O-GlcNAc in cancer: An Oncometabolism-fueled vicious cycle

  • John A. Hanover
  • Weiping Chen
  • Michelle R. Bond
Mini-Review
  • 205 Downloads

Abstract

Cancer cells exhibit unregulated growth, altered metabolism, enhanced metastatic potential and altered cell surface glycans. Fueled by oncometabolism and elevated uptake of glucose and glutamine, the hexosamine biosynthetic pathway (HBP) sustains glycosylation in the endomembrane system. In addition, the elevated pools of UDP-GlcNAc drives the O-GlcNAc modification of key targets in the cytoplasm, nucleus and mitochondrion. These targets include transcription factors, kinases, key cytoplasmic enzymes of intermediary metabolism, and electron transport chain complexes. O-GlcNAcylation can thereby alter epigenetics, transcription, signaling, proteostasis, and bioenergetics, key ‘hallmarks of cancer’. In this review, we summarize accumulating evidence that many cancer hallmarks are linked to dysregulation of O-GlcNAc cycling on cancer-relevant targets. We argue that onconutrient and oncometabolite-fueled elevation increases HBP flux and triggers O-GlcNAcylation of key regulatory enzymes in glycolysis, Kreb’s cycle, pentose-phosphate pathway, and the HBP itself. The resulting rerouting of glucose metabolites leads to elevated O-GlcNAcylation of oncogenes and tumor suppressors further escalating elevation in HBP flux creating a ‘vicious cycle’. Downstream, elevated O-GlcNAcylation alters DNA repair and cellular stress pathways which influence oncogenesis. The elevated steady-state levels of O-GlcNAcylated targets found in many cancers may also provide these cells with a selective advantage for sustained growth, enhanced metastatic potential, and immune evasion in the tumor microenvironment.

Keywords

O-GlcNAc Epigenetics Cancer Oncometabolism Oxidative phosphorylation Glycolysis DNA damage Tumor suppressors Oncogenes Hexosamine biosythetic pathway 

Supplementary material

10863_2018_9751_MOESM1_ESM.xlsx (16 kb)
Supplemental Table I. Listing of the top 50 human genes mutated in diverse tumor types derived from the Cancer Genome atlas. Details of the ranking analysis are available elsewhere (Lawrence et al. 2014). (XLSX 15 kb)

References

  1. Akan I, Love DC, Harwood KR, Bond MR, Hanover JA (2016) Drosophila O-GlcNAcase Deletion Globally Perturbs Chromatin O-GlcNAcylation. J Biol Chem 291:9906–9919CrossRefGoogle Scholar
  2. Arvanitis DL, Arvanitis LD, Panourias IG, Kitsoulis P, Kanavaros P (2005) Mitochondria-rich normal, metaplastic, and neoplastic cells show overexpression of the epitope H recognized by the monoclonal antibody H. Pathol Res Pract 201:319–324CrossRefGoogle Scholar
  3. Arvanitis LD, Vassiou K, Kotrotsios A, Sgantzos MN (2011) Hypoxia upregulates the expression of the O-linked N-acetylglucosamine containing epitope H in human ependymal cells. Pathol Res Pract 207:91–96CrossRefGoogle Scholar
  4. Atlante A, de Bari L, Bobba A, Amadoro G (2017) A disease with a sweet tooth: exploring the Warburg effect in Alzheimer’s disease. Biogerontology 18:301–319CrossRefGoogle Scholar
  5. Baldini SF, Steenackers A, Olivier-Van Stichelen S, Mir AM, Mortuaire M, Lefebvre T, Guinez C (2016) Glucokinase expression is regulated by glucose through O-GlcNAc glycosylation. Biochem Biophys Res Commun 478:942–948CrossRefGoogle Scholar
  6. Banerjee S, Sangwan V, McGinn O, Chugh R, Dudeja V, Vickers SM, Saluja AK (2013) Triptolide-induced cell death in pancreatic cancer is mediated by O-GlcNAc modification of transcription factor Sp1. J Biol Chem 288:33927–33938CrossRefGoogle Scholar
  7. Banerjee PS, Ma J, Hart GW (2015) Diabetes-associated dysregulation of O-GlcNAcylation in rat cardiac mitochondria. Proc Natl Acad Sci U S A 112:6050–6055CrossRefGoogle Scholar
  8. Bauer C, Göbel K, Nagaraj N, Colantuoni C, Wang M, Müller U, Kremmer E, Rottach A, Leonhardt H (2015) Phosphorylation of TET proteins is regulated via O-GlcNAcylation by the O-linked N-acetylglucosamine transferase (OGT). J Biol Chem 290:4801–4812CrossRefGoogle Scholar
  9. Bektas M, Rubenstein DS (2011) The role of intracellular protein O-glycosylation in cell adhesion and disease. J Biomed Res 25:227–236CrossRefGoogle Scholar
  10. Blackwell TK, Steinbaugh MJ, Hourihan JM, Ewald CY, Isik M (2015) SKN-1/Nrf, stress responses, and aging in Caenorhabditis elegans. Free Radic Biol Med 88:290–301CrossRefGoogle Scholar
  11. Boehmelt G, Wakeham A, Elia A, Sasaki T, Plyte S, Potter J, Yang Y, Tsang E, Ruland J, Iscove NN, Dennis JW, Mak TW (2000) Decreased UDP-GlcNAc levels abrogate proliferation control in EMeg32-deficient cells. EMBO J 19:5092–5104CrossRefGoogle Scholar
  12. Bond MR, Hanover JA (2013) O-GlcNAc cycling: a link between metabolism and chronic disease. Annu Rev Nutr 33:205–229CrossRefGoogle Scholar
  13. Bond MR, Hanover JA (2015) A little sugar goes a long way: the cell biology of O-GlcNAc. J Cell Biol 208:869–880CrossRefGoogle Scholar
  14. Burén S, Gomes AL, Teijeiro A, Fawal MA, Yilmaz M, Tummala KS, Perez M, Rodriguez-Justo M, Campos-Olivas R, Megías D, Djouder N (2016) Regulation of OGT by URI in Response to Glucose Confers c-MYC-Dependent Survival Mechanisms. Cancer Cell 30:290–307CrossRefGoogle Scholar
  15. 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 29:2831–2842CrossRefGoogle Scholar
  16. Carvalho-Cruz P, Alisson-Silva F, Todeschini AR, Dias WB (2017) Cellular glycosylation senses metabolic changes and modulates cell plasticity during epithelial to mesenchymal transition. Dev Dyn 247:481–491CrossRefGoogle Scholar
  17. Chaiyawat P, Netsirisawan P, Svasti J, Champattanachai V (2014) Aberrant O-GlcNAcylated Proteins: New Perspectives in Breast and Colorectal Cancer. Front Endocrinol (Lausanne) 5:193Google Scholar
  18. Chaiyawat P, Chokchaichamnankit D, Lirdprapamongkol K, Srisomsap C, Svasti J, Champattanachai V (2015) Alteration of O-GlcNAcylation affects serine phosphorylation and regulates gene expression and activity of pyruvate kinase M2 in colorectal cancer cells. Oncol Rep 34:1933–1942CrossRefGoogle Scholar
  19. Chaiyawat P, Weeraphan C, Netsirisawan P, Chokchaichamnankit D, Srisomsap C, Svasti J, Champattanachai V (2016) Elevated O-GlcNAcylation of Extracellular Vesicle Proteins Derived from Metastatic Colorectal Cancer Cells. Cancer Genomics Proteomics 13:387–398Google Scholar
  20. Champattanachai V, Netsirisawan P, Chaiyawat P, Phueaouan T, Charoenwattanasatien R, Chokchaichamnankit D, Punyarit P, Srisomsap C, Svasti J (2013) Proteomic analysis and abrogated expression of O-GlcNAcylated proteins associated with primary breast cancer. Proteomics 13:2088–2099CrossRefGoogle Scholar
  21. Chen H, Chan DC (2017) Mitochondrial Dynamics in Regulating the Unique Phenotypes of Cancer and Stem Cells. Cell Metab 26:39–48CrossRefGoogle Scholar
  22. Chen Q, Yu X (2016) OGT restrains the expansion of DNA damage signaling. Nucleic Acids Res 44:9266–9278Google Scholar
  23. Chen J, Liu X, Lü F, Liu X, Ru Y, Ren Y, Yao L, Zhang Y (2015) Transcription factor Nrf1 is negatively regulated by its O-GlcNAcylation status. FEBS Lett 589:2347–2358CrossRefGoogle Scholar
  24. Chen PH, Smith TJ, Wu J, Siesser PF, Bisnett BJ, Khan F, Hogue M, Soderblom E, Tang F, Marks JR, Major MB, Swarts BM, Boyce M, Chi JT (2017) Glycosylation of KEAP1 links nutrient sensing to redox stress signaling. EMBO J 36:2233–2250CrossRefGoogle Scholar
  25. Chou TY, Hart GW (2001) O-linked N-acetylglucosamine and cancer: messages from the glycosylation of c-Myc. Adv Exp Med Biol 491:413–418CrossRefGoogle Scholar
  26. Chou TY, Hart GW, Dang CV (1995) c-Myc is glycosylated at threonine 58, a known phosphorylation site and a mutational hot spot in lymphomas. J Biol Chem 270:18961–18965CrossRefGoogle Scholar
  27. Chu CS, Lo PW, Yeh YH, Hsu PH, Peng SH, Teng YC, Kang ML, Wong CH, Juan LJ (2014) O-GlcNAcylation regulates EZH2 protein stability and function. Proc Natl Acad Sci U S A 111:1355–1360CrossRefGoogle Scholar
  28. Clark PM, Dweck JF, Mason DE, Hart CR, Buck SB, Peters EC, Agnew BJ, Hsieh-Wilson LC (2008) Direct in-gel fluorescence detection and cellular imaging of O-GlcNAc-modified proteins. J Am Chem Soc 130:11576–11577CrossRefGoogle Scholar
  29. Courtnay R, Ngo DC, Malik N, Ververis K, Tortorella SM, Karagiannis TC (2015) Cancer metabolism and the Warburg effect: the role of HIF-1 and PI3K. Mol Biol Rep 42:841–851CrossRefGoogle Scholar
  30. Crabtree HG (1928) The carbohydrate metabolism of certain pathological overgrowths. Biochem J 22:1289–1298CrossRefGoogle Scholar
  31. Crabtree HG (1929) Observations on the carbohydrate metabolism of tumours. Biochem J 23:536–545CrossRefGoogle Scholar
  32. Dall’Olio F, Trinchera M (2017) Epigenetic Bases of Aberrant Glycosylation in Cancer. Int J Mol Sci 18:998CrossRefGoogle Scholar
  33. Dauphinee SM, Ma M, Too CK (2005) Role of O-linked beta-N-acetylglucosamine modification in the subcellular distribution of alpha4 phosphoprotein and Sp1 in rat lymphoma cells. J Cell Biochem 96:579–588CrossRefGoogle Scholar
  34. de Queiroz RM, Carvalho E, Dias W (2014) O-GlcNAcylation: The Sweet Side of the Cancer. Front Oncol 4:132CrossRefGoogle Scholar
  35. de Queiroz RM, Madan R, Chien J, Dias WB, Slawson C (2016) Changes in O-Linked N-Acetylglucosamine (O-GlcNAc) Homeostasis Activate the p53 Pathway in Ovarian Cancer Cells. J Biol Chem 291:18897–18914CrossRefGoogle Scholar
  36. Deen AJ, Arasu UT, Pasonen-Seppänen S, Hassinen A, Takabe P, Wojciechowski S, Kärnä R, Rilla K, Kellokumpu S, Tammi R, Tammi M, Oikari S (2016) UDP-sugar substrates of HAS3 regulate its O-GlcNAcylation, intracellular traffic, extracellular shedding and correlate with melanoma progression. Cell Mol Life Sci 73:3183–3204CrossRefGoogle Scholar
  37. Dehennaut V, Leprince D, Lefebvre T (2014) O-GlcNAcylation, an Epigenetic Mark. Focus on the Histone Code, TET Family Proteins, and Polycomb Group Proteins. Front Endocrinol (Lausanne) 5:155Google Scholar
  38. Dell’ Antone P (2012) Energy metabolism in cancer cells: how to explain the Warburg and Crabtree effects. Med Hypotheses 79:388–392CrossRefGoogle Scholar
  39. Dennis JW, Lau KS, Demetriou M, Nabi IR (2009) Adaptive regulation at the cell surface by N-glycosylation. Traffic 10:1569–1578CrossRefGoogle Scholar
  40. Deplus R, Delatte B, Schwinn MK, Defrance M, Méndez J, Murphy N, Dawson MA, Volkmar M, Putmans P, Calonne E, Shih AH, Levine RL, Bernard O, Mercher T, Solary E, Urh M, Daniels DL, Fuks F (2013) TET2 and TET3 regulate GlcNAcylation and H3K4 methylation through OGT and SET1/COMPASS. EMBO J 32:645–655CrossRefGoogle Scholar
  41. Devic S (2016) Warburg Effect - a Consequence or the Cause of Carcinogenesis. J Cancer 7:817–822CrossRefGoogle Scholar
  42. Diaz-Ruiz R, Rigoulet M, Devin A (2011) The Warburg and Crabtree effects: On the origin of cancer cell energy metabolism and of yeast glucose repression. Biochim Biophys Acta 1807:568–576CrossRefGoogle Scholar
  43. Ding X, Jiang W, Zhou P, Liu L, Wan X, Yuan X, Wang X, Chen M, Chen J, Yang J, Kong C, Li B, Peng C, Wong CC, Hou F, Zhang Y (2015) Mixed Lineage Leukemia 5 (MLL5) Protein Stability Is Cooperatively Regulated by O-GlcNac Transferase (OGT) and Ubiquitin Specific Protease 7 (USP7). PLoS One 10:e0145023CrossRefGoogle Scholar
  44. Donadio AC, Lobo C, Tosina M, de la Rosa V, Martín-Rufián M, Campos-Sandoval JA, Matés JM, Márquez J, Alonso FJ, Segura JA (2008) Antisense glutaminase inhibition modifies the O-GlcNAc pattern and flux through the hexosamine pathway in breast cancer cells. J Cell Biochem 103:800–811CrossRefGoogle Scholar
  45. Efimova EV, Takahashi S, Shamsi NA, Wu D, Labay E, Ulanovskaya OA, Weichselbaum RR, Kozmin SA, Kron SJ (2016) Linking Cancer Metabolism to DNA Repair and Accelerated Senescence. Mol Cancer Res 14:173–184CrossRefGoogle Scholar
  46. Fardini Y, Perez-Cervera Y, Camoin L, Pagesy P, Lefebvre T, Issad T (2015) Regulatory O-GlcNAcylation sites on FoxO1 are yet to be identified. Biochem Biophys Res Commun 462:151–158CrossRefGoogle Scholar
  47. Ferrer CM, Lynch TP, Sodi VL, Falcone JN, Schwab LP, Peacock DL, Vocadlo DJ, Seagroves TN, Reginato MJ (2014) O-GlcNAcylation regulates cancer metabolism and survival stress signaling via regulation of the HIF-1 pathway. Mol Cell 54:820–831CrossRefGoogle Scholar
  48. Ferrer CM, Lu TY, Bacigalupa ZA, Katsetos CD, Sinclair DA, Reginato MJ (2017) O-GlcNAcylation regulates breast cancer metastasis via SIRT1 modulation of FOXM1 pathway. Oncogene 36:559–569CrossRefGoogle Scholar
  49. Fletcher BS, Dragstedt C, Notterpek L, Nolan GP (2002) Functional cloning of SPIN-2, a nuclear anti-apoptotic protein with roles in cell cycle progression. Leukemia 16:1507–1518CrossRefGoogle Scholar
  50. Fukushige T, Smith HE, Miwa J, Krause MW, Hanover JA (2017) A Genetic Analysis of the Caenorhabditis elegans Detoxification Response. Genetics 206:939–952CrossRefGoogle Scholar
  51. Gartel AL, Tyner AL (1999) Transcriptional regulation of the p21((WAF1/CIP1)) gene. Exp Cell Res 246:280–289CrossRefGoogle Scholar
  52. Gawlowski T, Suarez J, Scott B, Torres-Gonzalez M, Wang H, Schwappacher R, Han X, Yates JR, Hoshijima M, Dillmann W (2012) Modulation of dynamin-related protein 1 (DRP1) function by increased O-linked-β-N-acetylglucosamine modification (O-GlcNAc) in cardiac myocytes. J Biol Chem 287:30024–30034CrossRefGoogle Scholar
  53. Ge X, Kwok PY, Shieh JT (2015) Prioritizing genes for X-linked diseases using population exome data. Hum Mol Genet 24:599–608CrossRefGoogle Scholar
  54. Ghosh SK, Bond MR, Love DC, Ashwell GG, Krause MW, Hanover JA (2014) Disruption of O-GlcNAc Cycling in C. elegans Perturbs Nucleotide Sugar Pools and Complex Glycans. Front Endocrinol (Lausanne) 5:197Google Scholar
  55. Guppy M, Greiner E, Brand K (1993) The role of the Crabtree effect and an endogenous fuel in the energy metabolism of resting and proliferating thymocytes. Eur J Biochem 212:95–99CrossRefGoogle Scholar
  56. Haltiwanger RS, Philipsberg GA (1997) Mitotic arrest with nocodazole induces selective changes in the level of O-linked N-acetylglucosamine and accumulation of incompletely processed N-glycans on proteins from HT29 cells. J Biol Chem 272:8752–8758CrossRefGoogle Scholar
  57. Haltiwanger RS, Grove K, Philipsberg GA (1998) Modulation of O-linked N-acetylglucosamine levels on nuclear and cytoplasmic proteins in vivo using the peptide O-GlcNAc-beta-N-acetylglucosaminidase inhibitor O-(2-acetamido-2-deoxy-D-glucopyranosylidene)amino-N-phenylcarbamate. J Biol Chem 273:3611–3617CrossRefGoogle Scholar
  58. Hammad N, Rosas-Lemus M, Uribe-Carvajal S, Rigoulet M, Devin A (2016) The Crabtree and Warburg effects: Do metabolite-induced regulations participate in their induction. Biochim Biophys Acta 1857:1139–1146CrossRefGoogle Scholar
  59. Hanahan D, Weinberg RA (2011) Hallmarks of cancer: the next generation. Cell 144:646–674CrossRefGoogle Scholar
  60. Hanover JA (2001) Glycan-dependent signaling: O-linked N-acetylglucosamine. FASEB J 15:1865–1876CrossRefGoogle Scholar
  61. Hanover JA, Yu S, Lubas WB, Shin SH, Ragano-Caracciola M, Kochran J, Love DC (2003) Mitochondrial and nucleocytoplasmic isoforms of O-linked GlcNAc transferase encoded by a single mammalian gene. Arch Biochem Biophys 409:287–297CrossRefGoogle Scholar
  62. Hanover JA, Forsythe ME, Hennessey PT, Brodigan TM, Love DC, Ashwell G, Krause M (2005) A Caenorhabditis elegans model of insulin resistance: altered macronutrient storage and dauer formation in an OGT-1 knockout. Proc Natl Acad Sci U S A 102:11266–11271CrossRefGoogle Scholar
  63. Hanover JA, Krause MW, Love DC (2010) The hexosamine signaling pathway: O-GlcNAc cycling in feast or famine. Biochim Biophys Acta 1800:80–95CrossRefGoogle Scholar
  64. Hanover JA, Krause MW, Love DC (2012) Bittersweet memories: linking metabolism to epigenetics through O-GlcNAcylation. Nat Rev Mol Cell Biol 13:312–321CrossRefGoogle Scholar
  65. Hardie DG (2014) AMPK--sensing energy while talking to other signaling pathways. Cell Metab 20:939–952CrossRefGoogle Scholar
  66. Hart GW (2014a) Three Decades of Research on O-GlcNAcylation - A Major Nutrient Sensor That Regulates Signaling, Transcription and Cellular Metabolism. Front Endocrinol (Lausanne) 5:183Google Scholar
  67. Hart GW (2014b) Minireview series on the thirtieth anniversary of research on O-GlcNAcylation of nuclear and cytoplasmic proteins: Nutrient regulation of cellular metabolism and physiology by O-GlcNAcylation. J Biol Chem 289:34422–34423CrossRefGoogle Scholar
  68. Hart GW, Slawson C, Ramirez-Correa G, Lagerlof O (2011) Cross talk between O-GlcNAcylation and phosphorylation: roles in signaling, transcription, and chronic disease. Annu Rev Biochem 80:825–858CrossRefGoogle Scholar
  69. Harwood KR, Hanover JA (2014) Nutrient-driven O-GlcNAc cycling - think globally but act locally. J Cell Sci 127:1857–1867CrossRefGoogle Scholar
  70. Havaki S, Voloudakis-Baltatzis I, Goutas N, Arvanitis LD, Vassilaros SD, Arvanitis DL, Kittas C, Marinos E (2006) Nuclear localization of cytokeratin 8 and the O-linked N-acetylglucosamine-containing epitope H in epithelial cells of infiltrating ductal breast carcinomas: a combination of immunogold and EDTA regressive staining methods. Ultrastruct Pathol 30:177–186CrossRefGoogle Scholar
  71. Hazari YM, Bashir A, Haq EU, Fazili KM (2016) Emerging tale of UPR and cancer: an essentiality for malignancy. Tumour Biol 37:14381–14390CrossRefGoogle Scholar
  72. Howerton CL, Morgan CP, Fischer DB, Bale TL (2013) O-GlcNAc transferase (OGT) as a placental biomarker of maternal stress and reprogramming of CNS gene transcription in development. Proc Natl Acad Sci U S A 110:5169–5174CrossRefGoogle Scholar
  73. Hsieh AL, Walton ZE, Altman BJ, Stine ZE, Dang CV (2015) MYC and metabolism on the path to cancer. Semin Cell Dev Biol 43:11–21CrossRefGoogle Scholar
  74. Hu Y, Suarez J, Fricovsky E, Wang H, Scott BT, Trauger SA, Han W, Hu Y, Oyeleye MO, Dillmann WH (2009) Increased enzymatic O-GlcNAcylation of mitochondrial proteins impairs mitochondrial function in cardiac myocytes exposed to high glucose. J Biol Chem 284:547–555CrossRefGoogle Scholar
  75. Huang X, Pan Q, Sun D, Chen W, Shen A, Huang M, Ding J, Geng M (2013) O-GlcNAcylation of cofilin promotes breast cancer cell invasion. J Biol Chem 288:36418–36425CrossRefGoogle Scholar
  76. Issad T, Pagesy P (2014) Protein O-GlcNAcylation and regulation of cell signalling: involvement in pathophysiology. Biol Aujourdhui 208:109–117CrossRefGoogle Scholar
  77. 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 cells. Cancer Res 73:5277–5287CrossRefGoogle Scholar
  78. Jang TJ, Kim UJ (2016) O-GlcNAcylation is associated with the development and progression of gastric carcinoma. Pathol Res Pract 212:622–630CrossRefGoogle Scholar
  79. Jeoung NH, Harris CR, Harris RA (2014) Regulation of pyruvate metabolism in metabolic-related diseases. Rev Endocr Metab Disord 15:99–110CrossRefGoogle Scholar
  80. Jiang K, Gao Y, Hou W, Tian F, Ying W, Li L, Bai B, Hou G, Wang PG, Zhang L (2016) Proteomic analysis of O-GlcNAcylated proteins in invasive ductal breast carcinomas with and without lymph node metastasis. Amino Acids 48:365–374CrossRefGoogle Scholar
  81. Jin FZ, Yu C, Zhao DZ, Wu MJ, Yang Z (2013) A correlation between altered O-GlcNAcylation, migration and with changes in E-cadherin levels in ovarian cancer cells. Exp Cell Res 319:1482–1490CrossRefGoogle Scholar
  82. Johnson SC, Rabinovitch PS, Kaeberlein M (2013) mTOR is a key modulator of ageing and age-related disease. Nature 493:338–345CrossRefGoogle Scholar
  83. Jonckheere AI, Smeitink JA, Rodenburg RJ (2012) Mitochondrial ATP synthase: architecture, function and pathology. J Inherit Metab Dis 35:211–225CrossRefGoogle Scholar
  84. Jones DR, Keune WJ, Anderson KE, Stephens LR, Hawkins PT, Divecha N (2014) The hexosamine biosynthesis pathway and O-GlcNAcylation maintain insulin-stimulated PI3K-PKB phosphorylation and tumour cell growth after short-term glucose deprivation. FEBS J 281:3591–3608CrossRefGoogle Scholar
  85. Kakade PS, Budnar S, Kalraiya RD, Vaidya MM (2016) Functional Implications of O-GlcNAcylation-dependent Phosphorylation at a Proximal Site on Keratin 18. J Biol Chem 291:12003–12013CrossRefGoogle Scholar
  86. Kang ES, Han D, Park J, Kwak TK, Oh MA, Lee SA, Choi S, Park ZY, Kim Y, Lee JW (2008) O-GlcNAc modulation at Akt1 Ser473 correlates with apoptosis of murine pancreatic beta cells. Exp Cell Res 314:2238–2248CrossRefGoogle Scholar
  87. Kang JG, Park SY, Ji S, Jang I, Park S, Kim HS, Kim SM, Yook JI, Park YI, Roth J, Cho JW (2009) O-GlcNAc protein modification in cancer cells increases in response to glucose deprivation through glycogen degradation. J Biol Chem 284:34777–34784CrossRefGoogle Scholar
  88. Kang KA, Piao MJ, Ryu YS, Kang HK, Chang WY, Keum YS, Hyun JW (2016) Interaction of DNA demethylase and histone methyltransferase upregulates Nrf2 in 5-fluorouracil-resistant colon cancer cells. Oncotarget 7:40594–40620Google Scholar
  89. Kankova K, Hrstka R (2012) Cancer as a metabolic disease and diabetes as a cancer risk, Klin Onkol 25 Suppl 2: 2S26-31Google Scholar
  90. 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 10:611–618CrossRefGoogle Scholar
  91. 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 106:3431–3436CrossRefGoogle Scholar
  92. Kim EJ, Bond MR, Love DC, Hanover JA (2014) Chemical tools to explore nutrient-driven O-GlcNAc cycling. Crit Rev Biochem Mol Biol 49:327–342CrossRefGoogle Scholar
  93. Kim M, Kim YS, Kim H, Kang MY, Park J, Lee DH, Roh GS, Kim HJ, Kang SS, Cho GJ, Park JK, Cho JW, Shin JK, Choi WS (2016) O-linked N-acetylglucosamine transferase promotes cervical cancer tumorigenesis through human papillomaviruses E6 and E7 oncogenes. Oncotarget 7:44596–44607Google Scholar
  94. Kim SH, Kim YS, Choi MY, Kim M, Yang JH, Park HO, Jang IS, Moon SH, Kim HO, Song DH, Lee DH, Roh GS, Kim HJ, Kang SS, Cho GJ, Choi JY, Choi WS (2017) O-linked-N-acetylglucosamine transferase is associated with metastatic spread of human papillomavirus E6 and E7 oncoproteins to the lungs of mice. Biochem Biophys Res Commun 483:793–802CrossRefGoogle Scholar
  95. Kornfeld S, Kornfeld R, Neufeld EF, O’brien PJ (1964) The feedback control of sugar nucleotide biosynthesis in liver. Proc Natl Acad Sci U S A 52:371–379CrossRefGoogle Scholar
  96. Krzeslak A, Pomorski L, Lipinska A (2010) Elevation of nucleocytoplasmic beta-N-acetylglucosaminidase (O-GlcNAcase) activity in thyroid cancers. Int J Mol Med 25:643–648CrossRefGoogle Scholar
  97. Krześlak A, Jóźwiak P, Lipińska A (2011) Down-regulation of β-N-acetyl-D-glucosaminidase increases Akt1 activity in thyroid anaplastic cancer cells. Oncol Rep 26:743–749Google Scholar
  98. Krześlak A, Wójcik-Krowiranda K, Forma E, Bieńkiewicz A, Bryś M (2012) Expression of genes encoding for enzymes associated with O-GlcNAcylation in endometrial carcinomas: clinicopathologic correlations. Ginekol Pol 83:22–26Google Scholar
  99. Kwei KA, Baker JB, Pelham RJ (2012) Modulators of sensitivity and resistance to inhibition of PI3K identified in a pharmacogenomic screen of the NCI-60 human tumor cell line collection. PLoS One 7:e46518CrossRefGoogle Scholar
  100. Lawrence MS, Stojanov P, Mermel CH, Robinson JT, Garraway LA, Golub TR, Meyerson M, Gabriel SB, Lander ES, Getz G (2014) Discovery and saturation analysis of cancer genes across 21 tumour types. Nature 505:495–501CrossRefGoogle Scholar
  101. Lazarus BD, Love DC, Hanover JA (2006) Recombinant O-GlcNAc transferase isoforms: identification of O-GlcNAcase, yes tyrosine kinase, and tau as isoform-specific substrates. Glycobiology 16:415–421CrossRefGoogle Scholar
  102. 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 469:564–567CrossRefGoogle Scholar
  103. Lee N, Kim D (2016) Cancer Metabolism: Fueling More than Just Growth. Mol Cell 39:847–854CrossRefGoogle Scholar
  104. Lefebvre T, Pinte S, Guérardel C, Deltour S, Martin-Soudant N, Slomianny MC, Michalski JC, Leprince D (2004) The tumor suppressor HIC1 (hypermethylated in cancer 1) is O-GlcNAc glycosylated. Eur J Biochem 271:3843–3854CrossRefGoogle Scholar
  105. Lewis BA, Hanover JA (2014) O-GlcNAc and the epigenetic regulation of gene expression. J Biol Chem 289:34440–34448CrossRefGoogle Scholar
  106. Li B, Dewey CN (2011) RSEM: accurate transcript quantification from RNA-Seq data with or without a reference genome. BMC Bioinformatics 12:323CrossRefGoogle Scholar
  107. Li H, Liu X, Wang D, Su L, Zhao T, Li Z, Lin C, Zhang Y, Huang B, Lu J, Li X (2017) O-GlcNAcylation of SKN-1 modulates the lifespan and oxidative stress resistance in Caenorhabditis elegans. Sci Rep 7:43601CrossRefGoogle Scholar
  108. Liberti MV, Locasale JW (2016) The Warburg Effect: How Does it Benefit Cancer Cells. Trends Biochem Sci 41:211–218CrossRefGoogle Scholar
  109. Liu Q, Tao T, Liu F, Ni R, Lu C, Shen A (2016) Hyper-O-GlcNAcylation of YB-1 affects Ser102 phosphorylation and promotes cell proliferation in hepatocellular carcinoma. Exp Cell Res 349:230–238CrossRefGoogle Scholar
  110. Liu Y, Huang H, Cao Y, Wu Q, Li W, Zhang J (2017a) Suppression of OGT by microRNA24 reduces FOXA1 stability and prevents breast cancer cells invasion. Biochem Biophys Res Commun 487:755–762CrossRefGoogle Scholar
  111. Liu Y, Huang H, Liu M, Wu Q, Li W, Zhang J (2017b) MicroRNA-24-1 suppresses mouse hepatoma cell invasion and metastasis via directly targeting O-GlcNAc transferase. Biomed Pharmacother 91:731–738CrossRefGoogle Scholar
  112. Love DC, Kochan J, Cathey RL, Shin SH, Hanover JA, Kochran J (2003) Mitochondrial and nucleocytoplasmic targeting of O-linked GlcNAc transferase. J Cell Sci 116:647–654CrossRefGoogle Scholar
  113. Love DC, Ghosh S, Mondoux MA, Fukushige T, Wang P, Wilson MA, Iser WB, Wolkow CA, Krause MW, Hanover JA (2010a) Dynamic O-GlcNAc cycling at promoters of Caenorhabditis elegans genes regulating longevity, stress, and immunity. Proc Natl Acad Sci U S A 107:7413–7418CrossRefGoogle Scholar
  114. Love DC, Krause MW, Hanover JA (2010b) O-GlcNAc cycling: emerging roles in development and epigenetics. Semin Cell Dev Biol 21:646–654CrossRefGoogle Scholar
  115. Lu L, Fan D, Hu CW, Worth M, Ma ZX, Jiang J (2016) Distributive O-GlcNAcylation on the Highly Repetitive C-Terminal Domain of RNA Polymerase II. Biochemistry 55:1149–1158CrossRefGoogle Scholar
  116. Lucena MC, Carvalho-Cruz P, Donadio JL, Oliveira IA, de Queiroz RM, Marinho-Carvalho MM, Sola-Penna M, de Paula IF, Gondim KC, McComb ME, Costello CE, Whelan SA, Todeschini AR, Dias WB (2016) Epithelial Mesenchymal Transition Induces Aberrant Glycosylation through Hexosamine Biosynthetic Pathway Activation. J Biol Chem 291:12917–12929CrossRefGoogle Scholar
  117. 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 288:15121–15130CrossRefGoogle Scholar
  118. Majumdar G, Harmon A, Candelaria R, Martinez-Hernandez A, Raghow R, Solomon SS (2003) O-glycosylation of Sp1 and transcriptional regulation of the calmodulin gene by insulin and glucagon. Am J Physiol Endocrinol Metab 285:E584–E591CrossRefGoogle Scholar
  119. Majumdar G, Wright J, Markowitz P, Martinez-Hernandez A, Raghow R, Solomon SS (2004) Insulin stimulates and diabetes inhibits O-linked N-acetylglucosamine transferase and O-glycosylation of Sp1. Diabetes 53:3184–3192CrossRefGoogle Scholar
  120. Maynard JC, Burlingame AL, Medzihradszky KF (2016) Cysteine S-linked N-acetylglucosamine (S-GlcNAcylation), A New Post-translational Modification in Mammals. Mol Cell Proteomics 15:3405–3411CrossRefGoogle Scholar
  121. 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 1812:514–519CrossRefGoogle Scholar
  122. Mitchell MI, Engelbrecht AM (2017) Metabolic hijacking: A survival strategy cancer cells exploit. Crit Rev Oncol Hematol 109:1–8CrossRefGoogle Scholar
  123. Morrish F, Isern N, Sadilek M, Jeffrey M, Hockenbery DM (2009) c-Myc activates multiple metabolic networks to generate substrates for cell-cycle entry. Oncogene 28:2485–2491CrossRefGoogle Scholar
  124. Netsirisawan P, Chokchaichamnankit D, Srisomsap C, Svasti J, Champattanachai V (2015) Proteomic Analysis Reveals Aberrant O-GlcNAcylation of Extracellular Proteins from Breast Cancer Cell Secretion. Cancer Genomics Proteomics 12:201–209Google Scholar
  125. Neubert P, Halim A, Zauser M, Essig A, Joshi HJ, Zatorska E, Larsen IS, Loibl M, Castells-Ballester J, Aebi M, Clausen H, Strahl S (2016) Mapping the O-Mannose Glycoproteome in Saccharomyces cerevisiae. Mol Cell Proteomics 15:1323–1337CrossRefGoogle Scholar
  126. Niu Y, Xia Y, Wang J, Shi X (2017) O-GlcNAcylation promotes migration and invasion in human ovarian cancer cells via the RhoA/ROCK/MLC pathway. Mol Med Rep 15:2083–2089CrossRefGoogle Scholar
  127. Noach N, Segev Y, Levi I, Segal S, Priel E (2007) Modification of topoisomerase I activity by glucose and by O-GlcNAcylation of the enzyme protein. Glycobiology 17:1357–1364CrossRefGoogle Scholar
  128. Nugent BM, Bale TL (2015) The omniscient placenta: Metabolic and epigenetic regulation of fetal programming. Front Neuroendocrinol 39:28–37CrossRefGoogle Scholar
  129. Ohashi N, Morino K, Ida S, Sekine O, Lemecha M, Kume S, Park SY, Choi CS, Ugi S, Maegawa H (2017) Pivotal Role of O-GlcNAc Modification in Cold-Induced Thermogenesis by Brown Adipose Tissue Through Mitochondrial Biogenesis. Diabetes 66:2351–2362CrossRefGoogle Scholar
  130. Oikari S, Makkonen K, Deen AJ, Tyni I, Kärnä R, Tammi RH, Tammi MI (2016) Hexosamine biosynthesis in keratinocytes: roles of GFAT and GNPDA enzymes in the maintenance of UDP-GlcNAc content and hyaluronan synthesis. Glycobiology 26:710–722CrossRefGoogle Scholar
  131. Olivier-Van Stichelen S, Hanover JA (2015) You are what you eat: O-linked N-acetylglucosamine in disease, development and epigenetics. Curr Opin Clin Nutr Metab Care 18:339–345CrossRefGoogle Scholar
  132. Olivier-Van Stichelen S, Abramowitz LK, Hanover JA (2014a) X marks the spot: does it matter that O-GlcNAc transferase is an X-linked gene. Biochem Biophys Res Commun 453:201–207CrossRefGoogle Scholar
  133. Olivier-Van Stichelen S, Dehennaut V, Buzy A, Zachayus JL, Guinez C, Mir AM, El Yazidi-Belkoura I, Copin MC, Boureme D, Loyaux D, Ferrara P, Lefebvre T (2014b) O-GlcNAcylation stabilizes β-catenin through direct competition with phosphorylation at threonine 41. FASEB J 28:3325–3338CrossRefGoogle Scholar
  134. Palorini R, Cammarata FP, Cammarata F, Balestrieri C, Monestiroli A, Vasso M, Gelfi C, Alberghina L, Chiaradonna F (2013) Glucose starvation induces cell death in K-ras-transformed cells by interfering with the hexosamine biosynthesis pathway and activating the unfolded protein response. Cell Death Dis 4:e732CrossRefGoogle Scholar
  135. Park SK, Zhou X, Pendleton KE, Hunter OV, Kohler JJ, O’Donnell KA, Conrad NK (2017) A Conserved Splicing Silencer Dynamically Regulates O-GlcNAc Transferase Intron Retention and O-GlcNAc Homeostasis. Cell Rep 20:1088–1099CrossRefGoogle Scholar
  136. Pavlova NN, Thompson CB (2016) The Emerging Hallmarks of Cancer Metabolism. Cell Metab 23:27–47CrossRefGoogle Scholar
  137. Pekkurnaz G, Trinidad JC, Wang X, Kong D, Schwarz TL (2014) Glucose regulates mitochondrial motility via Milton modification by O-GlcNAc transferase. Cell 158:54–68CrossRefGoogle Scholar
  138. Pepe F, Pagotto S, Soliman S, Rossi C, Lanuti P, Braconi C, Mariani-Costantini R, Visone R, Veronese A (2017) Regulation of miR-483-3p by the O-linked N-acetylglucosamine transferase links chemosensitivity to glucose metabolism in liver cancer cells. Oncogene 6:e328CrossRefGoogle Scholar
  139. Phoomak C, Vaeteewoottacharn K, Silsirivanit A, Saengboonmee C, Seubwai W, Sawanyawisuth K, Wongkham C, Wongkham S (2017) High glucose levels boost the aggressiveness of highly metastatic cholangiocarcinoma cells via O-GlcNAcylation. Sci Rep 7:43842CrossRefGoogle Scholar
  140. Phueaouan T, Chaiyawat P, Netsirisawan P, Chokchaichamnankit D, Punyarit P, Srisomsap C, Svasti J, Champattanachai V (2013) Aberrant O-GlcNAc-modified proteins expressed in primary colorectal cancer. Oncol Rep 30:2929–2936CrossRefGoogle Scholar
  141. Ruan HB, Singh JP, Li MD, Wu J, Yang X (2013) Cracking the O-GlcNAc code in metabolism. Trends Endocrinol Metab 24:301–309CrossRefGoogle Scholar
  142. Sacoman JL, Dagda RY, Burnham-Marusich AR, Dagda RK, Berninsone PM (2017) Mitochondrial O-GlcNAc Transferase (mOGT) Regulates Mitochondrial Structure, Function, and Survival in HeLa Cells. J Biol Chem 292:4499–4518CrossRefGoogle Scholar
  143. Saeed MT, Ahmad J, Kanwal S, Holowatyj AN, Sheikh IA, Zafar Paracha R, Shafi A, Siddiqa A, Bibi Z, Khan M, Ali A (2016) Formal modeling and analysis of the hexosamine biosynthetic pathway: role of O-linked N-acetylglucosamine transferase in oncogenesis and cancer progression. Peer J 4:e2348CrossRefGoogle Scholar
  144. Sancho P, Barneda D, Heeschen C (2016) Hallmarks of cancer stem cell metabolism. Br J Cancer 114:1305–1312CrossRefGoogle Scholar
  145. Schimpl M, Zheng X, Borodkin VS, Blair DE, Ferenbach AT, Schüttelkopf AW, Navratilova I, Aristotelous T, Albarbarawi O, Robinson DA, Macnaughtan MA, van Aalten DM (2012) O-GlcNAc transferase invokes nucleotide sugar pyrophosphate participation in catalysis. Nat Chem Biol 8:969–974CrossRefGoogle Scholar
  146. Selvan N, Williamson R, Mariappa D, Campbell DG, Gourlay R, Ferenbach AT, Aristotelous T, Hopkins-Navratilova I, Trost M, van Aalten DMF (2017) A mutant O-GlcNAcase enriches Drosophila developmental regulators. Nat Chem Biol 13:882–887CrossRefGoogle Scholar
  147. Sgantzos MN, Galani V, Arvanitis LD, Charchanti A, Psathas P, Nakou M, Havaki S, Kallioras V, Marinos E, Vamvakopoulos NC, Kittas C (2007) Expression of the O-linked N-acetylglucosamine containing epitope H in normal myometrium and uterine smooth muscle cell tumors. Pathol Res Pract 203:31–37CrossRefGoogle Scholar
  148. Shafi R, Iyer SP, Ellies LG, O’Donnell N, Marek KW, Chui D, Hart GW, Marth JD (2000) The O-GlcNAc transferase gene resides on the X chromosome and is essential for embryonic stem cell viability and mouse ontogeny. Proc Natl Acad Sci U S A 97:5735–5739CrossRefGoogle Scholar
  149. 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 24:1588–1598CrossRefGoogle Scholar
  150. Shin SH, Love DC, Hanover JA (2011) Elevated O-GlcNAc-dependent signaling through inducible mOGT expression selectively triggers apoptosis. Amino Acids 40:885–893CrossRefGoogle Scholar
  151. Sinclair DA, Syrzycka M, Macauley MS, Rastgardani T, Komljenovic I, Vocadlo DJ, Brock HW, Honda BM (2009) Drosophila O-GlcNAc transferase (OGT) is encoded by the Polycomb group (PcG) gene, super sex combs (sxc). Proc Natl Acad Sci U S A 106:13427–13432CrossRefGoogle Scholar
  152. Singh JP, Zhang K, Wu J, Yang X (2015) O-GlcNAc signaling in cancer metabolism and epigenetics. Cancer Lett 356:244–250CrossRefGoogle Scholar
  153. Slawson C, Hart GW (2011) O-GlcNAc signalling: implications for cancer cell biology. Nat Rev Cancer 11:678–684CrossRefGoogle Scholar
  154. Slawson C, Copeland RJ, Hart GW (2010) O-GlcNAc signaling: a metabolic link between diabetes and cancer. Trends Biochem Sci 35:547–555CrossRefGoogle Scholar
  155. Sodi VL, Khaku S, Krutilina R, Schwab LP, Vocadlo DJ, Seagroves TN, Reginato MJ (2015) mTOR/MYC Axis Regulates O-GlcNAc Transferase Expression and O-GlcNAcylation in Breast Cancer. Mol Cancer Res 13:923–933CrossRefGoogle Scholar
  156. Solary E, Bernard OA, Tefferi A, Fuks F, Vainchenker W (2014) The Ten-Eleven Translocation-2 (TET2) gene in hematopoiesis and hematopoietic diseases. Leukemia 28:485–496CrossRefGoogle Scholar
  157. Srikanth B, Vaidya MM, Kalraiya RD (2010) O-GlcNAcylation determines the solubility, filament organization, and stability of keratins 8 and 18. J Biol Chem 285:34062–34071CrossRefGoogle Scholar
  158. Taguchi K, Yamamoto M (2017) The KEAP1-NRF2 System in Cancer. Front Oncol 7:85CrossRefGoogle Scholar
  159. Tan EP, Villar MT, E L LJ, Selfridge JE, Artigues A, Swerdlow RH, Slawson C (2014) Altering O-linked β-N-acetylglucosamine cycling disrupts mitochondrial function. J Biol Chem 289:14719–14730CrossRefGoogle Scholar
  160. Taparra K, Tran PT, Zachara NE (2016) Hijacking the Hexosamine Biosynthetic Pathway to Promote EMT-Mediated Neoplastic Phenotypes. Front Oncol 6:85CrossRefGoogle Scholar
  161. Thomas TM, Yu JS (2017) Metabolic regulation of glioma stem-like cells in the tumor micro-environment., Cancer LettGoogle Scholar
  162. 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 259:3308–3317Google Scholar
  163. Trapannone R, Mariappa D, Ferenbach AT, van Aalten DM (2016) Nucleocytoplasmic human O-GlcNAc transferase is sufficient for O-GlcNAcylation of mitochondrial proteins. Biochem J 473:1693–1702CrossRefGoogle Scholar
  164. Tvaroška I, Kozmon S, Wimmerová M, Koča J (2012) Substrate-assisted catalytic mechanism of O-GlcNAc transferase discovered by quantum mechanics/molecular mechanics investigation. J Am Chem Soc 134:15563–15571CrossRefGoogle Scholar
  165. Vaidyanathan K, Niranjan T, Selvan N, Teo CF, May M, Patel S, Weatherly B, Skinner C, Opitz J, Carey J, Viskochil D, Gecz J, Shaw M, Peng Y, Alexov E, Wang T, Schwartz C, Wells L (2017) Identification and characterization of a missense mutation in the O-linked β-N-acetylglucosamine (O-GlcNAc) transferase gene that segregates with X-linked intellectual disability. J Biol Chem 292:8948–8963CrossRefGoogle Scholar
  166. Vajaria BN, Patel PS (2017) Glycosylation: a hallmark of cancer. Glycoconj J 34:147–156CrossRefGoogle Scholar
  167. Valero V, Pawlik TM, Anders RA (2015) Emerging role of Hpo signaling and YAP in hepatocellular carcinoma. J Hepatocell Carcinoma 2:69–78Google Scholar
  168. Varki A, Kannagi R, Toole B, Stanley P (2015) Glycosylation Changes in Cancer, Essentials of GlycobiologyGoogle Scholar
  169. Varmus H, Pao W, Politi K, Podsypanina K, Du YC (2005) Oncogenes come of age. Cold Spring Harb Symp Quant Biol 70:1–9CrossRefGoogle Scholar
  170. Vocadlo DJ (2012) O-GlcNAc processing enzymes: catalytic mechanisms, substrate specificity, and enzyme regulation. Curr Opin Chem Biol 16:488–497CrossRefGoogle Scholar
  171. Wang T, Marquardt C, Foker J (1976) Aerobic glycolysis during lymphocyte proliferation. Nature 261:702–705CrossRefGoogle Scholar
  172. Warburg O, Wind F, Negelein E (1927) The metabolism of tumors in the body. J Gen Physiol 8:519–530CrossRefGoogle Scholar
  173. Willis RE (2012) Human gene control by vital oncogenes: revisiting a theoretical model and its implications for targeted cancer therapy. Int J Mol Sci 13:316–335CrossRefGoogle Scholar
  174. Wu D (2017) Cai Y, Jin J. Potential coordination role between O-GlcNAcylation and epigenetics, Protein CellGoogle Scholar
  175. Xu Q, Yang C, Du Y, Chen Y, Liu H, Deng M, Zhang H, Zhang L, Liu T, Liu Q, Wang L, Lou Z, Pei H (2014) AMPK regulates histone H2B O-GlcNAcylation. Nucleic Acids Res 42:5594–5604CrossRefGoogle Scholar
  176. Yang WH, Kim JE, Nam HW, Ju JW, Kim HS, Kim YS, Cho JW (2006) Modification of p53 with O-linked N-acetylglucosamine regulates p53 activity and stability. Nat Cell Biol 8:1074–1083CrossRefGoogle Scholar
  177. Yang X, Ongusaha PP, Miles PD, Havstad JC, Zhang F, So WV, Kudlow JE, Michell RH, Olefsky JM, Field SJ, Evans RM (2008) Phosphoinositide signalling links O-GlcNAc transferase to insulin resistance. Nature 451:964–969CrossRefGoogle Scholar
  178. Yang Y, Yin X, Yang H, Xu Y (2015a) Histone demethylase LSD2 acts as an E3 ubiquitin ligase and inhibits cancer cell growth through promoting proteasomal degradation of OGT. Mol Cell 58:47–59CrossRefGoogle Scholar
  179. Yang YR, Jang HJ, Lee YH, Kim IS, Lee H, Ryu SH, Suh PG (2015b) O-GlcNAc cycling enzymes control vascular development of the placenta by modulating the levels of HIF-1α. Placenta 36:1063–1068CrossRefGoogle Scholar
  180. Yehezkel G, Cohen L, Kliger A, Manor E, Khalaila I (2012) 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 287:28755–28769CrossRefGoogle Scholar
  181. Yi W, Clark PM, Mason DE, Keenan MC, Hill C, Goddard WA, Peters EC, Driggers EM, Hsieh-Wilson LC (2012) Phosphofructokinase 1 glycosylation regulates cell growth and metabolism. Science 337:975–980CrossRefGoogle Scholar
  182. 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 149:656–670CrossRefGoogle Scholar
  183. Yu X, Li S (2017) Non-metabolic functions of glycolytic enzymes in tumorigenesis. Oncogene 36:2629–2636CrossRefGoogle Scholar
  184. Zeng Q, Zhao RX, Chen J, Li Y, Li XD, Liu XL, Zhang WM, Quan CS, Wang YS, Zhai YX, Wang JW, Youssef M, Cui R, Liang J, Genovese N, Chow LT, Li YL, Xu ZX (2016) O-linked GlcNAcylation elevated by HPV E6 mediates viral oncogenesis. Proc Natl Acad Sci U S A 113:9333–9338CrossRefGoogle Scholar
  185. Zhang N, Chen X (2016) Potential role of O-GlcNAcylation and involvement of PI3K/Akt1 pathway in the expression of oncogenic phenotypes of gastric cancer cells in vitro. Biotechnol Appl Biochem 63:841–851CrossRefGoogle Scholar
  186. Zhang Z, Tan EP, VandenHull NJ, Peterson KR, Slawson C (2014) O-GlcNAcase Expression is Sensitive to Changes in O-GlcNAc Homeostasis. Front Endocrinol (Lausanne) 5:206Google Scholar
  187. Zhang P, Wang C, Ma T, You S (2015) O-GlcNAcylation enhances the invasion of thyroid anaplastic cancer cells partially by PI3K/Akt1 pathway. Onco Targets Ther 8:3305–3313Google Scholar
  188. Zhang B, Zhou P, Li X, Shi Q, Li D, Ju X (2017a) Bitterness in sugar: O-GlcNAcylation aggravates pre-B acute lymphocytic leukemia through glycolysis via the PI3K/Akt/c-Myc pathway. Am J Cancer Res 7:1337–1349Google Scholar
  189. Zhang X, Qiao Y, Wu Q, Chen Y, Zou S, Liu X, Zhu G, Zhao Y, Chen Y, Yu Y, Pan Q, Wang J, Sun F (2017b) The essential role of YAP O-GlcNAcylation in high-glucose-stimulated liver tumorigenesis. Nat Commun 8:15280CrossRefGoogle Scholar
  190. Zhou F, Huo J, Liu Y, Liu H, Liu G, Chen Y, Chen B (2016) Elevated glucose levels impair the WNT/β-catenin pathway via the activation of the hexosamine biosynthesis pathway in endometrial cancer. J Steroid Biochem Mol Biol 159:19–25CrossRefGoogle Scholar
  191. Zhu G, Tao T, Zhang D, Liu X, Qiu H, Han L, Xu Z, Xiao Y, Cheng C, Shen A (2016) O-GlcNAcylation of histone deacetylases 1 in hepatocellular carcinoma promotes cancer progression. Glycobiology 26:820–833CrossRefGoogle Scholar

Copyright information

© This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply 2018

Authors and Affiliations

  1. 1.Laboratory of Cell Biochemistry and Molecular BiologyNIDDK, NIHBethesdaUSA
  2. 2.NIDDK Genomics CoreBethesdaUSA

Personalised recommendations