Glycoconjugate Journal

, Volume 31, Issue 3, pp 185–191 | Cite as

Regulation of cancer metabolism by O-GlcNAcylation

Article
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Abstract

Cancer cells exhibit increased uptake of glucose and glutamine, and rewire the metabolic flux toward anabolic pathways important for cell growth and proliferation. Understanding how this altered metabolism is regulated has recently emerged as an intense research focus in cancer biology. O-linked β-N-acetylglucosamine (O-GlcNAc) is a reversible posttranslational modification of serine and/or threonine residues of nuclear and cytosolic proteins. O-GlcNAcylation has been identified in numerous proteins that are involved in many important cellular functions, including transcription, translation, signal transduction, and stress responses. More recently, increasing evidence indicates that O-GlcNAcylation plays important roles in regulating cancer metabolic reprogramming by modifying key transcription factors, metabolic enzymes and major oncogenic signaling pathways. Thus, O-GlcNAcylation emerges as a novel regulatory mechanism linking altered metabolism to cancer pathogenesis.

Keywords

Cancer metabolism O-GlcNAcylation Posttranslational modification Oncogenic signaling 
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Notes

Acknowledgments

We thank Dr. Binghui Shen (City of Hope National Cancer Center, USA) for helpful discussions. This work was supported by the National Science Foundation of China (NSFC, grant nos. 31270865 and 31322019), the Thousand-Young-Talents Recruitment Program, the Fundamental Research Funds for the Central Universities, and Cao Guang-biao Research Development Funds.

References

  1. 1.
    Hanahan, D., Weinberg, R.A.: Hallmarks of cancer: the next generation. Cell 144(5), 646–674 (2011)PubMedCrossRefGoogle Scholar
  2. 2.
    Warburg, O.: On respiratory impairment in cancer cells. Science 124(3215), 269–270 (1956)PubMedGoogle Scholar
  3. 3.
    Warburg, O., Wind, F., Negelein, E.: The metabolism of tumors in the body. J. Gen. Physiol. 8(6), 519–530 (1927)PubMedCentralPubMedCrossRefGoogle Scholar
  4. 4.
    Vander Heiden, M.G., Cantley, L.C., Thompson, C.B.: Understanding the Warburg effect: the metabolic requirements of cell proliferation. Science 324(5930), 1029–1033 (2009)PubMedCentralPubMedCrossRefGoogle Scholar
  5. 5.
    DeBerardinis, R.J., Lum, J.J., Hatzivassiliou, G., Thompson, C.B.: The biology of cancer: metabolic reprogramming fuels cell growth and proliferation. Cell Metab. 7(1), 11–20 (2008)PubMedCrossRefGoogle Scholar
  6. 6.
    Lum, J.J., Bui, T., Gruber, M., Gordan, J.D., DeBerardinis, R.J., Covello, K.L., Simon, M.C., Thompson, C.B.: The transcription factor HIF-1alpha plays a critical role in the growth factor-dependent regulation of both aerobic and anaerobic glycolysis. Genes Dev. 21(9), 1037–1049 (2007)PubMedCentralPubMedCrossRefGoogle Scholar
  7. 7.
    Osthus, R.C., Shim, H., Kim, S., Li, Q., Reddy, R., Mukherjee, M., Xu, Y., Wonsey, D., Lee, L.A., Dang, C.V.: Deregulation of glucose transporter 1 and glycolytic gene expression by c-Myc. J. Biol. Chem. 275(29), 21797–21800 (2000)PubMedCrossRefGoogle Scholar
  8. 8.
    Ward, P.S., Thompson, C.B.: Signaling in control of cell growth and metabolism. Cold Spring Harb. Perspect. Biol. 4(7), a006783 (2012)PubMedCrossRefGoogle Scholar
  9. 9.
    David, C.J., Chen, M., Assanah, M., Canoll, P., Manley, J.L.: HnRNP proteins controlled by c-Myc deregulate pyruvate kinase mRNA splicing in cancer. Nature 463(7279), 364–368 (2010)PubMedCentralPubMedCrossRefGoogle Scholar
  10. 10.
    Shim, H., Dolde, C., Lewis, B.C., Wu, C.S., Dang, G., Jungmann, R.A., Dalla-Favera, R., Dang, C.V.: c-Myc transactivation of LDH-A: implications for tumor metabolism and growth. Proc. Natl. Acad. Sci. U. S. A. 94(13), 6658–6663 (1997)PubMedCentralPubMedCrossRefGoogle Scholar
  11. 11.
    Gao, P., Tchernyshyov, I., Chang, T.C., Lee, Y.S., Kita, K., Ochi, T., Zeller, K.I., De Marzo, A.M., Van Eyk, J.E., Mendell, J.T., Dang, C.V.: c-Myc suppression of miR-23a/b enhances mitochondrial glutaminase expression and glutamine metabolism. Nature 458(7239), 762–765 (2009)PubMedCentralPubMedCrossRefGoogle Scholar
  12. 12.
    Wise, D.R., DeBerardinis, R.J., Mancuso, A., Sayed, N., Zhang, X.Y., Pfeiffer, H.K., Nissim, I., Daikhin, E., Yudkoff, M., McMahon, S.B., Thompson, C.B.: Myc regulates a transcriptional program that stimulates mitochondrial glutaminolysis and leads to glutamine addiction. Proc. Natl. Acad. Sci. U. S. A. 105(48), 18782–18787 (2008)PubMedCentralPubMedCrossRefGoogle Scholar
  13. 13.
    Wellen, K.E., Thompson, C.B.: A two-way street: reciprocal regulation of metabolism and signalling. Nat. Rev. Mol. Cell Biol. 13(4), 270–276 (2012)PubMedGoogle Scholar
  14. 14.
    Ruan, H.B., Singh, J.P., Li, M.D., Wu, J., Yang, X.: Cracking the O-GlcNAc code in metabolism. Trends Endocrinol. Metab. 24(6), 301–309 (2013)PubMedCrossRefGoogle Scholar
  15. 15.
    Ma, Z., Vosseller, K.: O-GlcNAc in cancer biology. Amino Acids 45(4), 719–733 (2013)PubMedCrossRefGoogle Scholar
  16. 16.
    Ngoh, G.A., Jones, S.P.: New insights into metabolic signaling and cell survival: the role of beta-O-linkage of N-acetylglucosamine. J. Pharmacol. Exp. Ther. 327(3), 602–609 (2008)PubMedCrossRefGoogle Scholar
  17. 17.
    Vocadlo, D.J.: O-GlcNAc processing enzymes: catalytic mechanisms, substrate specificity, and enzyme regulation. Curr. Opin. Chem. Biol. 16(5–6), 488–497 (2012)PubMedCrossRefGoogle Scholar
  18. 18.
    Marshall, S., Bacote, V., Traxinger, R.R.: 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. 266(8), 4706–4712 (1991)PubMedGoogle Scholar
  19. 19.
    Ma, J., Hart, G.W.: Protein O-GlcNAcylation in diabetes and diabetic complications. Expert Rev. Proteomics 10(4), 365–380 (2013)PubMedCrossRefPubMedCentralGoogle Scholar
  20. 20.
    Wellen, K.E., Lu, C., Mancuso, A., Lemons, J.M., Ryczko, M., Dennis, J.W., Rabinowitz, J.D., Coller, H.A., Thompson, C.B.: The hexosamine biosynthetic pathway couples growth factor-induced glutamine uptake to glucose metabolism. Genes Dev. 24(24), 2784–2799 (2010)PubMedCentralPubMedCrossRefGoogle Scholar
  21. 21.
    Krzeslak, A., Forma, E., Bernaciak, M., Romanowicz, H., Brys, M.: Gene expression of O-GlcNAc cycling enzymes in human breast cancers. Clin. Exp. Med. 12(1), 61–65 (2012)PubMedCentralPubMedCrossRefGoogle Scholar
  22. 22.
    Mi, W., Gu, Y., Han, C., Liu, H., Fan, Q., Zhang, X., Cong, Q., Yu, W.: O-GlcNAcylation is a novel regulator of lung and colon cancer malignancy. Biochim. Biophys. Acta 1812(4), 514–519 (2011)PubMedCrossRefGoogle Scholar
  23. 23.
    Zhu, Q., Zhou, L., Yang, Z., Lai, M., Xie, H., Wu, L., Xing, C., Zhang, F., Zheng, S.: O-GlcNAcylation plays a role in tumor recurrence of hepatocellular carcinoma following liver transplantation. Med. Oncol. 29(2), 985–993 (2012)PubMedCrossRefGoogle Scholar
  24. 24.
    Rozanski, W., Krzeslak, A., Forma, E., Brys, M., Blewniewski, M., Wozniak, P., Lipinski, M.: Prediction of bladder cancer based on urinary content of MGEA5 and OGT mRNA level. Clin Lab 58(5–6), 579–583 (2012)PubMedGoogle Scholar
  25. 25.
    Krzeslak, A., Wojcik-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. 83(1), 22–26 (2012)PubMedGoogle Scholar
  26. 26.
    Lynch, T.P., Ferrer, C.M., Jackson, S.R., Shahriari, K.S., Vosseller, K., Reginato, M.J.: Critical role of O-Linked beta-N-acetylglucosamine transferase in prostate cancer invasion, angiogenesis, and metastasis. J. Biol. Chem. 287(14), 11070–11081 (2012)PubMedCentralPubMedCrossRefGoogle Scholar
  27. 27.
    Shi, Y., Tomic, J., Wen, F., Shaha, S., Bahlo, A., Harrison, R., Dennis, J.W., Williams, R., Gross, B.J., Walker, S., Zuccolo, J., Deans, J.P., Hart, G.W., Spaner, D.E.: Aberrant O-GlcNAcylation characterizes chronic lymphocytic leukemia. Leukemia 24(9), 1588–1598 (2010)PubMedCrossRefGoogle Scholar
  28. 28.
    Ma, Z., Vocadlo, D.J., Vosseller, K.: Hyper-O-GlcNAcylation is anti-apoptotic and maintains constitutive NF-kappaB activity in pancreatic cancer cells. J. Biol. Chem. 288(21), 15121–15130 (2013)PubMedCrossRefGoogle Scholar
  29. 29.
    Yi, W., Clark, P.M., Mason, D.E., Keenan, M.C., Hill, C., Goddard 3rd, W.A., Peters, E.C., Driggers, E.M., Hsieh-Wilson, L.C.: Phosphofructokinase 1 glycosylation regulates cell growth and metabolism. Science 337(6097), 975–980 (2012)PubMedCentralPubMedCrossRefGoogle Scholar
  30. 30.
    Caldwell, S.A., Jackson, S.R., Shahriari, K.S., Lynch, T.P., Sethi, G., Walker, S., Vosseller, K., Reginato, M.J.: Nutrient sensor O-GlcNAc transferase regulates breast cancer tumorigenesis through targeting of the oncogenic transcription factor FoxM1. Oncogene 29(19), 2831–2842 (2010)PubMedCrossRefGoogle Scholar
  31. 31.
    Yang, W.H., Kim, J.E., Nam, H.W., Ju, J.W., Kim, H.S., Kim, Y.S., Cho, J.W.: Modification of p53 with O-linked N-acetylglucosamine regulates p53 activity and stability. Nat. Cell Biol. 8(10), 1074–1083 (2006)PubMedCrossRefGoogle Scholar
  32. 32.
    Yang, X., Su, K., Roos, M.D., Chang, Q., Paterson, A.J., Kudlow, J.E.: O-linkage of N-acetylglucosamine to Sp1 activation domain inhibits its transcriptional capability. Proc. Natl. Acad. Sci. U. S. A. 98(12), 6611–6616 (2001)PubMedCentralPubMedCrossRefGoogle Scholar
  33. 33.
    Chou, T.Y., Hart, G.W., Dang, C.V.: c-Myc is glycosylated at threonine 58, a known phosphorylation site and a mutational hot spot in lymphomas. J. Biol. Chem. 270(32), 18961–18965 (1995)PubMedCrossRefGoogle Scholar
  34. 34.
    Yang, W.H., Park, S.Y., Nam, H.W., do Kim, H., Kang, J.G., Kang, E.S., Kim, Y.S., Lee, H.C., Kim, K.S., Cho, J.W.: NFkappaB activation is associated with its O-GlcNAcylation state under hyperglycemic conditions. Proc. Natl. Acad. Sci. U. S. A. 105(45), 17345–17350 (2008)PubMedCentralPubMedCrossRefGoogle Scholar
  35. 35.
    Moore, J.P., Hancock, D.C., Littlewood, T.D., Evan, G.I.: A sensitive and quantitative enzyme-linked immunosorbence assay for the c-myc and N-myc oncoproteins. Oncogene Res 2(1), 65–80 (1987)PubMedGoogle Scholar
  36. 36.
    Gregory, M.A., Qi, Y., Hann, S.R.: Phosphorylation by glycogen synthase kinase-3 controls c-myc proteolysis and subnuclear localization. J. Biol. Chem. 278(51), 51606–51612 (2003)PubMedCrossRefGoogle Scholar
  37. 37.
    Itkonen, H.M., Minner, S., Guldvik, I.J., Sandmann, M.J., Tsourlakis, M.C., Berge, V., Svindland, A., Schlomm, T., Mills, I.G.: O-GlcNAc transferase integrates metabolic pathways to regulate the stability of c-MYC in human prostate cancer cells. Cancer Res. 73(16), 5277–5287 (2013)PubMedCrossRefGoogle Scholar
  38. 38.
    Kruse, J.P., Gu, W.: Modes of p53 regulation. Cell 137(4), 609–622 (2009)PubMedCentralPubMedCrossRefGoogle Scholar
  39. 39.
    Dai, C., Gu, W.: p53 post-translational modification: deregulated in tumorigenesis. Trends Mol. Med. 16(11), 528–536 (2010)PubMedCentralPubMedCrossRefGoogle Scholar
  40. 40.
    Ide, T., Brown-Endres, L., Chu, K., Ongusaha, P.P., Ohtsuka, T., El-Deiry, W.S., Aaronson, S.A., Lee, S.W.: GAMT, a p53-inducible modulator of apoptosis, is critical for the adaptive response to nutrient stress. Mol. Cell 36(3), 379–392 (2009)PubMedCentralPubMedCrossRefGoogle Scholar
  41. 41.
    Bensaad, K., Tsuruta, A., Selak, M.A., Vidal, M.N., Nakano, K., Bartrons, R., Gottlieb, E., Vousden, K.H.: TIGAR, a p53-inducible regulator of glycolysis and apoptosis. Cell 126(1), 107–120 (2006)PubMedCrossRefGoogle Scholar
  42. 42.
    Kondoh, H., Lleonart, M.E., Gil, J., Wang, J., Degan, P., Peters, G., Martinez, D., Carnero, A., Beach, D.: Glycolytic enzymes can modulate cellular life span. Cancer Res. 65(1), 177–185 (2005)PubMedGoogle Scholar
  43. 43.
    Matoba, S., Kang, J.G., Patino, W.D., Wragg, A., Boehm, M., Gavrilova, O., Hurley, P.J., Bunz, F., Hwang, P.M.: p53 regulates mitochondrial respiration. Science 312(5780), 1650–1653 (2006)PubMedCrossRefGoogle Scholar
  44. 44.
    Brosh, R., Rotter, V.: When mutants gain new powers: news from the mutant p53 field. Nat. Rev. Cancer 9(10), 701–713 (2009)PubMedGoogle Scholar
  45. 45.
    Oren, M., Rotter, V.: Mutant p53 gain-of-function in cancer. Cold Spring Harb. Perspect. Biol. 2(2), a001107 (2010)PubMedCentralPubMedCrossRefGoogle Scholar
  46. 46.
    Rivlin, N., Brosh, R., Oren, M., Rotter, V.: Mutations in the p53 tumor suppressor gene: important milestones at the various steps of tumorigenesis. Genes Cancer 2(4), 466–474 (2011)PubMedCentralPubMedCrossRefGoogle Scholar
  47. 47.
    Bensaad, K., Vousden, K.H.: p53: new roles in metabolism. Trends Cell Biol. 17(6), 286–291 (2007)PubMedCrossRefGoogle Scholar
  48. 48.
    Karin, M.: Nuclear factor-kappaB in cancer development and progression. Nature 441(7092), 431–436 (2006)PubMedCrossRefGoogle Scholar
  49. 49.
    Perkins, N.D.: The diverse and complex roles of NF-kappaB subunits in cancer. Nat. Rev. Cancer 12(2), 121–132 (2012)PubMedGoogle Scholar
  50. 50.
    Kawauchi, K., Araki, K., Tobiume, K., Tanaka, N.: p53 regulates glucose metabolism through an IKK-NF-kappaB pathway and inhibits cell transformation. Nat. Cell Biol. 10(5), 611–618 (2008)PubMedCrossRefGoogle Scholar
  51. 51.
    Johnson, R.F., Witzel, I.I., Perkins, N.D.: p53-dependent regulation of mitochondrial energy production by the RelA subunit of NF-kappaB. Cancer Res. 71(16), 5588–5597 (2011)PubMedCentralPubMedCrossRefGoogle Scholar
  52. 52.
    Kawauchi, K., Araki, K., Tobiume, K., Tanaka, N.: Loss of p53 enhances catalytic activity of IKKbeta through O-linked beta-N-acetyl glucosamine modification. Proc. Natl. Acad. Sci. U. S. A. 106(9), 3431–3436 (2009)PubMedCentralPubMedCrossRefGoogle Scholar
  53. 53.
    Tong, X., Zhao, F., Mancuso, A., Gruber, J.J., Thompson, C.B.: The glucose-responsive transcription factor ChREBP contributes to glucose-dependent anabolic synthesis and cell proliferation. Proc. Natl. Acad. Sci. U. S. A. 106(51), 21660–21665 (2009)PubMedCentralPubMedCrossRefGoogle Scholar
  54. 54.
    Ma, L., Robinson, L.N., Towle, H.C.: ChREBP*Mlx is the principal mediator of glucose-induced gene expression in the liver. J. Biol. Chem. 281(39), 28721–28730 (2006)PubMedCrossRefGoogle Scholar
  55. 55.
    Sakiyama, H., Fujiwara, N., Noguchi, T., Eguchi, H., Yoshihara, D., Uyeda, K., Suzuki, K.: The role of O-linked GlcNAc modification on the glucose response of ChREBP. Biochem. Biophys. Res. Commun. 402(4), 784–789 (2010)PubMedCrossRefGoogle Scholar
  56. 56.
    Guinez, C., Filhoulaud, G., Rayah-Benhamed, F., Marmier, S., Dubuquoy, C., Dentin, R., Moldes, M., Burnol, A.F., Yang, X., Lefebvre, T., Girard, J., Postic, C.: O-GlcNAcylation increases ChREBP protein content and transcriptional activity in the liver. Diabetes 60(5), 1399–1413 (2011)PubMedCentralPubMedCrossRefGoogle Scholar
  57. 57.
    Clark, P.M., Dweck, J.F., Mason, D.E., Hart, C.R., Buck, S.B., Peters, E.C., Agnew, B.J., Hsieh-Wilson, L.C.: Direct in-gel fluorescence detection and cellular imaging of O-GlcNAc-modified proteins. J. Am. Chem. Soc. 130(35), 11576–11577 (2008)PubMedCentralPubMedCrossRefGoogle Scholar
  58. 58.
    Moens, U., Kostenko, S.: Structure and function of MK5/PRAK: the loner among the mitogen-activated protein kinase-activated protein kinases. Biol. Chem. 394(9), 1115–1132 (2013)PubMedCrossRefGoogle Scholar
  59. 59.
    Sebolt-Leopold, J.S.: Advances in the development of cancer therapeutics directed against the RAS-mitogen-activated protein kinase pathway. Clin. Cancer Res. 14(12), 3651–3656 (2008)PubMedCrossRefGoogle Scholar
  60. 60.
    Kneass, Z.T., Marchase, R.B.: Protein O-GlcNAc modulates motility-associated signaling intermediates in neutrophils. J. Biol. Chem. 280(15), 14579–14585 (2005)PubMedCrossRefGoogle Scholar
  61. 61.
    Olivier-Van Stichelen, S., Drougat, L., Dehennaut, V., El Yazidi-Belkoura, I., Guinez, C., Mir, A.M., Michalski, J.C., Vercoutter-Edouart, A.S., Lefebvre, T.: Serum-stimulated cell cycle entry promotes ncOGT synthesis required for cyclin D expression. Oncogenesis 1, e36 (2012)PubMedCentralPubMedCrossRefGoogle Scholar
  62. 62.
    Dehennaut, V., Slomianny, M.C., Page, A., Vercoutter-Edouart, A.S., Jessus, C., Michalski, J.C., Vilain, J.P., Bodart, J.F., Lefebvre, T.: Identification of structural and functional O-linked N-acetylglucosamine-bearing proteins in Xenopus laevis oocyte. Mol. Cell. Proteomics 7(11), 2229–2245 (2008)PubMedCrossRefGoogle Scholar
  63. 63.
    Neckers, L.: Using natural product inhibitors to validate Hsp90 as a molecular target in cancer. Curr. Top. Med. Chem. 6(11), 1163–1171 (2006)PubMedCrossRefGoogle Scholar
  64. 64.
    Fardini, Y., Dehennaut, V., Lefebvre, T., Issad, T.: O-GlcNAcylation: a new cancer hallmark? Front. Endocrinol. (Lausanne) 4, 99 (2013)Google Scholar
  65. 65.
    Nandi, A., Sprung, R., Barma, D.K., Zhao, Y., Kim, S.C., Falck, J.R.: Global identification of O-GlcNAc-modified proteins. Anal. Chem. 78(2), 452–458 (2006)PubMedCrossRefGoogle Scholar
  66. 66.
    Perez-Cervera, Y., Dehennaut, V., Aquino Gil, M., Guedri, K., Solorzano Mata, C.J., Olivier-Van Stichelen, S., Michalski, J.C., Foulquier, F., Lefebvre, T.: Insulin signaling controls the expression of O-GlcNAc transferase and its interaction with lipid microdomains. FASEB J. 27(9), 3478–3486 (2013)PubMedCrossRefGoogle Scholar
  67. 67.
    Kanwal, S., Fardini, Y., Pagesy, P., N’Tumba-Byn, T., Pierre-Eugene, C., Masson, E., Hampe, C., Issad, T.: O-GlcNAcylation-inducing treatments inhibit estrogen receptor alpha expression and confer resistance to 4-OH-tamoxifen in human breast cancer-derived MCF-7 cells. PLoS One 8(7), e69150 (2013)PubMedCentralPubMedCrossRefGoogle Scholar
  68. 68.
    Fay, J.R., Steele, V., Crowell, J.A.: Energy homeostasis and cancer prevention: the AMP-activated protein kinase. Cancer Prev. Res. (Phila) 2(4), 301–309 (2009)CrossRefGoogle Scholar
  69. 69.
    Faubert, B., Boily, G., Izreig, S., Griss, T., Samborska, B., Dong, Z., Dupuy, F., Chambers, C., Fuerth, B.J., Viollet, B., Mamer, O.A., Avizonis, D., DeBerardinis, R.J., Siegel, P.M., Jones, R.G.: AMPK is a negative regulator of the Warburg effect and suppresses tumor growth in vivo. Cell Metab. 17(1), 113–124 (2013)PubMedCentralPubMedCrossRefGoogle Scholar
  70. 70.
    Luo, B., Parker, G.J., Cooksey, R.C., Soesanto, Y., Evans, M., Jones, D., McClain, D.A.: Chronic hexosamine flux stimulates fatty acid oxidation by activating AMP-activated protein kinase in adipocytes. J. Biol. Chem. 282(10), 7172–7180 (2007)PubMedCrossRefGoogle Scholar
  71. 71.
    Cheung, W.D., Hart, G.W.: AMP-activated protein kinase and p38 MAPK activate O-GlcNAcylation of neuronal proteins during glucose deprivation. J. Biol. Chem. 283(19), 13009–13020 (2008)PubMedCentralPubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2013

Authors and Affiliations

  1. 1.Institute of Biochemistry, College of Life SciencesZhejiang UniversityHangzhouChina
  2. 2.Collaborative Innovation Center for Diagnosis and Treatment of Infectious DiseasesHangzhouChina

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