title: SREBP maintains lipid biosynthesis and viability of cancer cells under lipid- and oxygen-deprived conditions and defines a gene signature associated with poor survival in glioblastoma multiforme.
abstract: Oxygen and nutrient limitation are common features of the tumor microenvironment and are associated with cancer progression and induction of metastasis. The inefficient vascularization of tumor tissue also limits the penetration of other serum-derived factors, such as lipids and lipoproteins, which can be rate limiting for cell proliferation and survival. Here we have investigated the effect of hypoxia and serum deprivation on sterol regulatory element-binding protein (SREBP) activity and the expression of lipid metabolism genes in human glioblastoma multiforme (GBM) cancer cells. We found that SREBP transcriptional activity was induced by serum depletion both in normoxic and hypoxic cells and that activation of SREBP was required to maintain the expression of fatty acid and cholesterol metabolism genes under hypoxic conditions. Moreover, expression of stearoyl-CoA desaturase, the enzyme required for the generation of mono-unsaturated fatty acids, and fatty acid-binding protein 7, a regulator of glioma stem cell function, was strongly dependent on SREBP function. Inhibition of SREBP function blocked lipid biosynthesis in hypoxic cancer cells and impaired cell survival under hypoxia and in a three-dimensional spheroid model. Finally, gene expression analysis revealed that SREBP defines a gene signature that is associated with poor survival in glioblastoma.
authors.affiliation: Gene Expression Analysis Laboratory, Cancer Research UK London Research Institute, London, UK.
authors.forename: C A
authors.initials: CA
authors.lastname: Lewis
authors.affiliation: Theodor-Boveri-Institute, Biocenter, Am Hubland, Würzburg, Germany.
authors.forename: C
authors.initials: C
authors.lastname: Brault
authors.affiliation: Gene Expression Analysis Laboratory, Cancer Research UK London Research Institute, London, UK.
authors.forename: B
authors.initials: B
authors.lastname: Peck
authors.affiliation: CRUK Growth Factor Group, The Weatherall Institute of Molecular Medicine, University of Oxford, Headington, Oxford, UK.
authors.forename: K
authors.initials: K
authors.lastname: Bensaad
authors.affiliation: Gene Expression Analysis Laboratory, Cancer Research UK London Research Institute, London, UK.
authors.forename: B
authors.initials: B
authors.lastname: Griffiths
authors.affiliation: Bioinformatics and Biostatistics Service, Cancer Research UK London Research Institute, London, UK.
authors.forename: R
authors.initials: R
authors.lastname: Mitter
authors.affiliation: Bioinformatics and Biostatistics Service, Cancer Research UK London Research Institute, London, UK.
authors.forename: P
authors.initials: P
authors.lastname: Chakravarty
authors.affiliation: Bioinformatics and Biostatistics Service, Cancer Research UK London Research Institute, London, UK.
authors.forename: P
authors.initials: P
authors.lastname: East
authors.affiliation: Theodor-Boveri-Institute, Biocenter, Am Hubland, Würzburg, Germany.
authors.forename: B
authors.initials: B
authors.lastname: Dankworth
authors.affiliation: Light Microscopy Core, Cancer Research UK London Research Institute, London, UK.
authors.forename: D
authors.initials: D
authors.lastname: Alibhai
authors.affiliation: CRUK Growth Factor Group, The Weatherall Institute of Molecular Medicine, University of Oxford, Headington, Oxford, UK.
authors.forename: A L
authors.initials: AL
authors.lastname: Harris
authors.affiliation: Gene Expression Analysis Laboratory, Cancer Research UK London Research Institute, London, UK.|Theodor-Boveri-Institute, Biocenter, Am Hubland, Würzburg, Germany.|Comprehensive Cancer Center Mainfranken Würzburg, Germany.
authors.forename: A
authors.initials: A
authors.lastname: Schulze
mesh_terms: D001932:Brain Neoplasms / Q000378:metabolism / Q000401:mortality / Q000473:pathology*; D015687:Cell Hypoxia / Q000502:physiology; D002460:Cell Line; D002470:Cell Survival / Q000502:physiology*; D005909:Glioblastoma / Q000378:metabolism / Q000401:mortality / Q000473:pathology*; D006801:Humans; D007150:Immunohistochemistry; D050356:Lipid Metabolism / Q000502:physiology; D020411:Oligonucleotide Array Sequence Analysis; D016133:Polymerase Chain Reaction; D016016:Proportional Hazards Models; D034741:RNA, Small Interfering; D051780:Sterol Regulatory Element Binding Protein 1 / Q000378:metabolism*; D059467:Transcriptome; D014162:Transfection
chemical_list: D034741:RNA, Small Interfering; C497387:SREBF1 protein, human; D051780:Sterol Regulatory Element Binding Protein 1