FTO enhances OSCC progression via m⁶A-dependent stabilization of PKM2 mRNA through YTHDF2 modulation.
Oral squamous cell carcinoma (OSCC) is a highly aggressive malignancy with poor prognosis and limited treatment options. N6-methyladenosine (m⁶A) modification represents a pivotal layer of epitranscriptomic regulation in cancer. Fat mass and obesity-associated protein (FTO), an m⁶A demethylase, has been implicated in several malignancies. While FTO's involvement in OSCC is emerging, its regulation of glycolytic metabolism remains uncharacterized. This study aimed to investigate the biological function of FTO in OSCC and determine whether it modulates PKM2 expression through an m⁶A-dependent mechanism involving YTHDF2.
FTO expression was analyzed in OSCC tissues by immunohistochemistry and Western blotting. Functional assays were performed in SCC25 and CAL27 cells with stable FTO knockdown or overexpression to assess proliferation, migration, invasion, and glycolytic activity. Global m⁶A levels, RNA-protein associations, and mRNA stability were examined using dot blot, RIP-qPCR, and actinomycin D treatment. NF-κB pathway activation was evaluated by Western blotting. In vivo tumorigenicity was assessed using xenograft models.
FTO was markedly upregulated in OSCC tissues and correlated with aggressive clinical features. Silencing FTO attenuated malignant phenotypes and glycolytic flux. Mechanistically, FTO stabilized PKM2 mRNA by reducing YTHDF2-mediated degradation via m⁶A demethylation. FTO expression also coincided with enhanced NF-κB signaling activity.
These findings define an FTO/m⁶A/YTHDF2/PKM2 axis that promotes OSCC progression through glycolytic reprogramming and tumor growth, highlighting a potential metabolic vulnerability for therapeutic intervention.
FTO expression was analyzed in OSCC tissues by immunohistochemistry and Western blotting. Functional assays were performed in SCC25 and CAL27 cells with stable FTO knockdown or overexpression to assess proliferation, migration, invasion, and glycolytic activity. Global m⁶A levels, RNA-protein associations, and mRNA stability were examined using dot blot, RIP-qPCR, and actinomycin D treatment. NF-κB pathway activation was evaluated by Western blotting. In vivo tumorigenicity was assessed using xenograft models.
FTO was markedly upregulated in OSCC tissues and correlated with aggressive clinical features. Silencing FTO attenuated malignant phenotypes and glycolytic flux. Mechanistically, FTO stabilized PKM2 mRNA by reducing YTHDF2-mediated degradation via m⁶A demethylation. FTO expression also coincided with enhanced NF-κB signaling activity.
These findings define an FTO/m⁶A/YTHDF2/PKM2 axis that promotes OSCC progression through glycolytic reprogramming and tumor growth, highlighting a potential metabolic vulnerability for therapeutic intervention.