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Background Lung adenocarcinoma (LUAD)  is the most common subtype of lung cancer. Patient prognosis is poor, and the existing therapeutic strategies for LUAD are far from satisfactory. Recently, targeting N6-methyladenosine (m 6 A) modification of RNA has been suggested as a potential strategy to impede tumor progression. However, the roles of m 6 A modification in LUAD tumorigenesis is unknown. Methods Global m 6 A levels and expressions of m 6 A writers, erasers and readers were evaluated by RNA methylation assay, dot blot, immunoblotting, immunohistochemistry and ELISA in human LUAD, mouse models and cell lines. Cell viability, 3D-spheroid generation,  in vivo  LUAD formation, experiments in cell- and patient-derived xenograft mice and survival analysis were conducted to explore the impact of m 6 A on LUAD. The RNA-protein interactions, translation, putative m 6 A sites and glycolysis were explored in the investigation of the mechanism underlying how m 6 A stimulates tumorigenesis. Results The elevation of global m 6 A level in most human LUAD specimens resulted from the combined upregulation of m 6 A writer methyltransferase 3 (METTL3) and downregulation of eraser alkB homolog 5 (ALKBH5). Elevated global m 6 A level was associated with a poor overall survival in LUAD patients. Reducing m 6 A levels by knocking out METTL3 and overexpressing ALKBH5 suppressed 3D-spheroid generation in LUAD cells and intra-pulmonary tumor formation in mice. Mechanistically, m 6 A-dependent stimulation of glycolysis and tumorigenesis occurred via enolase 1 (ENO1).  ENO1  mRNA was m 6 A methylated at 359 A, which facilitated it’s binding with the m 6 A reader YTH N6-methyladenosine RNA binding protein 1 (YTHDF1) and resulted in enhanced translation of ENO1. ENO1 positively correlated with METTL3 and global m 6 A levels, and negatively correlated with ALKBH5 in human LUAD. In addition, m 6 A-dependent elevation of ENO1 was associated with LUAD progression. In preclinical models, tumors with a higher global m 6 A level showed a more sensitive response to the inhibition of pan-methylation, glycolysis and ENO activity in LUAD. Conclusions The m 6 A-dependent stimulation of glycolysis and tumorigenesis in LUAD is at least partially orchestrated by the upregulation of METTL3, downregulation of ALKBH5, and stimulation of YTHDF1-mediated ENO1 translation. Blocking this mechanism may represent a potential treatment strategy for m 6 A-dependent LUAD.

The essential roles of m6A RNA modification to stimulate ENO1-dependent glycolysis and tumorigenesis in lung adenocarcinoma