METTL3 promotes esophageal squamous cell carcinoma progression through the GLUT4-mTORC1 axis

Abstract Background: Methyltransferase-like 3 (METTL3) is an essential methyltransferase for N6-methyladenosine (m6A) modification that participates in the pathogenesis of various malignancies including esophageal cancer. Yet, its mechanism of action is still not very clear. In this study, we hypothesized that METTL3 might control the progression of esophageal squamous cell carcinoma (ESCC) by regulating its glycolysis metabolism.Methods: The expression and role of METTL3 in ESCC were elucidated based on the TCGA database. METTL3 expression in ESCC tissues was validated by immunohistochemical assay (IHC). The Cell Counting Kit-8 (CCK8), colony formation assay, wound healing, and cell migration assays were used to analyze the efficacy of targeting METTL3 on ESCC proliferation and migration in ESCC cell overexpressing METTL3 or with METTL3 knockdown. The biological mechanisms of METTL3 in glycolysis metabolism of ESCC were evaluated using western blot and quantitative real-time PCR (qRT-PCR).Results: METTL3 was significantly upregulated in ESCC both in the TCGA database and our cohort. Functionally, knockdown of METTL3 repressed ESCC cell proliferation and migration in vitro, while these phenomena were reversed after METTL3 was overexpressed in ESCC cells. In addition, METTL3 interacted with and mediated the glucose uptake and lactate production of ESCC cells. Intriguingly, METTL3 epigenetically regulated GLUT4 expression and lactate production, thereby activating the mTORC1 signaling pathway. Moreover, in METTL3-depleted ESCC cells, inhibiting mTORC1 had a significant anticancer effect.Conclusion: METTL3 is an oncogenic gene that can promote ESCC tumorigenesis via the GLUT4-mTORC1 axis, thus representing a promising therapeutic target for ESCC.