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      Acetyl-CoA Synthetase 2 Promotes Acetate Utilization and Maintains Cancer Cell Growth under Metabolic Stress

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          Summary

          A functional genomics study revealed that the activity of acetyl-CoA synthetase 2 (ACSS2) contributes to cancer cell growth under low-oxygen and lipid-depleted conditions. Comparative metabolomics and lipidomics demonstrated that acetate is used as a nutritional source by cancer cells in an ACSS2-dependent manner, and supplied a significant fraction of the carbon within the fatty acid and phospholipid pools. ACSS2 expression is upregulated under metabolically stressed conditions and ACSS2 silencing reduced the growth of tumor xenografts. ACSS2 exhibits copy-number gain in human breast tumors, and ACSS2 expression correlates with disease progression. These results signify a critical role for acetate consumption in the production of lipid biomass within the harsh tumor microenvironment.

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          Highlights

          • ACSS2 expression positively correlates with tumor stage and patient survival

          • Hypoxia and low lipid availability synergistically stimulate ACSS2 expression

          • Acetate is a major source of carbon for lipid synthesis during metabolic stress

          • ACSS2 is required for growth of tumor xenografts harboring ACSS2 copy-number gains

          Abstract

          Schug et al. show that ACSS2 expression is increased in cancer cells under metabolic stress, and it is critical for cancer cells to use acetate as a nutritional source for lipid biomass production under this condition. Importantly, the ACSS2 expression level correlates with breast cancer progression.

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          Most cited references55

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          SREBP Activity Is Regulated by mTORC1 and Contributes to Akt-Dependent Cell Growth

          Summary Cell growth (accumulation of mass) needs to be coordinated with metabolic processes that are required for the synthesis of macromolecules. The PI3-kinase/Akt signaling pathway induces cell growth via activation of complex 1 of the target of rapamycin (TORC1). Here we show that Akt-dependent lipogenesis requires mTORC1 activity. Furthermore, nuclear accumulation of the mature form of the sterol responsive element binding protein (SREBP1) and expression of SREBP target genes was blocked by the mTORC1 inhibitor rapamycin. We also show that silencing of SREBP blocks Akt-dependent lipogenesis and attenuates the increase in cell size in response to Akt activation in vitro. Silencing of dSREBP in flies caused a reduction in cell and organ size and blocked the induction of cell growth by dPI3K. Our results suggest that the PI3K/Akt/TOR pathway regulates protein and lipid biosynthesis in an orchestrated manner and that both processes are required for cell growth.
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            Hypoxia promotes isocitrate dehydrogenase-dependent carboxylation of α-ketoglutarate to citrate to support cell growth and viability.

            Citrate is a critical metabolite required to support both mitochondrial bioenergetics and cytosolic macromolecular synthesis. When cells proliferate under normoxic conditions, glucose provides the acetyl-CoA that condenses with oxaloacetate to support citrate production. Tricarboxylic acid (TCA) cycle anaplerosis is maintained primarily by glutamine. Here we report that some hypoxic cells are able to maintain cell proliferation despite a profound reduction in glucose-dependent citrate production. In these hypoxic cells, glutamine becomes a major source of citrate. Glutamine-derived α-ketoglutarate is reductively carboxylated by the NADPH-linked mitochondrial isocitrate dehydrogenase (IDH2) to form isocitrate, which can then be isomerized to citrate. The increased IDH2-dependent carboxylation of glutamine-derived α-ketoglutarate in hypoxia is associated with a concomitant increased synthesis of 2-hydroxyglutarate (2HG) in cells with wild-type IDH1 and IDH2. When either starved of glutamine or rendered IDH2-deficient by RNAi, hypoxic cells are unable to proliferate. The reductive carboxylation of glutamine is part of the metabolic reprogramming associated with hypoxia-inducible factor 1 (HIF1), as constitutive activation of HIF1 recapitulates the preferential reductive metabolism of glutamine-derived α-ketoglutarate even in normoxic conditions. These data support a role for glutamine carboxylation in maintaining citrate synthesis and cell growth under hypoxic conditions.
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              High resolution analysis of DNA copy number variation using comparative genomic hybridization to microarrays.

              Gene dosage variations occur in many diseases. In cancer, deletions and copy number increases contribute to alterations in the expression of tumour-suppressor genes and oncogenes, respectively. Developmental abnormalities, such as Down, Prader Willi, Angelman and Cri du Chat syndromes, result from gain or loss of one copy of a chromosome or chromosomal region. Thus, detection and mapping of copy number abnormalities provide an approach for associating aberrations with disease phenotype and for localizing critical genes. Comparative genomic hybridization (CGH) was developed for genome-wide analysis of DNA sequence copy number in a single experiment. In CGH, differentially labelled total genomic DNA from a 'test' and a 'reference' cell population are cohybridized to normal metaphase chromosomes, using blocking DNA to suppress signals from repetitive sequences. The resulting ratio of the fluorescence intensities at a location on the 'cytogenetic map', provided by the chromosomes, is approximately proportional to the ratio of the copy numbers of the corresponding DNA sequences in the test and reference genomes. CGH has been broadly applied to human and mouse malignancies. The use of metaphase chromosomes, however, limits detection of events involving small regions (of less than 20 Mb) of the genome, resolution of closely spaced aberrations and linking ratio changes to genomic/genetic markers. Therefore, more laborious locus-by-locus techniques have been required for higher resolution studies. Hybridization to an array of mapped sequences instead of metaphase chromosomes could overcome the limitations of conventional CGH (ref. 6) if adequate performance could be achieved. Copy number would be related to the test/reference fluorescence ratio on the array targets, and genomic resolution could be determined by the map distance between the targets, or by the length of the cloned DNA segments. We describe here our implementation of array CGH. We demonstrate its ability to measure copy number with high precision in the human genome, and to analyse clinical specimens by obtaining new information on chromosome 20 aberrations in breast cancer.
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                Author and article information

                Contributors
                Journal
                Cancer Cell
                Cancer Cell
                Cancer Cell
                Cell Press
                1535-6108
                1878-3686
                12 January 2015
                12 January 2015
                : 27
                : 1
                : 57-71
                Affiliations
                [1 ]Cancer Research UK, Beatson Institute, Garscube Estate, Switchback Road, Glasgow G61 1BD, UK
                [2 ]Cancer Research UK, London Institute, 44 Lincoln’s Inn Fields, London WC2A 3LY, UK
                [3 ]Molecular Oncology Laboratories, Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, Oxford OX3 9DS, UK
                [4 ]Babraham Institute, Babraham Research Campus, Cambridge CB22 3AT, UK
                [5 ]AstraZeneca, Mereside, Alderley Park, Macclesfield SK10 4TG, UK
                [6 ]Department of Surgery and Cancer, Imperial College London, Hammersmith Hospital, Du Cane Road, London W12 0NN, UK
                [7 ]Institute of Cancer Sciences, University of Glasgow, Garscube Estate, Switchback Road, Glasgow G61 1BD, UK
                Author notes
                []Corresponding author e.gottlieb@ 123456beatson.gla.ac.uk
                [8]

                Co-first author

                [9]

                Present address: Theodor Boveri Institute, Biocenter, University of Würzburg, Am Hubland, 97074 Würzburg, Germany

                [10]

                Present Address: Comprehensive Cancer Center Mainfranken, Josef-Schneider-Strasse 6, 97080 Würzburg, Germany

                [11]

                Present address: The Breakthrough Breast Cancer Research Centre, The Institute of Cancer Research, London SW3 6JB, UK

                Article
                S1535-6108(14)00511-X
                10.1016/j.ccell.2014.12.002
                4297291
                25584894
                b68bca1c-6f0b-4587-ae00-b389b1d3692e
                © 2015 The Authors

                This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/3.0/).

                History
                : 6 November 2014
                : 5 December 2014
                : 9 December 2014
                Categories
                Article

                Oncology & Radiotherapy
                Oncology & Radiotherapy

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