METTL3-IGF2BP1-dependent m6A methylation of LFNG drives oral squamous cell carcinoma progression

This study investigates the roles of methyltransferase-like protein 3 (METTL3) and insulin-like growth factor 2 mRNA-binding protein 1 (IGF2BP1) within the N6-methyladenosine (m6A) regulatory axis in the progression of oral squamous cell carcinoma (OSCC), elucidating the underlying molecular mechanisms. We found that both METTL3 and IGF2BP1 are co-overexpressed in OSCC and synergistically enhance the proliferation, migration, and invasion capabilities of malignant tumors, while inhibiting apoptosis, as demonstrated in both in vitro and xenograft models. Transcriptomic analysis, combined with m6A immunoprecipitation experiments, confirmed that LFNG is a direct downstream effector subject to METTL3-mediated m6A methylation modification and is stabilized by IGF2BP1. Both loss-of-function and rescue experiments demonstrated that LFNG mediates all oncogenic phenotypes induced by the METTL3-IGF2BP1 axis; specifically, silencing either METTL3 or IGF2BP1 and subsequently overexpressing LFNG fully restores the malignant behavior and growth capabilities of the tumors. Mechanistically, the METTL3-IGF2BP1-dependent m6A modification stabilizes LFNG mRNA, thereby activating the Notch signaling pathway to accelerate OSCC progression. This study reveals that the METTL3-IGF2BP1-m6A-LFNG axis drives OSCC progression through transcriptomic epigenetic regulation. Targeting this regulatory pathway represents a promising strategy for the treatment of OSCC.