METTL3-mediated m6A modification stabilizes circCDK6 to promote cervical cancer tumorigenesis via the miR-449a/CDK6 axis

Cervical cancer remains a significant global health burden. This study aimed to investigate whether the RNA methyltransferase METTL3 promotes cervical cancer progression by regulating the stability of circular RNA circCDK6 via N⁶-methyladenosine (m⁶A) modification. Clinical samples from cervical cancer patients were analyzed. In vitro and in vivo functional assays, including PCR, RNA immunoprecipitation, m⁶A-methylated RNA immunoprecipitation, RNA stability assays, CCK-8, colony formation, flow cytometry, dual-luciferase reporter assay, and xenograft models were employed using cervical cancer cell lines. METTL3 and circCDK6 were significantly upregulated in cervical cancer tissues, and high expression correlated with advanced disease and poor patient prognosis. METTL3 directly bound to circCDK6 and installed m⁶A modification, which enhanced circCDK6 RNA stability. Knockdown of METTL3 or circCDK6 suppressed cell proliferation, induced G0/G1 phase arrest, and inhibited tumor growth in mouse models. Mechanistically, circCDK6 functioned as a competitive endogenous RNA to sponge miR-449a, thereby de-repressing the expression of its target, CDK6, a key cell cycle regulator. Our findings unveil a novel oncogenic METTL3/m⁶A/circCDK6/miR-449a/CDK6 axis that promotes cervical cancer tumorigenesis, highlighting its potential as a therapeutic target for intervention.