METTL3-mediated m(6)A modification regulates OSCC progression via the HNRNPA2B1/FOXQ1 axis.

Oral squamous cell carcinoma (OSCC) is a major global health concern with a 5-year survival rate of approximately 50%, driven by high recurrence and metastasis. N(6)-methyladenosine (m(6)A) RNA modification, regulated by METTL3, plays a critical role in cancer progression, yet its mechanisms in OSCC remain underexplored. This study investigates the METTL3/HNRNPA2B1/FOXQ1 axis in OSCC tumorigenesis. m(6)A RNA immunoprecipitation sequencing (MeRIP-Seq) and motif analysis were performed to identify m(6)A modification sites in OSCC cell lines. METTL3, HNRNPA2B1, and FOXQ1 expression levels were assessed in OSCC and normal tissues using immunohistochemistry as a retrospectively registered. METTL3 was modulated in CAL27 cells to evaluate its effects on m(6)A levels, HNRNPA2B1/FOXQ1 expression, and mRNA stability via RT-qPCR, Western blotting, and RNA immunoprecipitation (RIP)-PCR. Functional assays (EdU, wound healing, Transwell) assessed proliferation, migration, invasion, and epithelial-mesenchymal transition (EMT). Xenograft models validated in vivo effects. MeRIP-Seq identified the "GGAC" motif as a predominant m(6)A site. METTL3, HNRNPA2B1, and FOXQ1 were significantly overexpressed in OSCC tissues (p < 0.05). METTL3 silencing reduced m(6)A levels, HNRNPA2B1/FOXQ1 expression, and mRNA stability, attenuating proliferation, migration, invasion, and EMT, while overexpression enhanced these phenotypes. RIP-PCR confirmed METTL3 binding to HNRNPA2B1/FOXQ1 mRNA. In vivo, METTL3 silencing decreased tumor growth and FOXQ1 expression. METTL3-mediated m(6)A modification promotes OSCC progression by stabilizing HNRNPA2B1 and FOXQ1 mRNA, driving EMT and malignancy. The METTL3/HNRNPA2B1/FOXQ1 axis is a potential diagnostic and therapeutic target for OSCC, offering novel insights into epigenetic regulation and treatment strategies.