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O-GlcNAc in cancer biology

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Abstract

O-linked β-N-actylglucosamine (O-GlcNAc) is a carbohydrate post-translational modification on hydroxyl groups of serine and/or threonine residues of cytosolic and nuclear proteins. Analogous to phosphorylation, O-GlcNAcylation plays crucial regulatory roles in a variety of cellular processes. O-GlcNAc was termed a nutritional sensor, as global levels of the modification are elevated in response to increased glucose and glutamine flux into the hexosamine biosynthetic pathway. A unique feature of cancer cell energy metabolism is a shift from oxidative phosphorylation to the less efficient glycolytic pathway (Warburg effect), necessitating greatly increased glucose uptake. Additionally, to help meet increased biosynthetic demands, cancer cells also up-regulate glutamine uptake. This led us to hypothesize that the universal feature of increased glucose and glutamine uptake by cancer cells might be linked to increased O-GlcNAc levels. Indeed, recent work in many different cancer types now indicates that hyper-O-GlcNAcylation is a general feature of cancer and contributes to transformed phenotypes. In this review, we describe known/potential links between hyper-O-GlcNAcylation and specific hallmarks of cancer, including cancer cell proliferation, survival, cell stresses, invasion and metastasis, aneuploidy, and energy metabolism. We also discuss inhibition of hyper-O-GlcNAcylation as a potential novel therapeutic target for cancer treatment.

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Abbreviations

HBP:

Hexosamine biosynthetic pathway

GlcNAc:

N-acetylglucosamine

PDAC:

Pancreatic ductal adenocarcinoma

OGA:

O-GlcNAcase

HPDE:

Human pancreatic duct epithelial cell

PPP:

Pentose phosphate pathway

HSR:

Heat shock response

EMT:

Epithelial to mesenchymal transition

References

  • Alison MR, Lin WR, Lim SM, Nicholson LJ (2012) Cancer stem cells: in the line of fire. Cancer Treat Rev 38(6):589–598. doi:10.1016/j.ctrv.2012.03.003

    Article  PubMed  CAS  Google Scholar 

  • Andres-Bergos J, Tardio L, Larranaga-Vera A, Gomez R, Herrero-Beaumont G, Largo R (2012) The increase in O-linked N-acetylglucosamine protein modification stimulates chondrogenic differentiation both in vitro and in vivo. J Biol Chem 287(40):33615–33628. doi:10.1074/jbc.M112.354241

    Article  PubMed  CAS  Google Scholar 

  • Badet B, Vermoote P, Haumont PY, Lederer F, LeGoffic F (1987) Glucosamine synthetase from Escherichia coli: purification, properties, and glutamine-utilizing site location. Biochemistry 26(7):1940–1948

    Article  PubMed  CAS  Google Scholar 

  • Baeriswyl V, Christofori G (2009) The angiogenic switch in carcinogenesis. Semin Cancer Biol 19(5):329–337. doi:10.1016/j.semcancer.2009.05.003

    Article  PubMed  CAS  Google Scholar 

  • Balch WE, Morimoto RI, Dillin A, Kelly JW (2008) Adapting proteostasis for disease intervention. Science 319(5865):916–919. doi:10.1126/science.1141448

    Article  PubMed  CAS  Google Scholar 

  • Bang D, Wilson W, Ryan M, Yeh JJ, Baldwin AS (2013) GSK-3alpha promotes oncogenic KRAS function in pancreatic cancer via TAK1-TAB stabilization and regulation of noncanonical NF-κB. Cancer discov 3(6):690–703. doi:10.1158/2159-8290.cd-12-0541

    Article  PubMed  CAS  Google Scholar 

  • Benz CC, Yau C (2008) Ageing, oxidative stress and cancer: paradigms in parallax. Nat Rev Cancer 8(11):875–879. doi:10.1038/nrc2522

    Article  PubMed  CAS  Google Scholar 

  • Bergers G, Brekken R, McMahon G, Vu TH, Itoh T, Tamaki K, Tanzawa K, Thorpe P, Itohara S, Werb Z, Hanahan D (2000) Matrix metalloproteinase-9 triggers the angiogenic switch during carcinogenesis. Nat Cell Biol 2(10):737–744. doi:10.1038/35036374

    Article  PubMed  CAS  Google Scholar 

  • Caldwell SA, Jackson SR, Shahriari KS, Lynch TP, Sethi G, Walker S, Vosseller K, Reginato MJ (2010) Nutrient sensor O-GlcNAc transferase regulates breast cancer tumorigenesis through targeting of the oncogenic transcription factor FoxM1. Oncogene 29(19):2831–2842. doi:10.1038/onc.2010.41

    Article  PubMed  CAS  Google Scholar 

  • Chou TY, Dang CV, Hart GW (1995a) Glycosylation of the c-Myc transactivation domain. Proc Natl Acad Sci U S A 92(10):4417–4421

    Article  PubMed  CAS  Google Scholar 

  • Chou TY, Hart GW, Dang CV (1995b) c-Myc is glycosylated at threonine 58, a known phosphorylation site and a mutational hot spot in lymphomas. J Biol Chem 270(32):18961–18965

    Article  PubMed  CAS  Google Scholar 

  • Dai C, Whitesell L, Rogers AB, Lindquist S (2007) Heat shock factor 1 is a powerful multifaceted modifier of carcinogenesis. Cell 130(6):1005–1018. doi:10.1016/j.cell.2007.07.020

    Article  PubMed  CAS  Google Scholar 

  • Dai C, Dai S, Cao J (2012) Proteotoxic stress of cancer: implication of the heat-shock response in oncogenesis. J Cell Physiol 227(8):2982–2987. doi:10.1002/jcp.24017

    Article  PubMed  CAS  Google Scholar 

  • DeBerardinis RJ (2008) Is cancer a disease of abnormal cellular metabolism? New angles on an old idea. Genet Med 10(11):767–777. doi:10.1097/GIM.0b013e31818b0d9b

    Article  PubMed  CAS  Google Scholar 

  • DeBerardinis RJ, Lum JJ, Hatzivassiliou G, Thompson CB (2008) The biology of cancer: metabolic reprogramming fuels cell growth and proliferation. Cell Metab 7(1):11–20. doi:10.1016/j.cmet.2007.10.002

    Article  PubMed  CAS  Google Scholar 

  • Dudeja V, Chugh RK, Sangwan V, Skube SJ, Mujumdar NR, Antonoff MB, Dawra RK, Vickers SM, Saluja AK (2011) Prosurvival role of heat shock factor 1 in the pathogenesis of pancreatobiliary tumors. Am J Phys Gastrointest Liver Physiol 300(6):G948–G955. doi:10.1152/ajpgi.00346.2010

    Article  CAS  Google Scholar 

  • Earhart RH, Amato DJ, Chang AY, Borden EC, Shiraki M, Dowd ME, Comis RL, Davis TE, Smith TJ (1990) Phase II trial of 6-diazo-5-oxo-L-norleucine versus aclacinomycin-A in advanced sarcomas and mesotheliomas. Invest New Drugs 8(1):113–119

    Article  PubMed  CAS  Google Scholar 

  • Friedl P, Wolf K (2003) Tumour-cell invasion and migration: diversity and escape mechanisms. Nat Rev Cancer 3(5):362–374. doi:10.1038/nrc1075

    Article  PubMed  CAS  Google Scholar 

  • Gao P, Tchernyshyov I, Chang TC, Lee YS, Kita K, Ochi T, Zeller KI, De Marzo AM, Van Eyk JE, Mendell JT, Dang CV (2009) c-Myc suppression of miR-23a/b enhances mitochondrial glutaminase expression and glutamine metabolism. Nature 458(7239):762–765. doi:10.1038/nature07823

    Article  PubMed  CAS  Google Scholar 

  • Gloster TM, Zandberg WF, Heinonen JE, Shen DL, Deng L, Vocadlo DJ (2011) Hijacking a biosynthetic pathway yields a glycosyltransferase inhibitor within cells. Nat Chem Biol 7(3):174–181. doi:10.1038/nchembio.520

    Article  PubMed  CAS  Google Scholar 

  • Gong J, Jing L (2011) Glutamine induces heat shock protein 70 expression via O-GlcNAc modification and subsequent increased expression and transcriptional activity of heat shock factor-1. Minerva Anestesiol 77(5):488–495

    PubMed  CAS  Google Scholar 

  • Gordon DJ, Resio B, Pellman D (2012) Causes and consequences of aneuploidy in cancer. Nat Rev Genet 13(3):189–203. doi:10.1038/nrg3123

    PubMed  CAS  Google Scholar 

  • Gregory MA, Qi Y, Hann SR (2003) Phosphorylation by glycogen synthase kinase-3 controls c-myc proteolysis and subnuclear localization. J Biol Chem 278(51):51606–51612. doi:10.1074/jbc.M310722200

    Article  PubMed  CAS  Google Scholar 

  • Gross BJ, Kraybill BC, Walker S (2005) Discovery of O-GlcNAc transferase inhibitors. J Am Chem Soc 127(42):14588–14589. doi:10.1021/ja0555217

    Article  PubMed  CAS  Google Scholar 

  • Gu Y, Mi W, Ge Y, Liu H, Fan Q, Han C, Yang J, Han F, Lu X, Yu W (2010) GlcNAcylation plays an essential role in breast cancer metastasis. Cancer Res 70(15):6344–6351. doi:10.1158/0008-5472.can-09-1887

    Article  PubMed  CAS  Google Scholar 

  • Guinez C, Lemoine J, Michalski JC, Lefebvre T (2004) 70-kDa-heat shock protein presents an adjustable lectinic activity towards O-linked N-acetylglucosamine. Biochem Biophys Res Commun 319(1):21–26. doi:10.1016/j.bbrc.2004.04.144

    Article  PubMed  CAS  Google Scholar 

  • Guinez C, Filhoulaud G, Rayah-Benhamed F, Marmier S, Dubuquoy C, Dentin R, Moldes M, Burnol AF, Yang X, Lefebvre T, Girard J, Postic C (2011) O-GlcNAcylation increases ChREBP protein content and transcriptional activity in the liver. Diabetes 60(5):1399–1413. doi:10.2337/db10-0452

    Article  PubMed  CAS  Google Scholar 

  • Gupta GP, Massague J (2006) Cancer metastasis: building a framework. Cell 127(4):679–695. doi:10.1016/j.cell.2006.11.001

    Article  PubMed  CAS  Google Scholar 

  • Hallor KH, Sciot R, Staaf J, Heidenblad M, Rydholm A, Bauer HC, Astrom K, Domanski HA, Meis JM, Kindblom LG, Panagopoulos I, Mandahl N, Mertens F (2009) Two genetic pathways, t(1;10) and amplification of 3p11-12, in myxoinflammatory fibroblastic sarcoma, haemosiderotic fibrolipomatous tumour, and morphologically similar lesions. J Pathol 217(5):716–727. doi:10.1002/path.2513

    Article  PubMed  CAS  Google Scholar 

  • Haltiwanger RS, Blomberg MA, Hart GW (1992) Glycosylation of nuclear and cytoplasmic proteins. Purification and characterization of a uridine diphospho-N-acetylglucosamine:polypeptide beta-N-acetylglucosaminyltransferase. J Biol Chem 267(13):9005–9013

    PubMed  CAS  Google Scholar 

  • Hanahan D, Folkman J (1996) Patterns and emerging mechanisms of the angiogenic switch during tumorigenesis. Cell 86(3):353–364

    Article  PubMed  CAS  Google Scholar 

  • Hanahan D, Weinberg RA (2011) Hallmarks of cancer: the next generation. Cell 144(5):646–674. doi:10.1016/j.cell.2011.02.013

    Article  PubMed  CAS  Google Scholar 

  • Hart GW (1997) Dynamic O-linked glycosylation of nuclear and cytoskeletal proteins. Annu Rev Biochem 66:315–335. doi:10.1146/annurev.biochem.66.1.315

    Article  PubMed  CAS  Google Scholar 

  • Hart GW, Housley MP, Slawson C (2007) Cycling of O-linked beta-N-acetylglucosamine on nucleocytoplasmic proteins. Nature 446(7139):1017–1022. doi:10.1038/nature05815

    Article  PubMed  CAS  Google Scholar 

  • Havula E, Hietakangas V (2012) Glucose sensing by ChREBP/MondoA-Mlx transcription factors. Semin Cell Dev Biol 23(6):640–647. doi:10.1016/j.semcdb.2012.02.007

    Article  PubMed  CAS  Google Scholar 

  • Ho SR, Wang K, Whisenhunt TR, Huang P, Zhu X, Kudlow JE, Paterson AJ (2010) O-GlcNAcylation enhances FOXO4 transcriptional regulation in response to stress. FEBS Lett 584(1):49–54. doi:10.1016/j.febslet.2009.11.059

    Article  PubMed  CAS  Google Scholar 

  • Itkonen HM, Minner S, Guldvik IJ, Sandmann MJ, Tsourlakis MC, Berge V, Svindland A, Schlomm T, Mills IG (2013) O-GlcNAc transferase integrates metabolic pathways to regulate the stability of c-MYC in human prostate cancer. Cancer Res. doi:10.1158/0008-5472.can-13-0549

  • Jang H, Kim TW, Yoon S, Choi SY, Kang TW, Kim SY, Kwon YW, Cho EJ, Youn HD (2012) O-GlcNAc regulates pluripotency and reprogramming by directly acting on core components of the pluripotency network. Cell Stem Cell 11(1):62–74. doi:10.1016/j.stem.2012.03.001

    Article  PubMed  CAS  Google Scholar 

  • Kawauchi K, Araki K, Tobiume K, Tanaka N (2008) p53 regulates glucose metabolism through an IKK-NF-kappaB pathway and inhibits cell transformation. Nat Cell Biol 10(5):611–618. doi:10.1038/ncb1724

    Article  PubMed  CAS  Google Scholar 

  • Kawauchi K, Araki K, Tobiume K, Tanaka N (2009) Loss of p53 enhances catalytic activity of IKKbeta through O-linked beta-N-acetyl glucosamine modification. Proc Natl Acad Sci U S A 106(9):3431–3436. doi:10.1073/pnas.0813210106

    Article  PubMed  CAS  Google Scholar 

  • Kazemi Z, Chang H, Haserodt S, McKen C, Zachara NE (2010) O-linked beta-N-acetylglucosamine (O-GlcNAc) regulates stress-induced heat shock protein expression in a GSK-3beta-dependent manner. J Biol Chem 285(50):39096–39107. doi:10.1074/jbc.M110.131102

    Article  PubMed  CAS  Google Scholar 

  • Kisner DL, Catane R, Muggia FM (1980) The rediscovery of DON (6-diazo-5-oxo-L-norleucine). Recent Results Cancer Res 74:258–263

    Article  PubMed  CAS  Google Scholar 

  • Kreppel LK, Hart GW (1999) Regulation of a cytosolic and nuclear O-GlcNAc transferase. Role of the tetratricopeptide repeats. J Biol Chem 274(45):32015–32022

    Article  PubMed  CAS  Google Scholar 

  • Kroemer G, Pouyssegur J (2008) Tumor cell metabolism: cancer’s Achilles’ heel. Cancer Cell 13(6):472–482. doi:10.1016/j.ccr.2008.05.005

    Article  PubMed  CAS  Google Scholar 

  • Lazarus MB, Nam Y, Jiang J, Sliz P, Walker S (2011) Structure of human O-GlcNAc transferase and its complex with a peptide substrate. Nature 469(7331):564–567. doi:10.1038/nature09638

    Article  PubMed  CAS  Google Scholar 

  • Liu J, Marchase RB, Chatham JC (2007) Glutamine-induced protection of isolated rat heart from ischemia/reperfusion injury is mediated via the hexosamine biosynthesis pathway and increased protein O-GlcNAc levels. J Mol Cell Cardiol 42(1):177–185. doi:10.1016/j.yjmcc.2006.09.015

    Article  PubMed  CAS  Google Scholar 

  • Livingston RB, Venditti JM, Cooney DA, Carter SK (1970) Glutamine antagonists in chemotherapy. Adv Pharmacol Chemother 8:57–120

    Article  PubMed  CAS  Google Scholar 

  • Luo J, Solimini NL, Elledge SJ (2009) Principles of cancer therapy: oncogene and non-oncogene addiction. Cell 136(5):823–837. doi:10.1016/j.cell.2009.02.024

    Article  PubMed  CAS  Google Scholar 

  • Lynch G, Kemeny N, Casper E (1982) Phase II evaluation of DON (6-diazo-5-oxo-L-norleucine) in patients with advanced colorectal carcinoma. Am J Clin Oncol 5(5):541–543

    PubMed  CAS  Google Scholar 

  • Lynch TP, Ferrer CM, Jackson SR, Shahriari KS, Vosseller K, Reginato MJ (2012) Critical role of O-Linked β-N-acetylglucosamine transferase in prostate cancer invasion, angiogenesis, and metastasis. J Biol Chem 287(14):11070–11081. doi:10.1074/jbc.M111.302547

    Article  PubMed  CAS  Google Scholar 

  • Ma Z, Vocadlo DJ, Vosseller K (2013) Hyper-O-GlcNAcylation is anti-apoptotic and maintains constitutive NF-κB activity in pancreatic cancer cells. J Biol Chem 288(21):15121–15130. doi:10.1074/jbc.M113.470047

    Article  PubMed  CAS  Google Scholar 

  • Manzari B, Kudlow JE, Fardin P, Merello E, Ottaviano C, Puppo M, Eva A, Varesio L (2007) Induction of macrophage glutamine: fructose-6-phosphate amidotransferase expression by hypoxia and by picolinic acid. Intern J Immunopathol Pharmacol 20(1):47–58

    CAS  Google Scholar 

  • Mariappa D, Sauert K, Marino K, Turnock D, Webster R, van Aalten DM, Ferguson MA, Muller HA (2011) Protein O-GlcNAcylation is required for fibroblast growth factor signaling in Drosophila. Sci Signal 4 (204): ra89. doi:10.1126/scisignal.2002335

  • Marotta NP, Cherwien CA, Abeywardana T, Pratt MR (2012) O-GlcNAc modification prevents peptide-dependent acceleration of α-synuclein aggregation. Chembiochem. doi:10.1002/cbic.201200478

  • Martindale JL, Holbrook NJ (2002) Cellular response to oxidative stress: signaling for suicide and survival. J Cell Physiol 192(1):1–15. doi:10.1002/jcp.10119

    Article  PubMed  CAS  Google Scholar 

  • McGranahan N, Burrell RA, Endesfelder D, Novelli MR, Swanton C (2012) Cancer chromosomal instability: therapeutic and diagnostic challenges. EMBO Rep 13(6):528–538. doi:10.1038/embor.2012.61

    Article  PubMed  CAS  Google Scholar 

  • Mi W, Gu Y, Han C, Liu H, Fan Q, Zhang X, Cong Q, Yu W (2011) O-GlcNAcylation is a novel regulator of lung and colon cancer malignancy. Biochim Biophys Acta 1812(4):514–519. doi:10.1016/j.bbadis.2011.01.009

    Article  PubMed  CAS  Google Scholar 

  • Moore EC, Lepage GA (1957) In vivo sensitivity of normal and neoplastic mouse tissues to azaserine. Cancer Res 17(8):804–808

    PubMed  CAS  Google Scholar 

  • Moreno-Sanchez R, Rodriguez-Enriquez S, Marin-Hernandez A, Saavedra E (2007) Energy metabolism in tumor cells. FEBS J 274(6):1393–1418. doi:10.1111/j.1742-4658.2007.05686.x

    Article  PubMed  CAS  Google Scholar 

  • Mueller MM, Fusenig NE (2004) Friends or foes—bipolar effects of the tumour stroma in cancer. Nat Rev Cancer 4(11):839–849. doi:10.1038/nrc1477

    Article  PubMed  CAS  Google Scholar 

  • Myatt SS, Lam EW (2007) The emerging roles of forkhead box (Fox) proteins in cancer. Nat Rev Cancer 7(11):847–859. doi:10.1038/nrc2223

    Article  PubMed  CAS  Google Scholar 

  • Myers SA, Panning B, Burlingame AL (2011) Polycomb repressive complex 2 is necessary for the normal site-specific O-GlcNAc distribution in mouse embryonic stem cells. Proc Natl Acad Sci U S A 108(23):9490–9495. doi:10.1073/pnas.1019289108

    Article  PubMed  CAS  Google Scholar 

  • Nandi A, Sprung R, Barma DK, Zhao Y, Kim SC, Falck JR (2006) Global identification of O-GlcNAc-modified proteins. Anal Chem 78(2):452–458. doi:10.1021/ac051207j

    Article  PubMed  CAS  Google Scholar 

  • Neckers L, Workman P (2012) Hsp90 molecular chaperone inhibitors: are we there yet? Clin Cancer Res 18(1):64–76. doi:10.1158/1078-0432.ccr-11-1000

    Article  PubMed  CAS  Google Scholar 

  • Ngoh GA, Watson LJ, Facundo HT, Jones SP (2011) Augmented O-GlcNAc signaling attenuates oxidative stress and calcium overload in cardiomyocytes. Amino Acids 40(3):895–911. doi:10.1007/s00726-010-0728-7

    Article  PubMed  CAS  Google Scholar 

  • O’Donnell N, Zachara NE, Hart GW, Marth JD (2004) Ogt-dependent X-chromosome-linked protein glycosylation is a requisite modification in somatic cell function and embryo viability. Mol Cell Biol 24(4):1680–1690

    Article  PubMed  CAS  Google Scholar 

  • Ohn T, Kedersha N, Hickman T, Tisdale S, Anderson P (2008) A functional RNAi screen links O-GlcNAc modification of ribosomal proteins to stress granule and processing body assembly. Nat Cell Biol 10(10):1224–1231. doi:10.1038/ncb1783

    Article  PubMed  CAS  Google Scholar 

  • Osthus RC, Shim H, Kim S, Li Q, Reddy R, Mukherjee M, Xu Y, Wonsey D, Lee LA, Dang CV (2000) Deregulation of glucose transporter 1 and glycolytic gene expression by c-Myc. J Biol Chem 275(29):21797–21800. doi:10.1074/jbc.C000023200

    Article  PubMed  CAS  Google Scholar 

  • Ovejera AA, Houchens DP, Catane R, Sheridan MA, Muggia FM (1979) Efficacy of 6-diazo-5-oxo-L-norleucine and N-[N-gamma-glutamyl-6-diazo-5-oxo-norleucinyl]-6-diazo-5-oxo-norleucine against experimental tumors in conventional and nude mice. Cancer Res 39(8):3220–3224

    PubMed  CAS  Google Scholar 

  • Park SY, Kim HS, Kim NH, Ji S, Cha SY, Kang JG, Ota I, Shimada K, Konishi N, Nam HW, Hong SW, Yang WH, Roth J, Yook JI, Cho JW (2010a) Snail1 is stabilized by O-GlcNAc modification in hyperglycaemic condition. EMBO J. doi:10.1038/emboj.2010.254

  • Park SY, Kim HS, Kim NH, Ji S, Cha SY, Kang JG, Ota I, Shimada K, Konishi N, Nam HW, Hong SW, Yang WH, Roth J, Yook JI, Cho JW (2010b) Snail1 is stabilized by O-GlcNAc modification in hyperglycaemic condition. EMBO J 29(22):3787–3796. doi:10.1038/emboj.2010.254

    Article  PubMed  CAS  Google Scholar 

  • Pathak S, Borodkin VS, Albarbarawi O, Campbell DG, Ibrahim A, van Aalten DM (2012) O-GlcNAcylation of TAB 1 modulates TAK1-mediated cytokine release. EMBO J 31(6):1394–1404. doi:10.1038/emboj.2012.8

    Article  PubMed  CAS  Google Scholar 

  • Peinado H, Olmeda D, Cano A (2007) Snail, Zeb and bHLH factors in tumour progression: an alliance against the epithelial phenotype? Nat Rev Cancer 7(6):415–428. doi:10.1038/nrc2131

    Article  PubMed  CAS  Google Scholar 

  • Perkins ND (2012) The diverse and complex roles of NF-kappaB subunits in cancer. Nat Rev Cancer 12(2):121–132. doi:10.1038/nrc3204

    PubMed  CAS  Google Scholar 

  • Reuter S, Gupta SC, Chaturvedi MM, Aggarwal BB (2010) Oxidative stress, inflammation, and cancer: how are they linked? Free Radical Biol Med 49(11):1603–1616. doi:10.1016/j.freeradbiomed.2010.09.006

    Article  CAS  Google Scholar 

  • Rhodes DR, Kalyana-Sundaram S, Mahavisno V, Varambally R, Yu J, Briggs BB, Barrette TR, Anstet MJ, Kincead-Beal C, Kulkarni P, Varambally S, Ghosh D, Chinnaiyan AM (2007) Oncomine 3.0: genes, pathways, and networks in a collection of 18,000 cancer gene expression profiles. Neoplasia 9(2):166–180

    Article  PubMed  CAS  Google Scholar 

  • Rhodes DR, Yu J, Shanker K, Deshpande N, Varambally R, Ghosh D, Barrette T, Pandey A, Chinnaiyan AM (2004) Oncomine: a cancer microarray database and integrated data-mining platform. Neoplasia 6(1):1–6

    PubMed  CAS  Google Scholar 

  • Roos MD, Han IO, Paterson AJ, Kudlow JE (1996) Role of glucosamine synthesis in the stimulation of TGF-alpha gene transcription by glucose and EGF. Am J Physiol 270(3 Pt 1):C803–C811

    PubMed  CAS  Google Scholar 

  • Rozanski W, Krzeslak A, Forma E, Brys M, Blewniewski M, Wozniak P, Lipinski M (2012) Prediction of bladder cancer based on urinary content of MGEA5 and OGT mRNA level. Clin Lab 58(5–6):579–583

    PubMed  CAS  Google Scholar 

  • Sakiyama H, Fujiwara N, Noguchi T, Eguchi H, Yoshihara D, Uyeda K, Suzuki K (2010) The role of O-linked GlcNAc modification on the glucose response of ChREBP. Biochem Biophys Res Commun 402(4):784–789. doi:10.1016/j.bbrc.2010.10.113

    Article  PubMed  CAS  Google Scholar 

  • Shi Y, Tomic J, Wen F, Shaha S, Bahlo A, Harrison R, Dennis JW, Williams R, Gross BJ, Walker S, Zuccolo J, Deans JP, Hart GW, Spaner DE (2010) Aberrant O-GlcNAcylation characterizes chronic lymphocytic leukemia. Leukemia 24(9):1588–1598. doi:10.1038/leu.2010.152

    Article  PubMed  CAS  Google Scholar 

  • Singleton KD, Wischmeyer PE (2008) Glutamine induces heat shock protein expression via O-glycosylation and phosphorylation of HSF-1 and Sp1. JPEN J Parenter Enteral Nutr 32(4):371–376. doi:10.1177/0148607108320661

    Article  PubMed  CAS  Google Scholar 

  • Slawson C, Zachara NE, Vosseller K, Cheung WD, Lane MD, Hart GW (2005) Perturbations in O-linked beta-N-acetylglucosamine protein modification cause severe defects in mitotic progression and cytokinesis. J Biol Chem 280(38):32944–32956. doi:10.1074/jbc.M503396200

    Article  PubMed  CAS  Google Scholar 

  • Sola-Penna M, Da Silva D, Coelho WS, Marinho-Carvalho MM, Zancan P (2010) Regulation of mammalian muscle type 6-phosphofructo-1-kinase and its implication for the control of the metabolism. IUBMB Life 62(11):791–796. doi:10.1002/iub.393

    Article  PubMed  CAS  Google Scholar 

  • Tarnowski GS, Stock CC (1957) Effects of combinations of azaserine and of 6-diazo-5-oxo-L-norleucine with purine analogs and other antimetabolites on the growth of two mouse mammary carcinomas. Cancer Res 17(10):1033–1039

    PubMed  CAS  Google Scholar 

  • Teo CF, Ingale S, Wolfert MA, Elsayed GA, Not LG, Chatham JC, Wells L, Boons GJ (2010) Glycopeptide-specific monoclonal antibodies suggest new roles for O-GlcNAc. Nat Chem Biol 6(5):338–343. doi:10.1038/nchembio.338

    Article  PubMed  CAS  Google Scholar 

  • Thiery JP, Sleeman JP (2006) Complex networks orchestrate epithelial-mesenchymal transitions. Nat Rev Mol Cell Biol 7(2):131–142. doi:10.1038/nrm1835

    Article  PubMed  CAS  Google Scholar 

  • Thiery JP, Acloque H, Huang RY, Nieto MA (2009) Epithelial-mesenchymal transitions in development and disease. Cell 139(5):871–890. doi:10.1016/j.cell.2009.11.007

    Article  PubMed  CAS  Google Scholar 

  • Tomic J, McCaw L, Li Y, Hough MR, Ben-David Y, Moffat J, Spaner DE (2013) Resveratrol has anti-leukemic activity associated with decreased O-Glcnacylated proteins. Exp Hematol. doi:10.1016/j.exphem.2013.04.004

  • Tong X, Zhao F, Mancuso A, Gruber JJ, Thompson CB (2009) The glucose-responsive transcription factor ChREBP contributes to glucose-dependent anabolic synthesis and cell proliferation. Proc Natl Acad Sci U S A 106(51):21660–21665. doi:10.1073/pnas.0911316106

    Article  PubMed  CAS  Google Scholar 

  • Torres CR, Hart GW (1984) Topography and polypeptide distribution of terminal N-acetylglucosamine residues on the surfaces of intact lymphocytes. Evidence for O-linked GlcNAc. J Biol Chem 259(5):3308–3317

    PubMed  CAS  Google Scholar 

  • Valastyan S, Weinberg RA (2011) Tumor metastasis: molecular insights and evolving paradigms. Cell 147(2):275–292. doi:10.1016/j.cell.2011.09.024

    Article  PubMed  CAS  Google Scholar 

  • Vander Heiden MG, Cantley LC, Thompson CB (2009) Understanding the Warburg effect: the metabolic requirements of cell proliferation. Science 324(5930):1029–1033. doi:10.1126/science.1160809

    Article  PubMed  CAS  Google Scholar 

  • Vervoorts J, Luscher-Firzlaff J, Luscher B (2006) The ins and outs of MYC regulation by posttranslational mechanisms. J Biol Chem 281(46):34725–34729. doi:10.1074/jbc.R600017200

    Article  PubMed  CAS  Google Scholar 

  • Vierbuchen T, Wernig M (2012) Molecular roadblocks for cellular reprogramming. Mol Cell 47(6):827–838. doi:10.1016/j.molcel.2012.09.008

    Article  PubMed  CAS  Google Scholar 

  • Walgren JL, Vincent TS, Schey KL, Buse MG (2003) High glucose and insulin promote O-GlcNAc modification of proteins, including alpha-tubulin. Am J Physiol Endocrinol Metabol 284(2):E424–E434. doi:10.1152/ajpendo.00382.2002

    CAS  Google Scholar 

  • Wang Z, Udeshi ND, Slawson C, Compton PD, Sakabe K, Cheung WD, Shabanowitz J, Hunt DF, Hart GW (2010) Extensive crosstalk between O-GlcNAcylation and phosphorylation regulates cytokinesis. Sci Signal 3 (104):ra2. doi:10.1126/scisignal.2000526

  • Warburg O (1956a) On respiratory impairment in cancer cells. Science 124(3215):269–270

    PubMed  CAS  Google Scholar 

  • Warburg O (1956b) On the origin of cancer cells. Science 123(3191):309–314

    Article  PubMed  CAS  Google Scholar 

  • Warburg O, Wind F, Negelein E (1927) The metabolism of tumors in the body. J General Physiol 8(6):519–530

    Article  CAS  Google Scholar 

  • Ward PS, Thompson CB (2012) Metabolic reprogramming: a cancer hallmark even warburg did not anticipate. Cancer Cell 21(3):297–308. doi:10.1016/j.ccr.2012.02.014

    Article  PubMed  CAS  Google Scholar 

  • Weis SM, Cheresh DA (2011) Tumor angiogenesis: molecular pathways and therapeutic targets. Nat Med 17(11):1359–1370. doi:10.1038/nm.2537

    Article  PubMed  CAS  Google Scholar 

  • Wells L, Vosseller K, Hart GW (2001) Glycosylation of nucleocytoplasmic proteins: signal transduction and O-GlcNAc. Science 291(5512):2376–2378

    Article  PubMed  CAS  Google Scholar 

  • Wells L, Vosseller K, Hart GW (2003) A role for N-acetylglucosamine as a nutrient sensor and mediator of insulin resistance. Cell Mol Life Sci 60(2):222–228

    Article  PubMed  CAS  Google Scholar 

  • Wise DR, DeBerardinis RJ, Mancuso A, Sayed N, Zhang XY, Pfeiffer HK, Nissim I, Daikhin E, Yudkoff M, McMahon SB, Thompson CB (2008) Myc regulates a transcriptional program that stimulates mitochondrial glutaminolysis and leads to glutamine addiction. Proc Natl Acad Sci U S A 105(48):18782–18787. doi:10.1073/pnas.0810199105

    Article  PubMed  CAS  Google Scholar 

  • Wu Y, Deng J, Rychahou PG, Qiu S, Evers BM, Zhou BP (2009) Stabilization of snail by NF-kappaB is required for inflammation-induced cell migration and invasion. Cancer Cell 15(5):416–428. doi:10.1016/j.ccr.2009.03.016

    Article  PubMed  CAS  Google Scholar 

  • Xia Y, Rocchi P, Iovanna JL, Peng L (2012) Targeting heat shock response pathways to treat pancreatic cancer. Drug Discov Today 17(1–2):35–43. doi:10.1016/j.drudis.2011.09.016

    Article  PubMed  CAS  Google Scholar 

  • Yehezkel G, Cohen L, Kliger A, Manor E, Khalaila I (2012) O-GlcNAcylation in primary and metastatic colorectal cancer clones and effect of O-GlcNAcase silencing on cell phenotype and transcriptome. J Biol Chem. doi:10.1074/jbc.M112.345546

  • Yi W, Clark PM, Mason DE, Keenan MC, Hill C, Goddard WA 3rd, Peters EC, Driggers EM, Hsieh-Wilson LC (2012) Phosphofructokinase 1 glycosylation regulates cell growth and metabolism. Science 337(6097):975–980. doi:10.1126/science.1222278

    Article  PubMed  CAS  Google Scholar 

  • Ying H, Kimmelman AC, Lyssiotis CA, Hua S, Chu GC, Fletcher-Sananikone E, Locasale JW, Son J, Zhang H, Coloff JL, Yan H, Wang W, Chen S, Viale A, Zheng H, Paik JH, Lim C, Guimaraes AR, Martin ES, Chang J, Hezel AF, Perry SR, Hu J, Gan B, Xiao Y, Asara JM, Weissleder R, Wang YA, Chin L, Cantley LC, DePinho RA (2012) Oncogenic Kras maintains pancreatic tumors through regulation of anabolic glucose metabolism. Cell 149(3):656–670. doi:10.1016/j.cell.2012.01.058

    Article  PubMed  CAS  Google Scholar 

  • Yuneva M, Zamboni N, Oefner P, Sachidanandam R, Lazebnik Y (2007) Deficiency in glutamine but not glucose induces MYC-dependent apoptosis in human cells. J Cell Biol 178(1):93–105. doi:10.1083/jcb.200703099

    Article  PubMed  CAS  Google Scholar 

  • Yuzwa SA, Shan X, Macauley MS, Clark T, Skorobogatko Y, Vosseller K, Vocadlo DJ (2012) Increasing O-GlcNAc slows neurodegeneration and stabilizes tau against aggregation. Nat Chem Biol 8(4):393–399. doi:10.1038/nchembio.797

    Article  PubMed  CAS  Google Scholar 

  • Zachara NE, Hart GW (2004) O-GlcNAc a sensor of cellular state: the role of nucleocytoplasmic glycosylation in modulating cellular function in response to nutrition and stress. Biochim Biophy Acta 1673(1–2):13–28

    CAS  Google Scholar 

  • Zachara NE, O’Donnell N, Cheung WD, Mercer JJ, Marth JD, Hart GW (2004) Dynamic O-GlcNAc modification of nucleocytoplasmic proteins in response to stress. A survival response of mammalian cells. J Biol Chem 279(29):30133–30142. doi:10.1074/jbc.M403773200

    Article  PubMed  CAS  Google Scholar 

  • Zhu W, Leber B, Andrews DW (2001) Cytoplasmic O-glycosylation prevents cell surface transport of E-cadherin during apoptosis. EMBO J 20(21):5999–6007. doi:10.1093/emboj/20.21.5999

    Article  PubMed  CAS  Google Scholar 

  • Zhu Q, Zhou L, Yang Z, Lai M, Xie H, Wu L, Xing C, Zhang F, Zheng S (2012) O-GlcNAcylation plays a role in tumor recurrence of hepatocellular carcinoma following liver transplantation. Med Oncol 29(2):985–993. doi:10.1007/s12032-011-9912-1

    Article  PubMed  CAS  Google Scholar 

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Ma, Z., Vosseller, K. O-GlcNAc in cancer biology. Amino Acids 45, 719–733 (2013). https://doi.org/10.1007/s00726-013-1543-8

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