METTL3-IGF2BP3 as a glucose sensor in hyperglycemic microenvironment promotes tumorigenesis and glycolysis

Glycemic disorders, especially diabetes characterized by elevated blood glucose, significantly increase the risk of various cancers, including increasing the risk of hepatocellular carcinoma (HCC) by 239%. Diabetes mellitus has now been confirmed as an independent risk factor for the development of HCC, with T2DM increasing the risk by 4.59 times. However, little is known about mechanisms regulate glucose signal transduction in HCC. We investigated the relationship between high glucose levels and methylation-related gene expression in HCC. The effects of METTL3-IGF2BP3 on transcriptome profiles were used to identify downstream molecules. Proliferation, glucose uptake, lactate production, ATP levels, extracellular acidification rate, and oxygen consumption rate were examined in HCC cells. The mechanism by which METTL3-IGF2BP3 activates the PI3K-AKT pathway was explored. The results showed that m⁶A modification levels were significantly elevated in HCC cells under a hyperglycemic microenvironment, primarily due to transcriptional activation of c-MYC-initiated METTL3. Additionally, glucose could directly bind to IGF2BP3 and promote its function in recognizing m⁶A sites. SLC39A10 as a downstream molecule of METTL3-IGF2BP3, promoting the uptake of Zn²⁺ in HCC. METTL3, IGF2BP3, or SLC39A10 silencing inhibited proliferation, colony formation, glycolysis in HCC cells. Mechanistically, silencing METTL3-IGF2BP3 significantly reduced the methylation level and function of SLC39A10, decreased intracellular Zn²⁺ levels, inhibited ADAM17 activity, and thus attenuated EGFR phosphorylation-induced PI3K-AKT pathway activation. Concurrently, alterations in intracellular Zn²⁺ levels are associated with altered immune cell infiltration in the HCC tumor microenvironment. In conclusion, the METTL3-IGF2BP3 axis promotes HCC tumorigenesis by enhancing glycolytic reprogramming and remodeling the immunosuppressive tumor microenvironment.