N⁶-methyladenosine-modified circFUT8 competitively interacts with YTHDF2 and miR-186-5p to stabilize FUT8 mRNA to promote malignant progression in lung adenocarcinoma

Background: Lung cancer is the leading cause of cancer related to mortality worldwide, and the main pathological type is lung adenocarcinoma (LUAD). Circular RNAs (circRNAs) have been reported to be modified by N6-methyladenosine (m6A), which is involved in the progression of diverse tumors. However, the crosstalk between circRNAs and m6A modification has not been well elucidated in LUAD. Methods: MeRIP-seq and YTHDF2-RIP-seq datasets were explored to identify candidate circRNAs modified by YTHDF2. Dual-luciferase reporter assay, RIP, and rescue assays were performed to explore the relationship between circFUT8 and its parent mRNA of FUT8. In vitro and in vivo experiments were utilized to uncover the function of circFUT8. Results: In this study, we identified a novel m6A-modified circFUT8, derived from exon 3 of FUT8, which was elevated in tumor tissues compared with adjacent noncancerous tissues. The m6A reader YTHDF2 recognized and destabilized circFUT8 in an m6A-dependent manner. YTHDF2 also combined with the line form of FUT8 (mFUT8), and circFUT8 competitively interacted with YTHDF2, blunting its binding to mFUT8, to stabilize the mRNA level of FUT8. Additionally, circFUT8 sponged miR-186-5p to elevate the expression of mFUT8. Finally, we revealed that circFUT8 promoted the malignant progression of LUAD dependent on the oncogenic function of FUT8. Conclusions: These findings identified a novel m6A-modified circFUT8 recognized and destabilized by YTHDF2, which competitively interacted with YTHDF2 and miR-186-5p to stabilize FUT8 mRNA to promote malignant progression in LUAD.