title: Hypoxia induces a lipogenic cancer cell phenotype via HIF1α-dependent and -independent pathways.
abstract: 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.
authors.affiliation: Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, UK.|Target Discovery Institute, Nuffield Department of Medicine, University of Oxford, Oxford, UK.|Mass Spectrometry Research Facility CRL, Department of Chemistry, University of Oxford, Oxford, UK.
authors.forename: Alessandro
authors.initials: A
authors.lastname: Valli
authors.affiliation: Centre for Omic Sciences, Rovira i Virgili University, Reus, Spain.|Biomedical Research Centre in Diabetes and Associated Metabolic Disorders, Madrid, Spain.
authors.forename: Miguel
authors.initials: M
authors.lastname: Rodriguez
authors.affiliation: The Wellcome Trust Centre for Human Genetics, Nuffield Department of Medicine, Oxford, UK.
authors.forename: Loukas
authors.initials: L
authors.lastname: Moutsianas
authors.affiliation: Target Discovery Institute, Nuffield Department of Medicine, University of Oxford, Oxford, UK.
authors.forename: Roman
authors.initials: R
authors.lastname: Fischer
authors.affiliation: Target Discovery Institute, Nuffield Department of Medicine, University of Oxford, Oxford, UK.
authors.forename: Vita
authors.initials: V
authors.lastname: Fedele
authors.affiliation: Target Discovery Institute, Nuffield Department of Medicine, University of Oxford, Oxford, UK.
authors.forename: Hong-Lei
authors.initials: HL
authors.lastname: Huang
authors.affiliation: Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, UK.
authors.forename: Ruud
authors.initials: R
authors.lastname: Van Stiphout
authors.affiliation: Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, UK.
authors.forename: Dylan
authors.initials: D
authors.lastname: Jones
authors.affiliation: Target Discovery Institute, Nuffield Department of Medicine, University of Oxford, Oxford, UK.
authors.forename: Michael
authors.initials: M
authors.lastname: Mccarthy
authors.affiliation: Centre for Omic Sciences, Rovira i Virgili University, Reus, Spain.|Biomedical Research Centre in Diabetes and Associated Metabolic Disorders, Madrid, Spain.
authors.forename: Maria
authors.initials: M
authors.lastname: Vinaxia
authors.affiliation: Institute for Advanced Biosciences, Keio University, Tsuruoka, Yamagata, Japan.
authors.forename: Kaori
authors.initials: K
authors.lastname: Igarashi
authors.affiliation: Institute for Advanced Biosciences, Keio University, Tsuruoka, Yamagata, Japan.
authors.forename: Maya
authors.initials: M
authors.lastname: Sato
authors.affiliation: Institute for Advanced Biosciences, Keio University, Tsuruoka, Yamagata, Japan.
authors.forename: Tomoyoshi
authors.initials: T
authors.lastname: Soga
authors.affiliation: Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, UK.
authors.forename: Francesca
authors.initials: F
authors.lastname: Buffa
authors.affiliation: Mass Spectrometry Research Facility CRL, Department of Chemistry, University of Oxford, Oxford, UK.
authors.forename: James
authors.initials: J
authors.lastname: Mccullagh
authors.affiliation: Centre for Omic Sciences, Rovira i Virgili University, Reus, Spain.|Biomedical Research Centre in Diabetes and Associated Metabolic Disorders, Madrid, Spain.
authors.forename: Oscar
authors.initials: O
authors.lastname: Yanes
authors.affiliation: Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, UK.
authors.forename: Adrian
authors.initials: A
authors.lastname: Harris
authors.affiliation: Target Discovery Institute, Nuffield Department of Medicine, University of Oxford, Oxford, UK.
authors.forename: Benedikt
authors.initials: B
authors.lastname: Kessler
mesh_terms: D000102:Acetyl-CoA C-Acyltransferase / Q000235:genetics / Q000378:metabolism; D000103:Acetyl-CoA Carboxylase / Q000235:genetics / Q000378:metabolism; D000368:Aged; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics / Q000378:metabolism; D015153:Blotting, Western; D015687:Cell Hypoxia; D045744:Cell Line, Tumor; D015179:Colorectal Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D005227:Fatty Acids / Q000096:biosynthesis; D005260:Female; D023281:Genomics / Q000379:methods; D045325:HCT116 Cells; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism*; D050356:Lipid Metabolism; D008055:Lipids / Q000096:biosynthesis*; D008297:Male; D055432:Metabolomics / Q000379:methods; D008875:Middle Aged; D010972:Platelet Activating Factor / Q000235:genetics / Q000378:metabolism; D040901:Proteomics / Q000379:methods; D034622:RNA Interference; D015398:Signal Transduction; D000099162:Endothelial PAS Domain-Containing Protein 1
chemical_list: D000102:Acetyl-CoA C-Acyltransferase; D000103:Acetyl-CoA Carboxylase; D051792:Basic Helix-Loop-Helix Proteins; D005227:Fatty Acids; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D008055:Lipids; D010972:Platelet Activating Factor; D000099162:Endothelial PAS Domain-Containing Protein 1; C570764:ACAA1 protein, human; C000588423:ACACA protein, human