m6A-mediated upregulation of miR-3690 drives HNSCC progression by regulating nuclear-cytoplasmic signaling pathway.

MicroRNAs (miRNAs) are involved in carcinogenesis. However, the biological roles and underlying mechanism of miR-3690 in head and neck squamous cell carcinoma (HNSCC) progression are far from elucidated. In this study, we found that the expression level of miR-3690 in HNSCC tissues was significantly higher and correlated with poor clinical prognosis. HNSCC cells proliferation, migration, and invasion were promoted by miR-3690 overexpression, both in vitro and in vivo. Mechanistically, miRNA pulldown DNA-seq and luciferase reporter assays revealed that miR-3690 could directly activate CKS2 expression through targeting its promoter. Meanwhile, RNA pull down and mass spectrometry (MS) analysis suggested that upregulation of CKS2 by miR-3690 correlated with increased BPTF occupancy and H3K4me3 at CKS2 promoter. Additionally, luciferase reporter assays showed that miR-3690 facilitated Wnt/β-catenin signaling in HNSCC by repressing NKD1 expression through directly targeting its 3'-UTR. Finally, methylated RNA Immunoprecipitation (meRIP) and RNA pull down indicated that METTL3 and METTL14-mediated m6A modification accelerated pri-miR-3690 maturation through regulating the processing of pri-miR-3690 by DGCR8. In conclusion, miR-3690 may be a prognostic indicator and potential therapeutic target for HNSCC.