Journal of Bioenergetics and Biomembranes

, Volume 50, Issue 3, pp 175–187 | Cite as

Hyperglycemia and aberrant O-GlcNAcylation: contributions to tumor progression

  • Andréia Vasconcelos-dos-Santos
  • Rafaela Muniz de Queiroz
  • Bruno da Costa Rodrigues
  • Adriane R. Todeschini
  • Wagner B. Dias


A number of cancer types have shown an increased prevalence and a higher mortality rate in patients with hyperglycemic associated pathologies. Although the correlation between diabetes and cancer incidence has been increasingly reported, the underlying molecular mechanisms beyond this association are not yet fully understood. Recent studies have suggested that high glucose levels support tumor progression through multiple mechanisms that are hallmarks of cancer, including cell proliferation, resistance to apoptosis, increased cell migration and invasiveness, epigenetic regulation (hyperglycemic memory), resistance to chemotherapy and altered metabolism. Most of the above occur because hyperglycemia through hexosamine biosynthetic pathway leads to aberrant O-GlcNAcylation of many intracellular proteins that are involved in those mechanisms. Deregulated O-GlcNAcylation is emerging as a general feature of cancer. Despite strong evidence suggesting that aberrant O-GlcNAcylation is or may be involved in the acquisition of all cancer hallmarks, it remains out of the list of the next generation of emerging hallmarks. Here, we discuss some of the current understanding on how hyperglycemia affects cancer cell biology and how aberrant O-GlcNAcylation stands in this context.


Hyperglycemia Cancer O-GlcNAcylation Hexosamine biosynthetic pathway 



The authors thank Dr. Frederico Alisson Silva for the critical review of the manuscript. This work was supported by Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq), Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES), Fundação de Amparo à Pesquisa do Estado do Rio de Janeiro (FAPERJ) and Fundação do Câncer.

Compliance with ethical standards

Conflicts of interest

The authors declare that they have no competing interests.


  1. Abdel Rahman AM, Ryczko M, Pawling J, Dennis JW (2013) Probing the hexosamine biosynthetic pathway in human tumor cells by multitargeted tandem mass spectrometry. ACS Chem Biol 8:2053–2062Google Scholar
  2. Alisson-Silva F, Freire-de-Lima L, Donadio JL, Lucena MC, Penha L, Sa-Diniz JN, Dias WB, Todeschini AR (2013) Increase of O-glycosylated oncofetal fibronectin in high glucose-induced epithelial-mesenchymal transition of cultured human epithelial cells. PLoS One 8:e60471Google Scholar
  3. 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 288:33927–33938Google Scholar
  4. Bao B, Wang Z, Ali S, Ahmad A, Azmi AS, Sarkar SH, Banerjee S, Kong D, Li Y, Thakur S et al (2012) Metformin inhibits cell proliferation, migration and invasion by attenuating CSC function mediated by deregulating miRNAs in pancreatic cancer cells. Cancer Prev Res 5:355–364Google Scholar
  5. Beckman JA, Creager MA, Libby P (2002) Diabetes and atherosclerosis: epidemiology, pathophysiology, and management. JAMA: J Am Med Assoc 287:2570–2581Google Scholar
  6. Beishline K, Azizkhan-Clifford J (2015) Sp1 and the 'hallmarks of cancer. FEBS J 282:224–258Google Scholar
  7. Biadgo B, Abebe M (2016) Type 2 diabetes mellitus and its association with the risk of pancreatic carcinogenesis: a review. The Korean J Gastroenterol= Taehan Sohwagi Hakhoe chi 67:168–177Google Scholar
  8. Biernacka KM, Uzoh CC, Zeng L, Persad RA, Bahl A, Gillatt D, Perks CM, Holly JM (2013) Hyperglycaemia-induced chemoresistance of prostate cancer cells due to IGFBP2. Endocr Relat Cancer 20:741–751Google Scholar
  9. Bird A (2002) DNA methylation patterns and epigenetic memory. Genes Dev 16:6–21Google Scholar
  10. Bond MR, Hanover JA (2013) O-GlcNAc cycling: a link between metabolism and chronic disease. Annu Rev Nutr 33:205–229Google Scholar
  11. Boulton AJ, Vinik AI, Arezzo JC, Bril V, Feldman EL, Freeman R, Malik RA, Maser RE, Sosenko JM, Ziegler D et al (2005) Diabetic neuropathies: a statement by the American Diabetes Association. Diabetes Care 28:956–962Google Scholar
  12. Brownlee M (2001) Biochemistry and molecular cell biology of diabetic complications. Nature 414:813–820Google Scholar
  13. Brunello A, Kapoor R, Extermann M (2011) Hyperglycemia during chemotherapy for hematologic and solid tumors is correlated with increased toxicity. Am J Clin Oncol 34:292–296Google Scholar
  14. 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 29:2831–2842Google Scholar
  15. Carvalho-Cruz, P., Alisson-Silva, F., Todeschini, A.R., and Dias, W.B. (2017). Cellular glycosylation senses metabolic changes and modulates cell plasticity during epithelial to mesenchymal transition. Developmental dynamics : an official publication of the American Association of AnatomistsGoogle Scholar
  16. Catrina SB, Okamoto K, Pereira T, Brismar K, Poellinger L (2004) Hyperglycemia regulates hypoxia-inducible factor-1alpha protein stability and function. Diabetes 53:3226–3232Google Scholar
  17. Chaiyawat P, Netsirisawan P, Svasti J, Champattanachai V (2014) Aberrant O-GlcNAcylated proteins: new perspectives in breast and colorectal cancer. Front Endocrinol 5:193Google Scholar
  18. Chatterjee S, Park ES, Soloff MS (2004) Proliferation of DU145 prostate cancer cells is inhibited by suppressing insulin-like growth factor binding protein-2. Int J Urol: Official J Japanese Urol Assoc 11:876–884Google Scholar
  19. Cheung N, Mitchell P, Wong TY (2010) Diabetic retinopathy. Lancet 376:124–136Google Scholar
  20. Chocarro-Calvo A, Garcia-Martinez JM, Ardila-Gonzalez S, De la Vieja A, Garcia-Jimenez C (2013) Glucose-induced beta-catenin acetylation enhances Wnt signaling in cancer. Mol Cell 49:474–486Google Scholar
  21. Coughlin SS, Calle EE, Teras LR, Petrelli J, Thun MJ (2004) Diabetes mellitus as a predictor of cancer mortality in a large cohort of US adults. Am J Epidemiol 159:1160–1167Google Scholar
  22. 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 96:579–588Google Scholar
  23. Degraff DJ, Aguiar AA, Sikes RA (2009) Disease evidence for IGFBP-2 as a key player in prostate cancer progression and development of osteosclerotic lesions. Am J Transl Res 1:115–130PubMedPubMedCentralGoogle Scholar
  24. Del Barco S, Vazquez-Martin A, Cufi S, Oliveras-Ferraros C, Bosch-Barrera J, Joven J, Martin-Castillo B, Menendez JA (2011) Metformin: multi-faceted protection against cancer. Oncotarget 2:896–917Google Scholar
  25. Dias WB, Hart GW (2007) O-GlcNAc modification in diabetes and Alzheimer's disease. Mol BioSyst 3:766–772Google Scholar
  26. Dias WB, Cheung WD, Wang Z, Hart GW (2009) Regulation of calcium/calmodulin-dependent kinase IV by O-GlcNAc modification. J Biol Chem 284:21327–21337Google Scholar
  27. Dias WB, Cheung WD, Hart GW (2012) O-GlcNAcylation of kinases. Biochem Biophys Res Commun 422:224–228Google Scholar
  28. Dobbs R, Sakurai H, Sasaki H, Faloona G, Valverde I, Baetens D, Orci L, Unger R (1975) Glucagon: role in the hyperglycemia of diabetes mellitus. Science 187:544–547Google Scholar
  29. Dong C, Yuan T, Wu Y, Wang Y, Fan TW, Miriyala S, Lin Y, Yao J, Shi J, Kang T et al (2013) Loss of FBP1 by snail-mediated repression provides metabolic advantages in basal-like breast cancer. Cancer Cell 23:316–331Google Scholar
  30. Dong T, Kang X, Liu Z, Zhao S, Ma W, Xuan Q, Liu H, Wang Z, Zhang Q (2016) Altered glycometabolism affects both clinical features and prognosis of triple-negative and neoadjuvant chemotherapy-treated breast cancer. Tumour Biol: J Int Soc OncodevelopBiol Med 37:8159–8168Google Scholar
  31. Donovan K, Alekseev O, Qi X, Cho W, Azizkhan-Clifford J (2014) O-GlcNAc modification of transcription factor Sp1 mediates hyperglycemia-induced VEGF-A upregulation in retinal cells. Invest Ophthalmol Vis Sci 55:7862–7873Google Scholar
  32. Du XL, Edelstein D, Rossetti L, Fantus IG, Goldberg H, Ziyadeh F, Wu J, Brownlee M (2000) Hyperglycemia-induced mitochondrial superoxide overproduction activates the hexosamine pathway and induces plasminogen activator inhibitor-1 expression by increasing Sp1 glycosylation. Proc Natl Acad Sci U S A 97:12222–12226Google Scholar
  33. Duan W, Shen X, Lei J, Xu Q, Yu Y, Li R, Wu E, Ma Q (2014) Hyperglycemia, a neglected factor during cancer progression. Biomed Res Int 2014:461917Google Scholar
  34. Duan F, Jia D, Zhao J, Wu W, Min L, Song S, Wu H, Wang L, Wang H, Ruan Y et al (2016) Loss of GFAT1 promotes epithelial-to-mesenchymal transition and predicts unfavorable prognosis in gastric cancer. Oncotarget 7:38427–38439Google Scholar
  35. Etoh T, Kanai Y, Ushijima S, Nakagawa T, Nakanishi Y, Sasako M, Kitano S, Hirohashi S (2004) Increased DNA methyltransferase 1 (DNMT1) protein expression correlates significantly with poorer tumor differentiation and frequent DNA hypermethylation of multiple CpG islands in gastric cancers. Am J Pathol 164:689–699Google Scholar
  36. Eustice M, Bond MR, Hanover JA (2017) O-GlcNAc cycling and the regulation of nucleocytoplasmic dynamics. Biochem Soc Trans 45:427–436Google Scholar
  37. Eyers PA, Keeshan K, Kannan N (2017) Tribbles in the 21st century: the evolving roles of tribbles Pseudokinases in biology and disease. Trends Cell Biol 27:284–298Google Scholar
  38. Ferrer CM, Sodi VL, Reginato MJ (2016) O-GlcNAcylation in cancer biology: linking metabolism and signaling. J Mol Biol 428:3282–3294Google Scholar
  39. Flores-Lopez LA, Martinez-Hernandez MG, Viedma-Rodriguez R, Diaz-Flores M, Baiza-Gutman LA (2016) High glucose and insulin enhance uPA expression, ROS formation and invasiveness in breast cancer-derived cells. Cell Oncol 39:365–378Google Scholar
  40. Fogar P, Pasquali C, Basso D, Floreani A, Piva MG, De Paoli M, Melis A, Sperti C, Pedrazzoli S, Plebani M (1998) Transforming growth factor beta, fibrogenesis and hyperglycemia in patients with chronic pancreatitis. J Med 29:277–287PubMedGoogle Scholar
  41. Garcia-Jimenez C, Garcia-Martinez JM, Chocarro-Calvo A, De la Vieja A (2014) A new link between diabetes and cancer: enhanced WNT/beta-catenin signaling by high glucose. J Mol Endocrinol 52:R51–R66Google Scholar
  42. Garufi A, D'Orazi G (2014) High glucose dephosphorylates serine 46 and inhibits p53 apoptotic activity. J Exp Clin Cancer Res: CR 33:79Google Scholar
  43. Giacco F, Brownlee M (2010) Oxidative stress and diabetic complications. Circ Res 107:1058–1070Google Scholar
  44. Giovannucci E, Harlan DM, Archer MC, Bergenstal RM, Gapstur SM, Habel LA, Pollak M, Regensteiner JG, Yee D (2010) Diabetes and cancer: a consensus report. Diabetes Care 33:1674–1685Google Scholar
  45. Guo L, Teng L (2015) YAP/TAZ for cancer therapy: opportunities and challenges (review). Int J Oncol 46:1444–1452Google Scholar
  46. Gupta C, Kaur J, Tikoo K (2014) Regulation of MDA-MB-231 cell proliferation by GSK-3beta involves epigenetic modifications under high glucose conditions. Exp Cell Res 324:75–83Google Scholar
  47. Hahn T, Barth S, Hofmann W, Reich O, Lang I, Desoye G (1998) Hyperglycemia regulates the glucose-transport system of clonal choriocarcinoma cells in vitro. A potential molecular mechanism contributing to the adjunct effect of glucose in tumor therapy. Int J Cancer J Int du cancer 78:353–360Google Scholar
  48. Han I, Kudlow JE (1997) Reduced O glycosylation of Sp1 is associated with increased proteasome susceptibility. Mol Cell Biol 17:2550–2558Google Scholar
  49. Han L, Ma Q, Li J, Liu H, Li W, Ma G, Xu Q, Zhou S, Wu E (2011) High glucose promotes pancreatic cancer cell proliferation via the induction of EGF expression and transactivation of EGFR. PLoS One 6:e27074Google Scholar
  50. Han J, Zhang L, Guo H, Wysham WZ, Roque DR, Willson AK, Sheng X, Zhou C, Bae-Jump VL (2015) Glucose promotes cell proliferation, glucose uptake and invasion in endometrial cancer cells via AMPK/mTOR/S6 and MAPK signaling. Gynecol Oncol 138:668–675Google Scholar
  51. Hanahan D, Weinberg RA (2000) The hallmarks of cancer. Cell 100:57–70Google Scholar
  52. Hanahan D, Weinberg RA (2011) Hallmarks of cancer: the next generation. Cell 144:646–674Google Scholar
  53. Hart GW, Housley MP, Slawson C (2007) Cycling of O-linked beta-N-acetylglucosamine on nucleocytoplasmic proteins. Nature 446:1017–1022Google Scholar
  54. 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 80:825–858Google Scholar
  55. He XY, Yuan YZ (2014) Advances in pancreatic cancer research: moving towards early detection. World J Gastroenterol: WJG 20:11241–11248Google Scholar
  56. Heilig C, Zaloga C, Lee M, Zhao X, Riser B, Brosius F, Cortes P (1995) Immunogold localization of high-affinity glucose transporter isoforms in normal rat kidney. Lab Invest 73:674–684Google Scholar
  57. Hernandez-Sanchez F, Guzman-Beltran S, Herrera MT, Gonzalez Y, Salgado M, Fabian G, Torres M (2017) High glucose induces O-GlcNAc glycosylation of the vitamin D receptor (VDR) in THP1 cells and in human macrophages derived from monocytes. Cell Biol Int 41:1065–1074Google Scholar
  58. Hou Y, Zhou M, Xie J, Chao P, Feng Q, Wu J (2017) High glucose levels promote the proliferation of breast cancer cells through GTPases. Breast Cancer (Dove Med Press) 9:429–436Google Scholar
  59. Isoe T, Makino Y, Mizumoto K, Sakagami H, Fujita Y, Honjo J, Takiyama Y, Itoh H, Haneda M (2010) High glucose activates HIF-1-mediated signal transduction in glomerular mesangial cells through a carbohydrate response element binding protein. Kidney Int 78:48–59Google Scholar
  60. 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 73:5277–5287Google Scholar
  61. Iwashita Y, Fukuchi N, Waki M, Hayashi K, Tahira T (2012) Genome-wide repression of NF-kappaB target genes by transcription factor MIBP1 and its modulation by O-linked beta-N-acetylglucosamine (O-GlcNAc) transferase. J Biol Chem 287:9887–9900Google Scholar
  62. Jalving M, Gietema JA, Lefrandt JD, de Jong S, Reyners AK, Gans RO, de Vries EG (2010) Metformin: taking away the candy for cancer? Eur J Cancer 46:2369–2380Google Scholar
  63. James LR, Tang D, Ingram A, Ly H, Thai K, Cai L, Scholey JW (2002) Flux through the hexosamine pathway is a determinant of nuclear factor kappaB- dependent promoter activation. Diabetes 51:1146–1156Google Scholar
  64. Jeronimo C, Bastian PJ, Bjartell A, Carbone GM, Catto JW, Clark SJ, Henrique R, Nelson WG, Shariat SF (2011) Epigenetics in prostate cancer: biologic and clinical relevance. Eur Urol 60:753–766Google Scholar
  65. Khan KH, Wong M, Rihawi K, Bodla S, Morganstein D, Banerji U, Molife LR (2016) Hyperglycemia and phosphatidylinositol 3-kinase/protein kinase B/mammalian target of rapamycin (PI3K/AKT/mTOR) inhibitors in phase I trials: incidence, predictive factors, and management. Oncologist 21:855–860Google Scholar
  66. Kim G, Cao L, Reece EA, Zhao Z (2017) Impact of protein O-GlcNAcylation on neural tube malformation in diabetic embryopathy. Sci Rep 7:11107Google Scholar
  67. Krechler T, Novotny J, Zeman M, Krska Z, Svestka T, Svab J, Lukas M, Filipova R, Zak A (2004) Pancreatic carcinoma and diabetes mellitus. Cas Lek Cesk 143:97–100PubMedGoogle Scholar
  68. Krzeslak A, Pomorski L, Lipinska A (2011) Expression, localization, and phosphorylation of Akt1 in benign and malignant thyroid lesions. Endocr Pathol 22:206–211Google Scholar
  69. Lee JW, Bae SH, Jeong JW, Kim SH, Kim KW (2004) Hypoxia-inducible factor (HIF-1)alpha: its protein stability and biological functions. Exp Mol Med 36:1–12Google Scholar
  70. Lee SK, Moon JW, Lee YW, Lee JO, Kim SJ, Kim N, Kim J, Kim HS, Park SH (2015) The effect of high glucose levels on the hypermethylation of protein phosphatase 1 regulatory subunit 3C (PPP1R3C) gene in colorectal cancer. J Genet 94:75–85Google Scholar
  71. Lee C, An D, Park J (2016) Hyperglycemic memory in metabolism and cancer. Horm Mol Biol Clin Invest 26:77–85Google Scholar
  72. Li W, Ma Q, Li J, Guo K, Liu H, Han L, Ma G (2011) Hyperglycemia enhances the invasive and migratory activity of pancreatic cancer cells via hydrogen peroxide. Oncol Rep 25:1279–1287PubMedGoogle Scholar
  73. Li W, Zhang L, Chen X, Jiang Z, Zong L, Ma Q (2016) Hyperglycemia promotes the epithelial-mesenchymal transition of pancreatic cancer via hydrogen peroxide. Oxidative Med Cell Longev 2016:5190314Google Scholar
  74. Li L, Shao M, Peng P, Yang C, Song S, Duan F, Jia D, Zhang M, Zhao J, Zhao R et al (2017) High expression of GFAT1 predicts unfavorable prognosis in patients with hepatocellular carcinoma. Oncotarget 8:19205–19217PubMedPubMedCentralGoogle Scholar
  75. Libby G, Donnelly LA, Donnan PT, Alessi DR, Morris AD, Evans JM (2009) New users of metformin are at low risk of incident cancer: a cohort study among people with type 2 diabetes. Diabetes Care 32:1620–1625Google Scholar
  76. Lipscombe LL, Goodwin PJ, Zinman B, McLaughlin JR, Hux JE (2006) Diabetes mellitus and breast cancer: a retrospective population-based cohort study. Breast Cancer Res Treat 98:349–356Google Scholar
  77. Liu B, Wang J, Li M, Yuan Q, Xue M, Xu F, Chen Y (2017) Inhibition of ALDH2 by O-GlcNAcylation contributes to the hyperglycemic exacerbation of myocardial ischemia/reperfusion injury. Oncotarget 8:19413–19426PubMedGoogle Scholar
  78. Lopez R, Arumugam A, Joseph R, Monga K, Boopalan T, Agullo P, Gutierrez C, Nandy S, Subramani R, de la Rosa JM et al (2013) Hyperglycemia enhances the proliferation of non-tumorigenic and malignant mammary epithelial cells through increased leptin/IGF1R signaling and activation of AKT/mTOR. PLoS One 8:e79708Google Scholar
  79. 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 et al (2016) Epithelial mesenchymal transition induces aberrant glycosylation through Hexosamine biosynthetic pathway activation. J Biol Chem 291:12917–12929Google Scholar
  80. Luo Z, Zang M, Guo W (2010) AMPK as a metabolic tumor suppressor: control of metabolism and cell growth. Future Oncol 6:457–470Google Scholar
  81. Luo Y, Ohmori H, Shimomoto T, Fujii K, Sasahira T, Chihara Y, Kuniyasu H (2011) Anti-angiotensin and hypoglycemic treatments suppress liver metastasis of colon cancer cells. Pathobiol: J Immunopathol, Mol Cell Biol 78:285–290Google Scholar
  82. Lynch TP, Ferrer CM, Jackson SR, Shahriari KS, Vosseller K, Reginato MJ (2012) Critical role of O-linked beta-N-acetylglucosamine transferase in prostate cancer invasion, angiogenesis, and metastasis. J Biol Chem 287:11070–11081Google Scholar
  83. Ma Z, Vosseller K (2014) Cancer metabolism and elevated O-GlcNAc in oncogenic signaling. J Biol Chem 289:34457–34465Google Scholar
  84. Ma Z, Vocadlo DJ, Vosseller K (2013) Hyper-O-GlcNAcylation is anti-apoptotic and maintains constitutive NF-kappaB activity in pancreatic cancer cells. J Biol Chem 288:15121–15130Google Scholar
  85. 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 53:3184–3192Google Scholar
  86. Martyn JA, Kaneki M, Yasuhara S (2008) Obesity-induced insulin resistance and hyperglycemia: etiologic factors and molecular mechanisms. Anesthesiology 109:137–148Google Scholar
  87. Masur K, Vetter C, Hinz A, Tomas N, Henrich H, Niggemann B, Zanker KS (2011) Diabetogenic glucose and insulin concentrations modulate transcriptome and protein levels involved in tumour cell migration, adhesion and proliferation. Br J Cancer 104:345–352Google Scholar
  88. Matsui C, Takatani-Nakase T, Hatano Y, Kawahara S, Nakase I, Takahashi K (2017). Zinc and its transporter ZIP6 are key mediators of breast cancer cell survival under high glucose conditions. FEBS Lett 591:3348–3359Google Scholar
  89. Meagher RB, Mussar KJ (2012) The influence of DNA sequence on epigenome-induced pathologies. Epigenetics Chromatin 5:11Google Scholar
  90. Mechanick JI (2006) Metabolic mechanisms of stress hyperglycemia. JPEN J Parenter Enteral Nutr 30:157–163Google Scholar
  91. Meier JJ, Giese A (2015) Diabetes associated with pancreatic diseases. Curr Opin Gastroenterol 31:400–406Google Scholar
  92. 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 1812:514–519Google Scholar
  93. Moloughney JG, Kim PK, Vega-Cotto NM, Wu CC, Zhang S, Adlam M, Lynch T, Chou PC, Rabinowitz JD, Werlen G et al (2016) mTORC2 responds to glutamine catabolite levels to modulate the Hexosamine biosynthesis enzyme GFAT1. Mol Cell 63:811–826Google Scholar
  94. Munkley J, Elliott DJ (2016) Hallmarks of glycosylation in cancer. Oncotarget 7:35478–35489Google Scholar
  95. Nakajima K, Kitazume S, Angata T, Fujinawa R, Ohtsubo K, Miyoshi E, Taniguchi N (2010) Simultaneous determination of nucleotide sugars with ion-pair reversed-phase HPLC. Glycobiology 20:865–871Google Scholar
  96. Nathan DM, Bayless M, Cleary P, Genuth S, Gubitosi-Klug R, Lachin JM, Lorenzi G, Zinman B, Group, D.E.R (2013) Diabetes control and complications trial/epidemiology of diabetes interventions and complications study at 30 years: advances and contributions. Diabetes 62:3976–3986Google Scholar
  97. Oki T, Yamazaki K, Kuromitsu J, Okada M, Tanaka I (1999) cDNA cloning and mapping of a novel subtype of glutamine:fructose-6-phosphate amidotransferase (GFAT2) in human and mouse. Genomics 57:227–234Google Scholar
  98. Okumura M, Yamamoto M, Sakuma H, Kojima T, Maruyama T, Jamali M, Cooper DR, Yasuda K (2002) Leptin and high glucose stimulate cell proliferation in MCF-7 human breast cancer cells: reciprocal involvement of PKC-alpha and PPAR expression. Biochim Biophys Acta 1592:107–116Google Scholar
  99. Olivier-Van Stichelen S, Guinez C, Mir AM, Perez-Cervera Y, Liu C, Michalski JC, Lefebvre T (2012) The hexosamine biosynthetic pathway and O-GlcNAcylation drive the expression of beta-catenin and cell proliferation. Am J Phys Endocrinol Metab 302:E417–E424Google Scholar
  100. Olivier-Van Stichelen S, Dehennaut V, Buzy A, Zachayus JL, Guinez C, Mir AM, El Yazidi-Belkoura I, Copin MC, Boureme D, Loyaux D et al (2014) O-GlcNAcylation stabilizes beta-catenin through direct competition with phosphorylation at threonine 41. FASEB J: Official Pub Federation Am Soc Exp Biol 28:3325–3338Google Scholar
  101. Onodera Y, Nam JM, Bissell MJ (2014) Increased sugar uptake promotes oncogenesis via EPAC/RAP1 and O-GlcNAc pathways. J Clin Invest 124:367–384Google Scholar
  102. Pan D (2010) The hippo signaling pathway in development and cancer. Dev Cell 19:491–505Google Scholar
  103. Paneni F, Volpe M, Luscher TF, Cosentino F (2013) SIRT1, p66(Shc), and Set7/9 in vascular hyperglycemic memory: bringing all the strands together. Diabetes 62:1800–1807Google Scholar
  104. Peng DF, Kanai Y, Sawada M, Ushijima S, Hiraoka N, Kitazawa S, Hirohashi S (2006) DNA methylation of multiple tumor-related genes in association with overexpression of DNA methyltransferase 1 (DNMT1) during multistage carcinogenesis of the pancreas. Carcinogenesis 27:1160–1168Google Scholar
  105. Peng C, Zhu Y, Zhang W, Liao Q, Chen Y, Zhao X, Guo Q, Shen P, Zhen B, Qian X et al (2017) Regulation of the hippo-YAP pathway by glucose sensor O-GlcNAcylation. Mol Cell 68(591–604):e595Google Scholar
  106. Pham LV, Bryant JL, Mendez R, Chen J, Tamayo AT, Xu-Monette ZY, Young KH, Manyam GC, Yang D, Medeiros LJ et al (2016) Targeting the hexosamine biosynthetic pathway and O-linked N-acetylglucosamine cycling for therapeutic and imaging capabilities in diffuse large B-cell lymphoma. Oncotarget 7:80599–80611Google Scholar
  107. 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 7:43842Google Scholar
  108. Pollak M (2008) Insulin and insulin-like growth factor signalling in neoplasia. Nat Rev Cancer 8:915–928Google Scholar
  109. Qiao Y, Zhang X, Zhang Y, Wang Y, Xu Y, Liu X, Sun F, Wang J (2016) High glucose stimulates tumorigenesis in hepatocellular carcinoma cells through AGER-dependent O-GlcNAcylation of c-Jun. Diabetes 65:619–632Google Scholar
  110. de Queiroz RM, Carvalho E, Dias WB (2014) O-GlcNAcylation: the sweet side of the cancer. Front Oncol 4:132Google Scholar
  111. Rajaram S, Baylink DJ, Mohan S (1997) Insulin-like growth factor-binding proteins in serum and other biological fluids: regulation and functions. Endocr Rev 18:801–831PubMedGoogle Scholar
  112. Rajasekar P, O'Neill CL, Eeles L, Stitt AW, Medina RJ (2015) Epigenetic changes in endothelial progenitors as a possible cellular basis for glycemic memory in diabetic vascular complications. J Diabetes Res 2015:436879Google Scholar
  113. Ramakrishnan P, Clark PM, Mason DE, Peters EC, Hsieh-Wilson LC, Baltimore D (2013) Activation of the transcriptional function of the NF-kappaB protein c-Rel by O-GlcNAc glycosylation. Sci Signal 6:ra75Google Scholar
  114. Reddy MA, Natarajan R (2011) Epigenetic mechanisms in diabetic vascular complications. Cardiovasc Res 90:421–429Google Scholar
  115. Saengboonmee C, Seubwai W, Pairojkul C, Wongkham S (2016) High glucose enhances progression of cholangiocarcinoma cells via STAT3 activation. Sci Rep 6:18995Google Scholar
  116. Safe S, Imanirad P, Sreevalsan S, Nair V, Jutooru I (2014) Transcription factor Sp1, also known as specificity protein 1 as a therapeutic target. Expert Opin Ther Targets 18:759–769Google Scholar
  117. Shikata K, Ninomiya T, Kiyohara Y (2013) Diabetes mellitus and cancer risk: review of the epidemiological evidence. Cancer Sci 104:9–14Google Scholar
  118. Slawson C, Copeland RJ, Hart GW (2010) O-GlcNAc signaling: a metabolic link between diabetes and cancer? Trends Biochem Sci 35:547–555Google Scholar
  119. Sodi VL, Bacigalupa ZA, Ferrer CM, Lee JV, Gocal WA, Mukhopadhyay D, Wellen KE, Ivan M, Reginato MJ (2017). Nutrient sensor O-GlcNAc transferase controls cancer lipid metabolism via SREBP-1 regulation. OncogeneGoogle Scholar
  120. Sowers JR, Epstein M, Frohlich ED (2001) Diabetes, hypertension, and cardiovascular disease: an update. Hypertension 37:1053–1059Google Scholar
  121. Srinivasan V, Sandhya N, Sampathkumar R, Farooq S, Mohan V, Balasubramanyam M (2007) Glutamine fructose-6-phosphate amidotransferase (GFAT) gene expression and activity in patients with type 2 diabetes: inter-relationships with hyperglycaemia and oxidative stress. Clin Biochem 40:952–957Google Scholar
  122. Staudt LM (2010) Oncogenic activation of NF-kappaB. Cold Spring Harb Perspect Biol 2:a000109Google Scholar
  123. Thakur R, Mishra DP (2013) Pharmacological modulation of beta-catenin and its applications in cancer therapy. J Cell Mol Med 17:449–456Google Scholar
  124. Thiery JP, Acloque H, Huang RY, Nieto MA (2009) Epithelial-mesenchymal transitions in development and disease. Cell 139:871–890Google Scholar
  125. Thomas F, Holly JM, Persad R, Bahl A, Perks CM (2010) Fibronectin confers survival against chemotherapeutic agents but not against radiotherapy in DU145 prostate cancer cells: involvement of the insulin like growth factor-1 receptor. Prostate 70:856–865PubMedGoogle Scholar
  126. Uzoh CC, Perks CM, Bahl A, Holly JM, Sugiono M, Persad RA (2009) PTEN-mediated pathways and their association with treatment-resistant prostate cancer. BJU Int 104:556–561Google Scholar
  127. Uzoh CC, Holly JM, Biernacka KM, Persad RA, Bahl A, Gillatt D, Perks CM (2011) Insulin-like growth factor-binding protein-2 promotes prostate cancer cell growth via IGF-dependent or -independent mechanisms and reduces the efficacy of docetaxel. Br J Cancer 104:1587–1593Google Scholar
  128. Vaira S, Friday E, Scott K, Conrad S, Turturro F (2012) Wnt/beta-catenin signaling pathway and thioredoxin-interacting protein (TXNIP) mediate the "glucose sensor" mechanism in metastatic breast cancer-derived cells MDA-MB-231. J Cell Physiol 227:578–586Google Scholar
  129. Vajaria BN, Patel PS (2017) Glycosylation: a hallmark of cancer? Glycoconj J 34:147–156Google Scholar
  130. Vasconcelos-Dos-Santos A, Oliveira IA, Lucena MC, Mantuano NR, Whelan SA, Dias WB, Todeschini AR (2015) Biosynthetic machinery involved in aberrant glycosylation: promising targets for developing of drugs against cancer. Front Oncol 5:138Google Scholar
  131. Vasconcelos-Dos-Santos A, Loponte HF, Mantuano NR, Oliveira IA, de Paula IF, Teixeira LK, de Freitas-Junior JC, Gondim KC, Heise N, Mohana-Borges R et al (2017) Hyperglycemia exacerbates colon cancer malignancy through hexosamine biosynthetic pathway. Oncogene 6:e306Google Scholar
  132. Vazquez-Martin A, Oliveras-Ferraros C, Cufi S, Del Barco S, Martin-Castillo B, Menendez JA (2010) Metformin regulates breast cancer stem cell ontogeny by transcriptional regulation of the epithelial-mesenchymal transition (EMT) status. Cell Cycle 9:3807–3814Google Scholar
  133. Viedma-Rodriguez R, Martinez-Hernandez MG, Flores-Lopez LA, Baiza-Gutman LA (2017). Epsilon-aminocaproic acid prevents high glucose and insulin induced-invasiveness in MDA-MB-231 breast cancer cells, modulating the plasminogen activator system. Mol Cell Biochem.
  134. Vigneri P, Frasca F, Sciacca L, Pandini G, Vigneri R (2009) Diabetes and cancer. Endocr Relat Cancer 16:1103–1123Google Scholar
  135. Vishvakarma NK, Kumar A, Singh V, Singh SM (2013) Hyperglycemia of tumor microenvironment modulates stage-dependent tumor progression and multidrug resistance: implication of cell survival regulatory molecules and altered glucose transport. Mol Carcinog 52:932–945Google Scholar
  136. Wahdan-Alaswad R, Fan Z, Edgerton SM, Liu B, Deng XS, Arnadottir SS, Richer JK, Anderson SM, Thor AD (2013) Glucose promotes breast cancer aggression and reduces metformin efficacy. Cell Cycle 12:3759–3769Google Scholar
  137. Walgren JL, Vincent TS, Schey KL, Buse MG (2003) High glucose and insulin promote O-GlcNAc modification of proteins, including alpha-tubulin. Am J Phys Endocrinol Metab 284:E424–E434Google Scholar
  138. Warburg O (1956) On the origin of cancer cells. Science 123:309–314Google Scholar
  139. Weinberg F, Hamanaka R, Wheaton WW, Weinberg S, Joseph J, Lopez M, Kalyanaraman B, Mutlu GM, Budinger GR, Chandel NS (2010) Mitochondrial metabolism and ROS generation are essential for Kras-mediated tumorigenicity. Proc Natl Acad Sci U S A 107:8788–8793Google Scholar
  140. Wheaton WW, Weinberg SE, Hamanaka RB, Soberanes S, Sullivan LB, Anso E, Glasauer A, Dufour E, Mutlu GM, Budigner GS et al (2014) Metformin inhibits mitochondrial complex I of cancer cells to reduce tumorigenesis. elife 3:e02242Google Scholar
  141. WHO (2016) Accessed 29 Sept 2017
  142. Wright JL, Plymate SR, Porter MP, Gore JL, Lin DW, Hu E, Zeliadt SB (2013) Hyperglycemia and prostate cancer recurrence in men treated for localized prostate cancer. Prostate Cancer Prostatic Dis 16:204–208Google Scholar
  143. Writing Team for the Diabetes, C., Complications Trial/Epidemiology of Diabetes, I., and Complications Research, G (2003) Sustained effect of intensive treatment of type 1 diabetes mellitus on development and progression of diabetic nephropathy: the epidemiology of diabetes interventions and complications (EDIC) study. JAMA: J Am Med Assoc 290:2159–2167Google Scholar
  144. Xia Y, Shen S, Verma IM (2014) NF-kappaB, an active player in human cancers. Cancer Immunol Res 2:823–830Google Scholar
  145. Yang X, Qian K (2017) Protein O-GlcNAcylation: emerging mechanisms and functions. Nat Rev Mol Cell Biol 18:452–465Google Scholar
  146. Yang WH, Park SY, Nam HW, Kim DH, Kang JG, Kang ES, Kim YS, Lee HC, Kim KS, Cho JW (2008) NFkappaB activation is associated with its O-GlcNAcylation state under hyperglycemic conditions. Proc Natl Acad Sci U S A 105:17345–17350Google Scholar
  147. Yang YR, Kim DH, Seo YK, Park D, Jang HJ, Choi SY, Lee YH, Lee GH, Nakajima K, Taniguchi N et al (2015) Elevated O-GlcNAcylation promotes colonic inflammation and tumorigenesis by modulating NF-kappaB signaling. Oncotarget 6:12529–12542Google Scholar
  148. Yang C, Peng P, Li L, Shao M, Zhao J, Wang L, Duan F, Song S, Wu H, Zhang J et al (2016a) High expression of GFAT1 predicts poor prognosis in patients with pancreatic cancer. Sci Rep 6:39044Google Scholar
  149. Yang IP, Tsai HL, Huang CW, Lu CY, Miao ZF, Chang SF, Juo SH, Wang JY (2016b) High blood sugar levels significantly impact the prognosis of colorectal cancer patients through down-regulation of microRNA-16 by targeting Myb and VEGFR2. Oncotarget 7:18837–18850Google Scholar
  150. Yao B, Xu Y, Wang J, Qiao Y, Zhang Y, Zhang X, Chen Y, Wu Q, Zhao Y, Zhu G et al (2016) Reciprocal regulation between O-GlcNAcylation and tribbles pseudokinase 2 (TRIB2) maintains transformative phenotypes in liver cancer cells. Cell Signal 28:1703–1712Google Scholar
  151. Yokoyama T, Nakamura T (2011) Tribbles in disease: signaling pathways important for cellular function and neoplastic transformation. Cancer Sci 102:1115–1122Google Scholar
  152. Zanconato F, Cordenonsi M, Piccolo S (2016) YAP/TAZ at the roots of cancer. Cancer Cell 29:783–803Google Scholar
  153. Zeng L, Biernacka KM, Holly JM, Jarrett C, Morrison AA, Morgan A, Winters ZE, Foulstone EJ, Shield JP, Perks CM (2010) Hyperglycaemia confers resistance to chemotherapy on breast cancer cells: the role of fatty acid synthase. Endocr Relat Cancer 17:539–551Google Scholar
  154. Zhan T, Rindtorff N, Boutros M (2017) Wnt signaling in cancer. Oncogene 36:1461–1473Google Scholar
  155. Zhang W, Liu J, Tian L, Liu Q, Fu Y, Garvey WT (2013) TRIB3 mediates glucose-induced insulin resistance via a mechanism that requires the hexosamine biosynthetic pathway. Diabetes 62:4192–4200Google Scholar
  156. Zhang JP, Zhang H, Wang HB, Li YX, Liu GH, Xing S, Li MZ, Zeng MS (2014) Down-regulation of Sp1 suppresses cell proliferation, clonogenicity and the expressions of stem cell markers in nasopharyngeal carcinoma. J Transl Med 12:222Google Scholar
  157. Zhang X, Qiao Y, Wu Q, Chen Y, Zou S, Liu X, Zhu G, Zhao Y, Chen Y, Yu Y et al (2017) The essential role of YAP O-GlcNAcylation in high-glucose-stimulated liver tumorigenesis. Nat Commun 8:15280Google Scholar
  158. Zhao Y, Zhang W, Guo Z, Ma F, Wu Y, Bai Y, Gong W, Chen Y, Cheng T, Zhi F et al (2013) Inhibition of the transcription factor Sp1 suppresses colon cancer stem cell growth and induces apoptosis in vitro and in nude mouse xenografts. Oncol Rep 30:1782–1792Google Scholar
  159. Zhao W, Chen R, Zhao M, Li L, Fan L, Che XM (2015) High glucose promotes gastric cancer chemoresistance in vivo and in vitro. Mol Med Rep 12:843–850Google Scholar
  160. Zhou F, Huo J, Liu Y, Liu H, Liu G, Chen Y, Chen B (2016) Elevated glucose levels impair the WNT/beta-catenin pathway via the activation of the hexosamine biosynthesis pathway in endometrial cancer. J Steroid Biochem Mol Biol 159:19–25Google Scholar
  161. Zhu S, Yao F, Li WH, Wan JN, Zhang YM, Tang Z, Khan S, Wang CH, Sun SR (2013) PKC?-dependent activation of the ubiquitin proteasome system is responsible for high glucose-induced human breast cancer MCF-7 cell proliferation, migration and invasion. Asian Pacific J Cancer Prevention: APJCP 14:5687–5692Google Scholar
  162. Ziyadeh FN, Sharma K (2003) Overview: combating diabetic nephropathy. J Am Soc Nephrol: JASN 14:1355–1357Google Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  • Andréia Vasconcelos-dos-Santos
    • 1
  • Rafaela Muniz de Queiroz
    • 1
  • Bruno da Costa Rodrigues
    • 1
  • Adriane R. Todeschini
    • 1
  • Wagner B. Dias
    • 1
  1. 1.Instituto de Biofísica Carlos Chagas FilhoUniversidade Federal do Rio de JaneiroRio de JaneiroBrazil

Personalised recommendations