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The biochemistry of cancer cells diverges significantly from normal cells as a result of a comprehensive reprogramming of metabolic pathways. A major factor influencing cancer metabolism is hypoxia, which is mediated by HIF1α and HIF2α. HIF1α represents one of the principal regulators of metabolism and energetic balance in cancer cells through its regulation of glycolysis, glycogen synthesis, Krebs cycle and the pentose phosphate shunt. However, less is known about the role of HIF1α in modulating lipid metabolism. Lipids serve cancer cells to provide molecules acting as oncogenic signals, energetic reserve, precursors for new membrane synthesis and to balance redox biological reactions. To study the role of HIF1α in these processes, we used HCT116 colorectal cancer cells expressing endogenous HIF1α and cells in which the hif1α gene was deleted to characterize HIF1α-dependent and independent effects on hypoxia regulated lipid metabolites. Untargeted metabolomics integrated with proteomics revealed that hypoxia induced many changes in lipids metabolites. Enzymatic steps in fatty acid synthesis and the Kennedy pathway were modified in a HIF1α-dependent fashion. Palmitate, stearate, PLD3 and PAFC16 were regulated in a HIF-independent manner. Our results demonstrate the impact of hypoxia on lipid metabolites, of which a distinct subset is regulated by HIF1α.

Original publication

DOI

10.18632/oncotarget.3058

Type

Journal article

Journal

Oncotarget

Publication Date

10/02/2015

Volume

6

Pages

1920 - 1941

Keywords

Acetyl-CoA C-Acyltransferase, Acetyl-CoA Carboxylase, Aged, Basic Helix-Loop-Helix Transcription Factors, Blotting, Western, Cell Hypoxia, Cell Line, Tumor, Colorectal Neoplasms, Fatty Acids, Female, Genomics, HCT116 Cells, Humans, Hypoxia-Inducible Factor 1, alpha Subunit, Lipid Metabolism, Lipids, Male, Metabolomics, Middle Aged, Platelet Activating Factor, Proteomics, RNA Interference, Signal Transduction