Loss of FBP1 by Snail-Mediated Repression Provides Metabolic Advantages in Basal-like Breast Cancer

Department of Molecular and Cellular Biochemistry , The University of Kentucky, College of Medicine, Lexington, KY 40506, USA
Cancer cell (Impact Factor: 23.52). 02/2013; 23(3). DOI: 10.1016/j.ccr.2013.01.022
Source: PubMed


The epithelial-mesenchymal transition (EMT) enhances cancer invasiveness and confers tumor cells with cancer stem cell (CSC)-like characteristics. We show 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, macromolecule biosynthesis, formation of tetrameric PKM2, and maintenance of ATP production under hypoxia. Loss of FBP1 also inhibits oxygen consumption and reactive oxygen species 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 T-cell factor. Our study indicates that the loss of FBP1 is a critical oncogenic event in EMT and BLBC.

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Available from: Daret K St Clair, Sep 03, 2015
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    • "Recent studies have revealed that a metabolic switch to glucose metabolism is a critical promotional event in the epithelial-to-mesenchymal (EMT)-driven CS-like phenotype. Epigenetic silencing of the gluconeogenic enzyme fructose-1,6-biphosphatase, which catalyzes the energy-consuming conversion of fructose 1,6-biphosphate to fructose-6-phosphate, is employed by CS cells as a mechanism of glucose flux maintenance via glycolysis and other associated biosynthetic pathways [21]. An increased reliance on glucose metabolism, in turn, reduces the level of reactive oxygen species (ROS) to promote EMT and the CS-like phenotype. "
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    • "This suggests that an appropriate culture condition may depend on cell types. Indeed, hematopoietic stem cells or progenitor cells require several growth factors, such as insulin, IL-3, IL-6, G-CSF and GM-CSF, but these are dispensable for the culture of tumor initiating cells [21], [22], [23]. "
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