Destabilization of hsa_circ_0015508 by YTHDF2 Enhances miR-496-Mediated FOXN3 Suppression to Drive Nasopharyngeal Carcinoma Progression.

Objectives: YTH N6-Methyladenosine RNA Binding Protein F2 (YTHDF2) had been implicated in nasopharyngeal carcinoma (NPC) progression. Increasing evidence indicated that numerous circular RNAs (circRNAs) were involved in regulating tumor progression. However, how the regulation of circRNAs by YTHDF2 contributes to NPC progression remains to be uncovered. In this study, we aimed to elucidate the role and mechanism of YTHDF2-mediated circRNA regulation in NPC migration and invasion. Methods: YTHDF2 expression in NPC was assessed using GEO datasets and immunohistochemistry. Functional experiments were performed in HNE1 and 5-8F cells, with migration/invasion evaluated by wound healing and transwell assays, and epithelial-mesenchymal transition (EMT) markers by Western blotting. CircRNA candidates were screened through circRNA sequencing. CircRNA m6A modification was assessed by methylated RNA immunoprecipitation-quantitative PCR (MeRIP-qPCR). The SELECT method (single-base elongation- and ligation-based qPCR amplification) was used to identify the specific m6A modification site. RNA stability was measured by actinomycin D assay. circRNA-miRNA and miRNA-target interactions were validated by luciferase reporter assays. Results: YTHDF2 expression was upregulated in NPC tissues and was found to promote in vitro migration and invasion phenotypes. Mechanistically, m6A-modified circ_0015508 was recognized and degraded by YTHDF2. YTHDF2-mediated pro-migration and pro-invasion effects were reversed by circ_0015508. FOXN3 was identified as a target of miR-496. Circ_0015508 was found to sequester miR-496, thereby de-repressing FOXN3 expression. Conclusion: In this study, a potential oncogenic pathway was delineated in which NPC migration and invasion were facilitated by YTHDF2 via degradation of circ_0015508, thereby the sponging effect of miR-496 was abolished and FOXN3 expression was suppressed.