SUMMARY Epithelial-mesenchymal transition (EMT) enhances invasiveness and confers tumor cells with cancer stem cell (CSC)-like characteristics. We showed that the Snail-G9a-Dnmt1 complex, which is critical for E-cadherin promoter silencing, is also required for the promoter methylation of fructose-1,6-biphosphatase (FBP1) in basal-like breast cancer (BLBC). Loss of FBP1 induces glycolysis and results in increased glucose uptake, macromolecules biosynthesis, formation of tetrameric PKM2, and maintenance of ATP production under hypoxia. Loss of FBP1 also inhibits oxygen consumption and ROS production by suppressing mitochondrial complex I activity; this metabolic reprogramming results in an increased CSC-like property and tumorigenicity by enhancing the interaction of β-catenin with TCF. Our study indicates that the loss of FBP1 is a critical oncogenic event in EMT and BLBC.

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