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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    • "Accumulating evidence demonstrates that G9a is up-regulated in various types of cancer. Dysregulation of G9a triggers an abnormal H3K9me2 expression pattern, resulting in silencing of tumor suppressor genes [7-11]. "
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    ABSTRACT: Head and neck squamous cell carcinoma (HNSCC) is a common cancer worldwide. Emerging evidence indicates that alteration of epigenetics might be a key event in HNSCC progression. Abnormal expression of histone methyltransferase G9a, which contributes to transcriptional repression of tumor suppressors, has been implicated in promoting cancerous malignancies. However, its role in HNSCC has not been previously characterized. In this study, we elucidate the function of G9a and its downstream mechanism in HNSCC. We investigated the clinical relevance of G9a in HNSCC using immunohistochemistry (IHC) staining. In vitro cell proliferation and tumorigenesis ability of G9a-manipulated HNSCC cells were examined with MTT assays, clonogenic assays, and soft agar assays. We examined different routes of cell death in HNSCC cells induced by G9a-depletion or enzymatic inhibition by immunoblot, flow cytometry, fluorescent and transmission electron microscopy analysis. Specific targets of G9a were identified by affymetrix microarray and quantitative reverse transcription-polymerase chain reaction (qRT-PCR). Lastly, functions of G9a in vivo were confirmed with a xenograft tumor model. G9a expression is positively correlated to proliferation marker Ki-67 and to poor prognosis in HNSCC patients. Genetic or pharmacological inhibition of G9a reduced cell proliferation without inducing necrosis or apoptosis. Instead, autophagic cell death was the major consequence, and our investigation of mechanisms suggested it is mediated via the dual specificity phosphatase-4 (DUSP4) dependent ERK inactivation pathway. An orthotopic tumor model further confirmed the growth inhibiting effect and induction of autophagy that followed suppression of G9a. In this study, we provide evidence that G9a confers the survival advantage of HNSCC. Genetic or pharmacological inhibition of G9a induces autophagic cell death; this finding provides a basis for new therapeutic targets for treating HNSCC.
    Molecular Cancer 07/2014; 13(1):172. DOI:10.1186/1476-4598-13-172 · 4.26 Impact Factor
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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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    ABSTRACT: The metabolic features of cancer stem (CS) cells and the effects of specific nutrients or metabolites on CS cells remain mostly unexplored. A preliminary study to delineate the nutritional phenome of CS cells exploited the landmark observation that upon experimental induction into an epithelial-to-mesenchymal (EMT) transition, the proportion of CS-like cells drastically increases within a breast cancer cell population. EMT-induced CS-like cells (HMLERshEcad) and isogenic parental cells (HMLERshCntrol) were simultaneously screened for their ability to generate energy-rich NADH when cultured in a standardized high-throughput metabolic phenotyping platform comprising >350 wells that were pre-loaded with different carbohydrates/starches, alcohols, fatty acids, ketones, carboxylic acids, amino acids, and bi-amino acids. The generation of "phenetic maps" of the carbon and nitrogen utilization patterns revealed that the acquisition of a CS-like cellular state provided an enhanced ability to utilize additional catabolic fuels, especially under starvation conditions. Crucially, the acquisition of cancer stemness activated a metabolic infrastructure that enabled the vectorial transfer of high-energy nutrients such as glycolysis end products (pyruvate, lactate) and bona fide ketone bodies (β-hydroxybutyrate) from the extracellular microenvironment to support mitochondrial energy production in CS-like cells. Metabolic reprogramming may thus constitute an efficient adaptive strategy through which CS-like cells would rapidly obtain an advantage in hostile conditions such as nutrient starvation following the inhibition of tumor angiogenesis. By understanding how specific nutrients could bioenergetically boost EMT-CS-like phenotypes, "smart foods" or systemic "metabolic nichotherapies" may be tailored to specific nutritional CSC phenomes, whereas high-resolution heavy isotope-labeled nutrient tracking may be developed to monitor the spatiotemporal distribution and functionality of CS-like cells in real time.
    Oncotarget 06/2014; 5(12). DOI:10.18632/oncotarget.2147 · 6.36 Impact Factor
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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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    PLoS ONE 01/2014; 9(1):e86813. DOI:10.1371/journal.pone.0086813 · 3.23 Impact Factor
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