Loss of FBP1 by Snail-Mediated Repression Provides Metabolic Advantages in Basal-like Breast Cancer
Menée in vitro, in vivo et sur des échantillons tumoraux prélevés sur 295 patientes atteintes d'un cancer du sein sans envahissement ganglionnaire, cette étude met en évidence des mécanismes par lesquels la perte du gène FBP1 favorise une transition épithélio-mésenchymateuse dans les cancers du sein de type "basal-like"
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. º The Snail-G9a-Dnmt1 complex is required for FBP1 silencing in BLBC º Loss of FBP1 enhances glycolytic flux, biomass synthesis, and PKM2 activation º Loss of FBP1 suppresses O2 consumption and ROS production º Loss of FBP1 enhances CSC-like traits and tumorigenicity by activating
β-catenin