Hijacking the hexosamine biosynthetic pathway to promote EMT-mediated neoplastic phenotypes

Frontiers in Oncology

Volumn 6, Issue APR, 2016, Pages

  Taparra, Kekoa ^a,b   Tran, Phuoc T ^a,b   Zachara, Natasha E ^b  

^a JOHNS HOPKINS UNIVERSITY   (United States)

^b JOHNS HOPKINS UNIVERSITY SCHOOL OF MEDICINE   (United States)

Author keywords

Cancer; EMT; Glycoproteins; Glycosylation; Metabolism; Nucleotide sugar; O GlcNAc; O GlcNAcylation

Indexed keywords

EPIDERMAL GROWTH FACTOR RECEPTOR; FIBRONECTIN; FRUCTOSE 6 PHOSPHATE; G PROTEIN COUPLED RECEPTOR; GLUCOSE; GLUTAMINE; GLYCOPROTEIN; HEXOSAMINE; HYPOXIA INDUCIBLE FACTOR 1ALPHA; INTEGRIN; JANUS KINASE; MATRIX METALLOPROTEINASE; MEMBRANE PROTEIN; MITOGEN ACTIVATED PROTEIN KINASE; N ACETYLGLUCOSAMINE; NERVE CELL ADHESION MOLECULE; NOTCH RECEPTOR; PROTEIN TYROSINE KINASE; SMAD PROTEIN; SONIC HEDGEHOG PROTEIN; STAT PROTEIN; TRANSCRIPTION FACTOR SNAIL; TRANSCRIPTION FACTOR TWIST; TRANSFORMING GROWTH FACTOR BETA; UNCLASSIFIED DRUG; UNINDEXED DRUG; URIDINE DIPHOSPHATE; UVOMORULIN; VIMENTIN; WNT PROTEIN; ZEB PROTEIN;

BIOSYNTHESIS; CANCER RESEARCH; CELL ADHESION; EPITHELIAL MESENCHYMAL TRANSITION; GENE OVEREXPRESSION; GLYCOBIOLOGY; GLYCOSYLATION; IMMUNE SYSTEM; METABOLISM; METABOLITE; MITOCHONDRION; NEOPLASM; PHENOTYPE; PROTEIN EXPRESSION; PROTEIN GLYCOSYLATION; SHORT SURVEY; SIGNAL TRANSDUCTION; TRANSCRIPTOMICS;

EID: 84973573467     PISSN: None     EISSN: 2234943X     Source Type: Journal    
DOI: 10.3389/fonc.2016.00085     Document Type: Short Survey

References (170)

1. Warburg O. On the origin of cancer cells. Science (1956) 123:309-14. doi:10.1126/science.123.3191.309
2. Warburg O. Injuring of respiration the origin of cancer cells. Science (1956) 123:309-14. doi:10.1126/science.123.3191.309
3. Koppenol WH, Bounds PL, Dang CV. Otto Warburg's contributions to current concepts of cancer metabolism. Nat Rev Cancer (2011) 11:325-37. doi:10.1038/nrc3108
4. Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell (2011) 144:646-74. doi:10.1016/j.cell.2011.02.013
5. Cairns RA, Harris IS, Mak TW. Regulation of cancer cell metabolism. Nat Rev Cancer (2011) 11:85-95. doi:10.1038/nrc2981
6. Potter VR. The biochemical approach to the cancer problem. Fed Proc (1958) 17:691-7
7. Vander Heiden MG, Cantley LC, Thompson CB. Understanding the Warburg effect: the metabolic requirements of cell proliferation. Science (2009) 324:1029-33. doi:10.1126/science.1160809
8. Kennedy KM, Dewhirst MW. Tumor metabolism of lactate: the influence and therapeutic potential for MCT and CD147 regulation. Future Oncol (2010) 6:127-48. doi:10.2217/fon.09.145
9. Feron O. Pyruvate into lactate and back: from the Warburg effect to symbiotic energy fuel exchange in cancer cells. Radiother Oncol (2009) 92:329-33. doi:10.1016/j.radonc.2009.06.025
10. Semenza GL. Tumor metabolism: cancer cells give and take lactate. J Clin Invest (2008) 118:3835-7. doi:10.1172/JCI37373
11. Yi W, Clark PM, Mason DE, Keenan MC, Hill C, Goddard WA, et al. Phosphofructokinase 1 glycosylation regulates cell growth and metabolism. Science (2012) 337:975-80. doi:10.1126/science.1222278
12. Lau KS, Dennis JW. N-glycans in cancer progression. Glycobiology (2008) 18:750-60. doi:10.1093/glycob/cwn071
13. Taniguchi N, Kizuka Y. Glycans and cancer: role of N-glycans in cancer biomarker, progression and metastasis, and therapeutics. Adv Cancer Res (2015) 126:11-51. doi:10.1016/bs.acr.2014.11.001
14. Love D, Hanover J. The hexosamine signaling pathway: deciphering the "O-GlcNAc code." Sci STKE (2005) 2005:re13. doi:10.1126/stke.3122005re13
15. Hanover JA, Krause MW, Love DC. The hexosamine signaling pathway: O-GlcNAc cycling in feast or famine. Biochim Biophys Acta (2010) 1800:80-95. doi:10.1016/j.bbagen.2009.07.017
16. Ferrer CM, Lynch TP, Sodi VL, Falcone JN, Schwab LP, Peacock DL, et al. O-GlcNAcylation regulates cancer metabolism and survival stress signaling via regulation of the HIF-1 pathway. Mol Cell (2014) 54:820-31. doi:10.1016/j.molcel.2014.04.026
17. Vasconcelos-dos-Santos A, Oliveira I, Lucena MC, Mantuano NR, Whelan S, Dias WB, et al. Biosynthetic machinery involved in aberrant glycosylation: promising targets for developing of drugs against cancer. Front Oncol (2015) 5:1-23. doi:10.3389/fonc.2015.00138
18. Lamouille S, Xu J, Derynck R. Molecular mechanisms of epithelial-mesenchymal transition. Nat Rev Mol Cell Biol (2014) 15:178-96. doi:10.1038/nrm3758
19. Smit MA, Peeper DS. Deregulating EMT and senescence: double impact by a single twist. Cancer Cell (2008) 14:5-7. doi:10.1016/j.ccr.2008.06.012
20. Tran PT, ShroffEH, Burns TF, Thiyagarajan S, Das ST, Zabuawala T, et al. Twist1 suppresses senescence programs and thereby accelerates and maintains mutant Kras-induced lung tumorigenesis. PLoS Genet (2012) 8:e1002650. doi:10.1371/journal.pgen.1002650
21. Ansieau S, Bastid J, Doreau A, Morel A-P, Bouchet BP, Thomas C, et al. Induction of EMT by twist proteins as a collateral effect of tumor-promoting inactivation of premature senescence. Cancer Cell (2008) 14:79-89. doi:10.1016/j.ccr.2008.06.005
22. Shaul YD, Freinkman E, Comb WC, Cantor JR, Tam WL, Thiru P, et al. Dihydropyrimidine accumulation is required for the epithelial-mesenchymal transition. Cell (2014) 158:1094-109. doi:10.1016/j.cell.2014.07.032
23. Hay ED. An overview of epithelio-mesenchymal transformation. Acta Anat (Basel) (1995) 154:8-20. doi:10.1159/000147748
24. Thiery JP, Acloque H, Huang RYJ, Nieto MA. Epithelial-mesenchymal transitions in development and disease. Cell (2009) 139:871-90. doi:10.1016/j.cell.2009.11.007
25. Schnaper HW, Hayashida T, Hubchak SC, Poncelet A-C. TGF-β signal transduction and mesangial cell fibrogenesis. Am J Physiol Renal Physiol (2003) 284:F243-52. doi:10.1152/ajprenal.00300.2002
26. Margadant C, Sonnenberg A. Integrin-TGF-beta crosstalk in fibrosis, cancer and wound healing. EMBO Rep (2010) 11:97-105. doi:10.1038/embor.2009.276
27. Yan C, Grimm WA, Garner WL, Qin L, Travis T, Tan N, et al. Epithelial to mesenchymal transition in human skin wound healing is induced by tumor necrosis factor-alpha through bone morphogenic protein-2. Am J Pathol (2010) 176:2247-58. doi:10.2353/ajpath.2010.090048
28. Brabletz T. EMT and MET in metastasis: where are the cancer stem cells? Cancer Cell (2012) 22:699-701. doi:10.1016/j.ccr.2012.11.009
29. Singh A, Settleman J. EMT, cancer stem cells and drug resistance: an emerging axis of evil in the war on cancer. Oncogene (2010) 29:4741-51. doi:10.1038/onc.2010.215
30. Mani SA, Guo W, Liao M-J, Eaton EN, Ayyanan A, Zhou AY, et al. The epithelial-mesenchymal transition generates cells with properties of stem cells. Cell (2008) 133:704-15. doi:10.1016/j.cell.2008.03.027
31. Fuxe J, Vincent T, De Herreros AG. Transcriptional crosstalk between TGFβ and stem cell pathways in tumor cell invasion: role of EMT promoting Smad complexes. Cell Cycle (2010) 9:2363-74. doi:10.4161/cc.9.12.12050
32. Nieto MA. The snail superfamily of zinc-finger transcription factors. Nat Rev Mol Cell Biol (2002) 3:155-66. doi:10.1038/nrm757
33. Kang Y, Massagué J. Epithelial-mesenchymal transitions: twist in development and metastasis. Cell (2004) 118:277-9. doi:10.1016/j.cell.2004.07.011
34. Peinado H, Olmeda D, Cano A. Snail, Zeb and bHLH factors in tumour progression: an alliance against the epithelial phenotype? Nat Rev Cancer (2007) 7:415-28. doi:10.1038/nrc2131
35. Tam WL, Weinberg RA. The epigenetics of epithelial-mesenchymal plasticity in cancer. Nat Med (2013) 19:1438-49. doi:10.1038/nm.3336
36. Moreno-Bueno G, Portillo F, Cano A. Transcriptional regulation of cell polarity in EMT and cancer. Oncogene (2008) 27:6958-69. doi:10.1038/onc.2008.346
37. Díaz V, Viñas-Castells R, García de Herreros A. Regulation of the protein stability of EMT transcription factors. Cell Adh Migr (2014) 8:418-28. doi:10.4161/19336918.2014.969998
38. Yilmaz M, Christofori G. EMT, the cytoskeleton, and cancer cell invasion. Cancer Metastasis Rev (2009) 28:15-33. doi:10.1007/s10555-008-9169-0
39. van Roy F. Beyond E-cadherin: roles of other cadherin superfamily members in cancer. Nat Rev Cancer (2014) 14:121-34. doi:10.1038/nrc3647
40. Araki K, Shimura T, Suzuki H, Tsutsumi S, Wada W, Yajima T, et al. E/N-cadherin switch mediates cancer progression via TGF-β-induced epithelial-to-mesenchymal transition in extrahepatic cholangiocarcinoma. Br J Cancer (2011) 105:1885-93. doi:10.1038/bjc.2011.452
41. Gheldof A, Berx G. Cadherins and epithelial-to-mesenchymal transition. Prog Mol Biol Transl Sci (2013) 116:317-36. doi:10.1016/B978-0-12-394311-8.00014-5
42. Vesuna F, van Diest P, Chen JH, Raman V. Twist is a transcriptional repressor of E-cadherin gene expression in breast cancer. Biochem Biophys Res Commun (2008) 367:235-41. doi:10.1016/j.bbrc.2007.11.151
43. Sánchez-Tilló E, Lázaro A, Torrent R, Cuatrecasas M, Vaquero EC, Castells A, et al. ZEB1 represses E-cadherin and induces an EMT by recruiting the SWI/SNF chromatin-remodeling protein BRG1. Oncogene (2010) 29:3490-500. doi:10.1038/onc.2010.102
44. Batlle E, Sancho E, Francí C, Domínguez D, Monfar M, Baulida J, et al. The transcription factor snail is a repressor of E-cadherin gene expression in epithelial tumour cells. Nat Cell Biol (2000) 2:84-9. doi:10.1038/35000034
45. Corallino S, Malabarba MG, Zobel M, Di Fiore PP, Scita G. Epithelial-to-mesenchymal plasticity harnesses endocytic circuitries. Front Oncol (2015) 5:45. doi:10.3389/fonc.2015.00045
46. Nakaya Y, Sheng G. EMT in developmental morphogenesis. Cancer Lett (2013) 341:9-15. doi:10.1016/j.canlet.2013.02.037
47. Revenu C, Gilmour D. EMT 2.0: shaping epithelia through collective migration. Curr Opin Genet Dev (2009) 19:338-42. doi:10.1016/j.gde.2009.04.007
48. Friedl P, Gilmour D. Collective cell migration in morphogenesis, regeneration and cancer. Nat Rev Mol Cell Biol (2009) 10:445-57. doi:10.1038/nrm2720
49. Stallings-Mann ML, Waldmann J, Zhang Y, Miller E, Gauthier ML, Visscher DW, et al. Matrix metalloproteinase induction of Rac1b, a key effector of lung cancer progression. Sci Transl Med (2012) 4:ra95-142. doi:10.1126/scitranslmed.3004062
50. Zheng G, Lyons JG, Tan TK, Wang Y, Hsu T-T, Min D, et al. Disruption of E-cadherin by matrix metalloproteinase directly mediates epithelial-mesenchymal transition downstream of transforming growth factor-beta1 in renal tubular epithelial cells. Am J Pathol (2009) 175:580-91. doi:10.2353/ajpath.2009.080983
51. Nelson CM, Khauv D, Bissell MJ, Radisky DC. Change in cell shape is required for matrix metalloproteinase-induced epithelial-mesenchymal transition of mammary epithelial cells. J Cell Biochem (2008) 105:25-33. doi:10.1002/jcb.21821
52. Szabova L, Chrysovergis K, Yamada SS, Holmbeck K. MT1-MMP is required for efficient tumor dissemination in experimental metastatic disease. Oncogene (2008) 27:3274-81. doi:10.1038/sj.onc.1210982
53. Wu Y, Zhou BP. More than EMT. Cell Adh Migr (2010) 4:199-203. doi:10.4161/cam.4.2.10943
54. López-Novoa JM, Nieto MA. Inflammation and EMT: an alliance towards organ fibrosis and cancer progression. EMBO Mol Med (2009) 1:303-14. doi:10.1002/emmm.200900043
55. Cha YH, Yook JI, Kim HS, Kim NH. Catabolic metabolism during cancer EMT. Arch Pharm Res (2015) 38:313-20. doi:10.1007/s12272-015-0567-x
56. Wise DR, DeBerardinis RJ, Mancuso A, Sayed N, Zhang X-Y, Pfeiffer HK, et al. Myc regulates a transcriptional program that stimulates mitochondrial glutaminolysis and leads to glutamine addiction. Proc Natl Acad Sci U S A (2008) 105:18782-7. doi:10.1073/pnas.0810199105
57. DeBerardinis RJ, Mancuso A, Daikhin E, Nissim I, YudkoffM, Wehrli S, et al. Beyond aerobic glycolysis: transformed cells can engage in glutamine metabolism that exceeds the requirement for protein and nucleotide synthesis. Proc Natl Acad Sci U S A (2007) 104:19345-50. doi:10.1073/pnas.0709747104
58. Eagle H. Nutrition needs of mammalian cells in tissue culture. Science (1955) 122:501-14. doi:10.1126/science.122.3168.501
59. Marshall S, Bacote V, Traxinger RR. Discovery of a metabolic pathway mediating glucose-induced desensitization of the glucose transport system: role of hexosamine biosynthesis in the induction of insulin resistance. J Biol Chem (1991) 266:4706-12
60. Abdel Rahman AM, Ryczko M, Pawling J, Dennis JW. Probing the hexosamine biosynthetic pathway in human tumor cells by multitargeted tandem mass spectrometry. ACS Chem Biol (2013) 8:2053-62. doi:10.1021/cb4004173
61. Nakajima K, Kitazume S, Angata T, Fujinawa R, Ohtsubo K, Miyoshi E, et al. Simultaneous determination of nucleotide sugars with ion-pair reversed-phase HPLC. Glycobiology (2010) 20:865-71. doi:10.1093/glycob/cwq044
62. Marshall S, Nadeau O, Yamasaki K. Dynamic actions of glucose and glucosamine on hexosamine biosynthesis in isolated adipocytes: differential effects on glucosamine 6-phosphate, UDP-N-acetylglucosamine, and ATP levels. J Biol Chem (2004) 279:35313-9. doi:10.1074/jbc. M404133200
63. Caldwell SA, Jackson SR, Shahriari KS, Lynch TP, Sethi G, Walker S, et al. Nutrient sensor O-GlcNAc transferase regulates breast cancer tumorigenesis through targeting of the oncogenic transcription factor FoxM1. Oncogene (2010) 29:2831-42. doi:10.1038/onc.2010.41
64. Krzeslak A, Forma E, Bernaciak M, Romanowicz H, Brys M. Gene expression of O-GlcNAc cycling enzymes in human breast cancers. Clin Exp Med (2012) 12:61-5. doi:10.1007/s10238-011-0138-5
65. Broschat KO, Gorka C, Page JD, Martin-Berger CL, Davies MS, Huang HC, et al. Kinetic characterization of human glutamine-fructose-6-phosphate amidotransferase I. Potent feedback inhibition by glucosamine 6-phosphate. J Biol Chem (2002) 277:14764-70. doi:10.1074/jbc. M201056200
66. Wellen KE, Lu C, Mancuso A, Lemons JMS, Ryczko M, Dennis JW, et al. The hexosamine biosynthetic pathway couples growth factor-induced glutamine uptake to glucose metabolism. Genes Dev (2010) 24:2784-99. doi:10.1101/gad.1985910
67. Wells L, Vosseller K, Hart GW. A role for N-acetylglucosamine as a nutrient sensor and mediator of insulin resistance. Cell Mol Life Sci (2003) 60:222-8. doi:10.1007/s000180300017
68. Sasai K, Ikeda Y, Fujii T, Tsuda T, Taniguchi N. UDP-GlcNAc concentration is an important factor in the biosynthesis of beta1,6-branched oligosaccharides: regulation based on the kinetic properties of N-acetylglucosaminyltransferase V. Glycobiology (2002) 12:119-27. doi:10.1093/glycob/12.2.119
69. Freeze HH, Elbein AD. Glycosylation precursors. 2nd ed. In: Varki A, Cummings RD, Esko JD, Freeze HH, Stanley P, Bertozzi CR, Hart GW, Etzler ME, editors. Source Essentials of Glycobiology, Chapter 4. Cold Spring Harbor, NY: Cold Spring Harbor Laboratory Press (2009). p. 47-61
70. Itkonen HM, Engedal N, Babaie E, Luhr M, Guldvik IJ, Minner S, et al. UAP1 is overexpressed in prostate cancer and is protective against inhibitors of N-linked glycosylation. Oncogene (2014) 34:1-7. doi:10.1038/onc.2014.307
71. Narimatsu H. Human glycogene cloning: focus on beta 3-glycosyltransferase and beta 4-glycosyltransferase families. Curr Opin Struct Biol (2006) 16:567-75. doi:10.1016/j.sbi.2006.09.001
72. Granovsky M, Fata J, Pawling J, Muller WJ, Khokha R, Dennis JW. Suppression of tumor growth and metastasis in Mgat5-deficient mice. Nat Med (2000) 6:306-12. doi:10.1038/73163
73. Li D, Li Y, Wu X, Li Q, Yu J, Gen J, et al. Knockdown of Mgat5 inhibits breast cancer cell growth with activation of CD4+ T cells and macrophages. J Immunol (2008) 180:3158-65. doi:10.4049/jimmunol.180.5.3158
74. Zhou X, Chen H, Wang Q, Zhang L, Zhao J. Knockdown of Mgat5 inhibits CD133+ human pulmonary adenocarcinoma cell growth in vitro and in vivo. Clin Invest Med (2011) 34:E155-62
75. Fernandes B, Sagman U, Auger M, Demetrio M, Dennis JW. Beta 1-6 branched oligosaccharides as a marker of tumor progression in human breast and colon neoplasia. Cancer Res (1991) 51:718-23
76. Seelentag WKF, Li W, Schmitz SH, Carcinoma C. Prognostic value of β 1, 6-branched oligosaccharides in human colorectal carcinoma. Cancer Res (1998) 58:5559-64
77. Murata K, Miyoshi E, Kameyama M, Ishikawa O, Kabuto T, Sasaki Y, et al. Expression of N-acetylglucosaminyltransferase V in colorectal cancer correlates with metastasis and poor prognosis. Clin Cancer Res (2000) 6:1772-7
78. Sethi MK, Thaysen-Andersen M, Smith JT, Baker MS, Packer NH, Hancock WS, et al. Comparative N-glycan profiling of colorectal cancer cell lines reveals unique bisecting GlcNAc and α-2,3-linked sialic acid determinants are associated with membrane proteins of the more metastatic/aggressive cell lines. J Proteome Res (2014) 13:277-88. doi:10.1021/pr400861m
79. Bubka M, Link-Lenczowski P, Janik M, Pochec E, Litynska A. Overexpression of N-acetylglucosaminyltransferases III and V in human melanoma cells. Implications for MCAM N-glycosylation. Biochimie (2014) 103:37-49. doi:10.1016/j.biochi.2014.04.003
80. Song Y, Aglipay JA, Bernstein JD, Goswami S, Stanley P. The bisecting GlcNAc on N-glycans inhibits growth factor signaling and retards mammary tumor progression. Cancer Res (2010) 70:3361-71. doi:10.1158/0008-5472.CAN-09-2719
81. Sengupta PK, Bouchie MP, Kukuruzinska MA. N-glycosylation gene DPAGT1 is a target of the Wnt/beta-catenin signaling pathway. J Biol Chem (2010) 285:31164-73. doi:10.1074/jbc. M110.149195
82. Pochec E, Janik M, Hoja-Lukowicz D, Link-Lenczowski P, Przybylo M, Litynska A. Expression of integrins α3β1 and α5β1 and GlcNAc β1,6 glycan branching influences metastatic melanoma cell migration on fibronectin. Eur J Cell Biol (2013) 92:355-62. doi:10.1016/j.ejcb.2013.10.007
83. McCarter C, Kletter D, Tang H, Partyka K, Ma Y, Singh S, et al. Prediction of glycan motifs using quantitative analysis of multi-lectin binding: motifs on MUC1 produced by cultured pancreatic cancer cells. Proteomics Clin Appl (2013) 7:632-41. doi:10.1002/prca.201300069
84. Tang H, Hsueh P, Kletter D, Bern M, Haab B. The detection and discovery of glycan motifs in biological samples using lectins and antibodies: new methods and opportunities. Adv Cancer Res (2015) 126:167-202. doi:10.1016/bs.acr.2014.11.003
85. Holst S, Wuhrer M, Rombouts Y. Glycosylation characteristics of colorectal cancer. Adv Cancer Res (2015) 126:203-56. doi:10.1016/bs.acr.2014.11.004
86. Guo H, Abbott KL. Functional impact of tumor-specific N-linked glycan changes in breast and ovarian cancers. Adv Cancer Res (2015) 126:281-303. doi:10.1016/bs.acr.2014.11.006
87. Lemjabbar-Alaoui H, McKinney A, Yang Y, Tran V, Phillips J. Glycosylation alterations in lung and brain cancer. Adv Cancer Res (2015) 126:305-44. doi:10.1016/bs.acr.2014.11.007
88. Mehta A, Herrera H, Block T. Glycosylation and liver cancer. Adv Cancer Res (2015) 126:257-79. doi:10.1016/bs.acr.2014.11.005
89. Drake RR, Jones EE, Powers TW, Nyalwidhe JO. Altered glycosylation in prostate cancer. Adv Cancer Res (2015) 126:345-82. doi:10.1016/bs.acr.2014.12.001
90. Liwosz A, Lei T, Kukuruzinska MA. N-glycosylation affects the molecular organization and stability of e-cadherin junctions. J Biol Chem (2006) 281:23138-49. doi:10.1074/jbc. M512621200
91. Pinho SS, Seruca R, Gärtner F, Yamaguchi Y, Gu J, Taniguchi N, et al. Modulation of E-cadherin function and dysfunction by N-glycosylation. Cell Mol Life Sci (2011) 68:1011-20. doi:10.1007/s00018-010-0595-0
92. Pinho SS, Oliveira P, Cabral J, Carvalho S, Huntsman D, Gärtner F, et al. Loss and recovery of Mgat3 and GnT-III mediated E-cadherin N-glycosylation is a mechanism involved in epithelial-mesenchymal-epithelial transitions. PLoS One (2012) 7:1-9. doi:10.1371/journal.pone.0033191
93. Carvalho S, Catarino TA, Dias AM, Kato M, Almeida A, Hessling B, et al. Preventing E-cadherin aberrant N-glycosylation at Asn-554 improves its critical function in gastric cancer. Oncogene (2016) 35:1619-31. doi:10.1038/onc.2015.225
94. Zhou F, Su J, Fu L, Yang Y, Zhang L, Wang L, et al. Unglycosylation at Asn-633 made extracellular domain of E-cadherin folded incorrectly and arrested in endoplasmic reticulum, then sequentially degraded by ERAD. Glycoconj J (2008) 25:727-40. doi:10.1007/s10719-008-9133-9
95. Pinho SS, Osório H, Nita-Lazar M, Gomes J, Lopes C, Gärtner F, et al. Role of E-cadherin N-glycosylation profile in a mammary tumor model. Biochem Biophys Res Commun (2009) 379:1091-6. doi:10.1016/j.bbrc.2009.01.024
96. Guo H-B, Lee I, Kamar M, Pierce M. N-acetylglucosaminyltransferase V expression levels regulate cadherin-associated homotypic cell-cell adhesion and intracellular signaling pathways. J Biol Chem (2003) 278:52412-24. doi:10.1074/jbc. M308837200
97. Guo HB, Johnson H, Randolph M, Pierce M. Regulation of homotypic cell-cell adhesion by branched N-glycosylation of N-cadherin extracellular EC2 and EC3 domains. J Biol Chem (2009) 284:34986-97. doi:10.1074/jbc. M109.060806
98. Boscher C, Zheng YZ, Lakshminarayan R, Johannes L, Dennis JW, Foster LJ, et al. Galectin-3 protein regulates mobility of N-cadherin and GM1 ganglioside at cell-cell junctions of mammary carcinoma cells. J Biol Chem (2012) 287:32940-52. doi:10.1074/jbc. M112.353334
99. Lajoie P, Partridge EA, Guay G, Goetz JG, Pawling J, Lagana A, et al. Plasma membrane domain organization regulates EGFR signaling in tumor cells. J Cell Biol (2007) 179:341-56. doi:10.1083/jcb.200611106
100. Partridge EA, Le Roy C, Di Guglielmo GM, Pawling J, Cheung P, Granovsky M, et al. Regulation of cytokine receptors by Golgi N-glycan processing and endocytosis. Science (2004) 306:120-4. doi:10.1126/science.1102109
101. Gu JG, Isaji T, Sato Y, Kariya Y, Fukuda T. Importance of N-glycosylation on alpha 5 beta 1 integrin for its biological functions. Biol Pharm Bull (2009) 32:780-5. doi:10.1248/bpb.32.780
102. Yang JT, Rayburn H, Hynes RO. Embryonic mesodermal defects in alpha 5 integrin-deficient mice. Development (1993) 119:1093-105
103. Goh KL, Yang JT, Hynes RO. Mesodermal defects and cranial neural crest apoptosis in alpha5 integrin-null embryos. Development (1997) 124:4309-19
104. George EL, Georges-Labouesse EN, Patel-King RS, Rayburn H, Hynes RO. Defects in mesoderm, neural tube and vascular development in mouse embryos lacking fibronectin. Development (1993) 119:1079-91
105. Sato Y, Isaji T, Tajiri M, Yoshida-Yamamoto S, Yoshinaka T, Somehara T, et al. An N-glycosylation site on the beta-propeller domain of the integrin alpha5 subunit plays key roles in both its function and site-specific modification by beta1,4-N-acetylglucosaminyltransferase III. J Biol Chem (2009) 284:11873-81. doi:10.1074/jbc. M807660200
106. Isaji T, Gu J, Nishiuchi R, Zhao Y, Takahashi M, Miyoshi E, et al. Introduction of bisecting GlcNAc into integrin alpha5beta11 reduces ligand binding and down-regulates cell adhesion and cell migration. J Biol Chem (2004) 279:19747-54. doi:10.1074/jbc. M311627200
107. Isaji T, Sato Y, Zhao Y, Miyoshi E, Wada Y, Taniguchi N, et al. N-glycosylation of the β-propeller domain of the integrin a5 subunit is essential for α5β1 heterodimerization, expression on the cell surface, and its biological function. J Biol Chem (2006) 281:33258-67. doi:10.1074/jbc. M607771200
108. Nabi IR, Shankar J, Dennis JW. The galectin lattice at a glance. J Cell Sci (2015) 128(13):2213-9. doi:10.1242/jcs.151159
109. Lau KS, Partridge EA, Grigorian A, Silvescu CI, Reinhold VN, Demetriou M, et al. Complex N-glycan number and degree of branching cooperate to regulate cell proliferation and differentiation. Cell (2007) 129:123-34. doi:10.1016/j.cell.2007.01.049
110. Kaszuba K, Grzybek M, Orlowski A, Danne R, Róg T, Simons K, et al. N-glycosylation as determinant of epidermal growth factor receptor conformation in membranes. Proc Natl Acad Sci U S A (2015) 112:2-7. doi:10.1073/pnas.1503262112
111. Kim Y-W, Park J, Lee H-J, Lee S-Y, Kim S-J. TGF-β sensitivity is determined by N-linked glycosylation of the type II TGF-β receptor. Biochem J (2012) 445:403-11. doi:10.1042/BJ20111923
112. Zhang H, Meng F, Wu S, Kreike B, Sethi S, Chen W, et al. Engagement of I-branching β-1, 6-N-acetylglucosaminyltransferase 2 in breast cancer metastasis and TGF-β signaling. Cancer Res (2011) 71:4846-56. doi:10.1158/0008-5472.CAN-11-0414
113. Komekado H, Yamamoto H, Chiba T, Kikuchi A. Glycosylation and palmitoylation of Wnt-3a are coupled to produce an active form of Wnt-3a. Genes Cells (2007) 12:521-34. doi:10.1111/j.1365-2443.2007.01068.x
114. Anagnostou SH, Shepherd PR. Glucose induces an autocrine activation of the Wnt/beta-catenin pathway in macrophage cell lines. Biochem J (2008) 416:211-8. doi:10.1042/BJ20081426
115. Miele L. Notch signaling. Science (2006) 12:225-32. doi:10.1158/1078-0432.CCR-05-2570
116. Kopan R, Ilagan MX. The canonical notch signaling pathway: unfolding the activation mechanism. Cell (2009) 137:216-33. doi:10.1016/j.cell.2009.03.045
117. Moloney DJ, Shair LH, Lu FM, Xia J, Locke R, Matta KL, et al. Mammalian Notch1 is modified with two unusual forms of O-linked glycosylation found on epidermal growth factor-like modules. J Biol Chem (2000) 275:9604-11. doi:10.1074/jbc.275.13.9604
118. Shao L, Moloney DJ, Haltiwanger R. Fringe modifies o-fucose on mouse Notch1 at epidermal growth factor-like repeats within the ligand-binding site and the Abruptex region. J Biol Chem (2003) 278:7775-82. doi:10.1074/jbc. M212221200
119. Matsuura A, Ito M, Sakaidani Y, Kondo T, Murakami K, Furukawa K, et al. O-linked N-acetylglucosamine is present on the extracellular domain of notch receptors. J Biol Chem (2008) 283:35486-95. doi:10.1074/jbc. M806202200
120. Rana NA, Nita-Lazar A, Takeuchi H, Kakuda S, Luther KB, Haltiwanger RS. O-glucose trisaccharide is present at high but variable stoichiometry at multiple sites on mouse Notch1. J Biol Chem (2011) 286:31623-37. doi:10.1074/jbc. M111.268243
121. Polizio AH, Chinchilla P, Chen X, Kim S, Manning DR, Riobo NA. Heterotrimeric Gi proteins link Hedgehog signaling to activation of Rho small GTPases to promote fibroblast migration. J Biol Chem (2011) 286:19589-96. doi:10.1074/jbc. M110.197111
122. Marada S, Navarro G, Truong A, Stewart DP, Arensdorf AM, Nachtergaele S, et al. Functional divergence in the role of N-linked glycosylation in smoothened signaling. PLoS Genet (2015) 11:e1005473. doi:10.1371/journal.pgen.1005473
123. Vigetti D, Karousou E, Viola M, Deleonibus S, De Luca G, Passi A. Hyaluronan: biosynthesis and signaling. Biochim Biophys Acta (2014) 1840:2452-9. doi:10.1016/j.bbagen.2014.02.001
124. Holmes MW, Bayliss MT, Muir H. Hyaluronic acid in human articular cartilage. Age-related changes in content and size. Biochem J (1988) 250:435-41. doi:10.1042/bj2500435
125. Hascall VC, Wang A, Tammi M, Oikari S, Tammi R, Passi A, et al. The dynamic metabolism of hyaluronan regulates the cytosolic concentration of UDP-GlcNAc. Matrix Biol (2014) 35:14-7. doi:10.1016/j.matbio.2014.01.014
126. Deen AJ, Arasu UT, Pasonen-Seppänen S, Hassinen A, Takabe P, Wojciechowski S, et al. UDP-sugar substrates of HAS3 regulate its O-GlcNAcylation, intracellular traffic, extracellular shedding and correlate with melanoma progression. Cell Mol Life Sci (2016). doi:10.1007/s00018-016-2158-5
127. Auvinen P, Tammi R, Parkkinen J, Tammi M, Agren U, Johansson R, et al. Hyaluronan in peritumoral stroma and malignant cells associates with breast cancer spreading and predicts survival. Am J Pathol (2000) 156:529-36. doi:10.1016/S0002-9440(10)64757-8
128. Auvinen P, Tammi R, Kosma V-M, Sironen R, Soini Y, Mannermaa A, et al. Increased hyaluronan content and stromal cell CD44 associate with HER2 positivity and poor prognosis in human breast cancer. Int J Cancer (2013) 132:531-9. doi:10.1002/ijc.27707
129. Auvinen P, Rilla K, Tumelius R, Tammi M, Sironen R, Soini Y, et al. Hyaluronan synthases (HAS1-3) in stromal and malignant cells correlate with breast cancer grade and predict patient survival. Breast Cancer Res Treat (2014) 143:277-86. doi:10.1007/s10549-013-2804-7
130. Lipponen P, Aaltomaa S, Tammi R, Tammi M, Agren U, Kosma VM. High stromal hyaluronan level is associated with poor differentiation and metastasis in prostate cancer. Eur J Cancer (2001) 37:849-56. doi:10.1016/S0959-8049(00)00448-2
131. Aaltomaa S, Lipponen P, Tammi R, Tammi M, Viitanen J, Kankkunen J-P, et al. Strong stromal hyaluronan expression is associated with PSA recurrence in local prostate cancer. Urol Int (2002) 69:266-72. doi:10.1159/000066123
132. Sá VK, Rocha TP, Moreira A, Soares FA, Takagaki T, Carvalho L, et al. Hyaluronidases and hyaluronan synthases expression is inversely correlated with malignancy in lung/bronchial pre-neoplastic and neoplastic lesions, affecting prognosis. Brazilian J Med Biol Res (2015) 48:1039-47. doi:10.1590/1414-431X20154693
133. Pirinen R, Leinonen T, Böhm J, Johansson R, Ropponen K, Kumpulainen E, et al. Versican in nonsmall cell lung cancer: relation to hyaluronan, clinicopathologic factors, and prognosis. Hum Pathol (2005) 36:44-50. doi:10.1016/j.humpath.2004.10.010
134. Cheng X-B, Sato N, Kohi S, Yamaguchi K. Prognostic impact of hyaluronan and its regulators in pancreatic ductal adenocarcinoma. PLoS One (2013) 8:e80765. doi:10.1371/journal.pone.0080765
135. Ropponen K, Tammi M, Parkkinen J, Eskelinen M, Tammi R, Lipponen P, et al. Tumor cell-associated hyaluronan as an unfavorable prognostic factor in colorectal cancer. Cancer Res (1998) 58:342-7
136. Anttila MA, Tammi RH, Tammi MI, Syrjanen KJ, Saarikoski SV, Kosma VM. High levels of stromal hyaluronan predict poor disease outcome in epithelial ovarian cancer. Cancer Res (2000) 60:150-5
137. Zoltan-Jones A, Huang L, Ghatak S, Toole BP. Elevated hyaluronan production induces mesenchymal and transformed properties in epithelial cells. J Biol Chem (2003) 278:45801-10. doi:10.1074/jbc. M308168200
138. Torres CR, Hart GW. Topography and polypeptide distribution of terminal N-acetylglucosamine residues on the surfaces of intact lymphocytes. Evidence for O-linked GlcNAc. J Biol Chem (1984) 259:3308-17
139. Slawson C, Hart GW. O-GlcNAc signalling: implications for cancer cell biology. Nat Rev Cancer (2011) 11:678-84. doi:10.1038/nrc3114
140. Iyer SPN, Hart GW. Dynamic nuclear and cytoplasmic glycosylation: enzymes of O-GlcNAc cycling. Biochemistry (2003) 42:2493-9. doi:10.1021/bi020685a
141. Champattanachai V, Netsirisawan P, Chaiyawat P, Phueaouan T, Charoenwattanasatien R, Chokchaichamnankit D, et al. Proteomic analysis and abrogated expression of O-GlcNAcylated proteins associated with primary breast cancer. Proteomics (2013) 13:2088-99. doi:10.1002/pmic.201200126
142. Gu Y, Mi W, Ge Y, Liu H, Fan Q, Han C, et al. GlcNAcylation plays an essential role in breast cancer metastasis. Cancer Res (2010) 70:6344-51. doi:10.1158/0008-5472.CAN-09-1887
143. Gu Y, Gao J, Han C, Zhang X, Liu H, Ma L, et al. O-GlcNAcylation is increased in prostate cancer tissues and enhances malignancy of prostate cancer cells. Mol Med Rep (2014) 10:897-904. doi:10.3892/mmr.2014.2269
144. Kamigaito T, Okaneya T, Kawakubo M, Shimojo H, Nishizawa O, Nakayama J. Overexpression of O-GlcNAc by prostate cancer cells is significantly associated with poor prognosis of patients. Prostate Cancer Prostatic Dis (2014) 17:18-22. doi:10.1038/pcan.2013.56
145. Lynch TP, Ferrer CM, Jackson SR, Shahriari KS, Vosseller K, Reginato MJ. Critical role of O-Linked β-N-acetylglucosamine transferase in prostate cancer invasion, angiogenesis, and metastasis. J Biol Chem (2012) 287:11070-81. doi:10.1074/jbc. M111.302547
146. Mi W, Gu Y, Han C, Liu H, Fan Q, Zhang X, et al. O-GlcNAcylation is a novel regulator of lung and colon cancer malignancy. Biochim Biophys Acta (2011) 1812:514-9. doi:10.1016/j.bbadis.2011.01.009
147. Ma Z, Vocadlo DJ, Vosseller K. Hyper-O-GlcNAcylation is anti-apoptotic and maintains constitutive NF-κB activity in pancreatic cancer cells. J Biol Chem (2013) 288:15121-30. doi:10.1074/jbc. M113.470047
148. Zhu Q, Zhou L, Yang Z, Lai M, Xie H, Wu L, et al. O-GlcNAcylation plays a role in tumor recurrence of hepatocellular carcinoma following liver transplantation. Med Oncol (2012) 29:985-93. doi:10.1007/s12032-011-9912-1
149. Phueaouan T, Chaiyawat P, Netsirisawan P, Chokchaichamnankit D, Punyarit P, Srisomsap C, et al. Aberrant O-GlcNAc-modified proteins expressed in primary colorectal cancer. Oncol Rep (2013) 30:2929-36. doi:10.3892/or.2013.2794
150. Yehezkel G, Cohen L, Kliger A, Manor E, Khalaila I. O-linked β-N-acetylglucosaminylation (O-GlcNAcylation) in primary and metastatic colorectal cancer clones and effect of N-acetyl-β-D-glucosaminidase silencing on cell phenotype and transcriptome. J Biol Chem (2012) 287:28755-69. doi:10.1074/jbc. M112.345546
151. Krzeslak A, Wójcik-Krowiranda K, Forma E, Bienkiewicz A, Brys M. Expression of genes encoding for enzymes associated with O-GlcNAcylation in endometrial carcinomas: clinicopathologic correlations. Ginekol Pol (2012) 83:22-6
152. Rozanski W, Krzeslak A, Forma E, Brys M, Blewniewski M, Wozniak P, et al. Prediction of bladder cancer based on urinary content of MGEA5 and OGT mRNA level. Clin Lab (2012) 58:579-83
153. Zhou BP, Deng J, Xia W, Xu J, Li YM, Gunduz M, et al. Dual regulation of Snail by GSK-3beta-mediated phosphorylation in control of epithelial-mesenchymal transition. Nat Cell Biol (2004) 6:931-40. doi:10.1038/ncb1173
154. Xu Y, Lee S-H, Kim HS, Kim NH, Piao S, Park S-H, et al. Role of CK1 in GSK3beta-mediated phosphorylation and degradation of snail. Oncogene (2010) 29:3124-33. doi:10.1038/onc.2010.77
155. Park SY, Kim HS, Kim NH, Ji S, Cha SY, Kang JG, et al. Snail1 is stabilized by O-GlcNAc modification in hyperglycaemic condition. EMBO J (2010) 29:3787-96. doi:10.1038/emboj.2010.254
156. Chou TY, Dang CV, Hart GW. Glycosylation of the c-Myc transactivation domain. Proc Natl Acad Sci U S A (1995) 92:4417-21. doi:10.1073/pnas.92.10.4417
157. Chou TY, Hart GW, Dang CV. c-Myc is glycosylated at threonine 58, a known phosphorylation site and a mutational hot spot in lymphomas. J Biol Chem (1995) 270:18961-5. doi:10.1074/jbc.270.32.18961
158. Olivier-Van Stichelen S, Dehennaut V, Buzy A, Zachayus J-L, Guinez C, Mir A-M, et al. O-GlcNAcylation stabilizes β-catenin through direct competition with phosphorylation at threonine 41. FASEB J (2014) 28:3325-38. doi:10.1096/fj.13-243535
159. Li X, Molina H, Huang H, Zhang Y-Y, Liu M, Qian S-W, et al. O-linked N-acetylglucosamine modification on CCAAT enhancer-binding protein beta: role during adipocyte differentiation. J Biol Chem (2009) 284:19248-54. doi:10.1074/jbc. M109.005678
160. Yang WH, Kim JE, Nam HW, Ju JW, Kim HS, Kim YS, et al. Modification of p53 with O-linked N-acetylglucosamine regulates p53 activity and stability. Nat Cell Biol (2006) 8:1074-83. doi:10.1038/ncb1470
161. Housley MP, Rodgers JT, Udeshi ND, Kelly TJ, Shabanowitz J, Hunt DF, et al. O-GlcNAc regulates FoxO activation in response to glucose. J Biol Chem (2008) 283:16283-92. doi:10.1074/jbc. M802240200
162. Yang WH, Park SY, Nam HW, Kim DH, Kang JG, Kang ES, et al. NFkappaB activation is associated with its O-GlcNAcylation state under hyperglycemic conditions. Proc Natl Acad Sci U S A (2008) 105:17345-50. doi:10.1073/pnas.0806198105
163. Allison DF, Wamsley JJ, Kumar M, Li D, Gray LG, Hart GW, et al. Modification of RelA by O-linked N-acetylglucosamine links glucose metabolism to NF-κB acetylation and transcription. Proc Natl Acad Sci U S A (2012) 109:16888-93. doi:10.1073/pnas.1208468109
164. Lee KE, Bar-Sagi D. Oncogenic KRas suppresses inflammation-associated senescence of pancreatic ductal cells. Cancer Cell (2010) 18:448-58. doi:10.1016/j.ccr.2010.10.020
165. Serrano M, Lin AW, McCurrach ME, Beach D, Lowe SW. Oncogenic ras provokes premature cell senescence associated with accumulation of p53 and p16INK4a. Cell (1997) 88:593-602. doi:10.1016/S0092-8674(00)81902-9
166. Lin H-K, Chen Z, Wang G, Nardella C, Lee S-W, Chan C-H, et al. Skp2 targeting suppresses tumorigenesis by Arf-p53-independent cellular senescence. Nature (2010) 464:374-9. doi:10.1038/nature08815
167. Olivier-Van Stichelen S, Drougat L, Dehennaut V, El Yazidi-Belkoura I, Guinez C, Mir A-M, et al. Serum-stimulated cell cycle entry promotes ncOGT synthesis required for cyclin D expression. Oncogenesis (2012) 1:e36. doi:10.1038/oncsis.2012.36
168. Slawson C, Zachara NE, Vosseller K, Cheung WD, Lane MD, Hart GW. Perturbations in O-linked β-N-acetylglucosamine protein modification cause severe defects in mitotic progression and cytokinesis. J Biol Chem (2005) 280:32944-56. doi:10.1074/jbc. M503396200
169. Zheng X, Carstens JL, Kim J, Scheible M, Kaye J, Sugimoto H, et al. Epithelial-to-mesenchymal transition is dispensable for metastasis but induces chemoresistance in pancreatic cancer. Nature (2015) 527:525-30. doi:10.1038/nature16064
170. Fischer KR, Durrans A, Lee S, Sheng J, Li F, Wong STC, et al. Epithelial-to-mesenchymal transition is not required for lung metastasis but contributes to chemoresistance. Nature (2015) 527:472-6. doi:10.1038/nature15748