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.
|Number of pages||16|
|State||Published - Mar 18 2013|
Bibliographical noteFunding Information:
We thank Ms. Ramya Balasubramaniam for technical assistance in metabolomics experiments, Dr. Sam Arumugam at J.G. Brown Cancer Center NMR facility for NMR data acquisition, and Dr. Cathy Anthony for critical reading and editing of this manuscript. This work was supported by grants from NIH (CA125454 to B.P.Z.; CA049797 and CA073599 to D.St.C.; P20CA1530343 to B.M.E.; CA118434-01A2 and 1R01ES022191-01 to T.W.M.F.), Susan G Komen Foundation (KG081310), Mary Kay Ash Foundation (to B.P.Z.), National Science Foundation (EPS-0447479 to T.W.M.F.), Edward P. Evans Foundation (to D.St.C.), and pre-doctoral fellowship (BC101068) from DoD Breast Cancer Research Program (to Y.L.).
ASJC Scopus subject areas
- Cancer Research