METTL3 expression is associated with glycolysis metabolism and sensitivity to glycolytic stress in hepatocellular carcinoma

摘要

METTL3 is an RNA methyltransferase implicated in the control of cell differentiation and proliferation in embryonic development and cancer. The current study was aimed to explore the function and underlying mechanism of METTL3 in hepatocellular carcinoma (HCC). We evaluated the expression and prognostic significance of METTL3 in 100 HCC cases and TCGA dataset. In HCC cases, both the RNA and protein expression of METTL3 were significantly upregulated and associated with poor prognosis. Gene set enrichment analysis of transcriptional profiles in HCC specimens revealed that METTL3 expression was associated with impaired glucose metabolism and mTOR signal pathway. In Huh‐7 and SMMC‐7721 HCC cells, downregulation of METTL3 by siRNA interference inhibited glycolytic capacity, which was proved by the decreased intracellular glucose uptake and lactate production. In terms of mechanism, we found mTORC1 activity was impaired by downregulation of METTL3, additional silencing of METTL3 cannot further decrease the phosphorylation level of mTORC1 and glycolysis activity in Rapamycin‐treated HCC cells. At last, we observed that downregulation of METTL3 synergizes with the glycolysis inhibitor 2‐deoxyglucose (2‐DG) to inhibit tumor growth in vitro. Our study provided evidence that METTL3 is involved in the regulation of glycolysis activity in HCC, suggesting that suppression of glycolysis via METTL3 inhibition was a potential treating strategy against HCC.