treatment of patients with GC.

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