Skip to main content

Advertisement

SpringerLink
Log in

The effect of epigenetic regulation of fucosylation on TRAIL-induced apoptosis

  • Published:
Glycoconjugate Journal Aims and scope Submit manuscript

Abstract

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) induces apoptosis in many cancer cells but not in normal ones. Recombinant TRAIL and agonistic antibodies to its cognate receptors are currently being studied as promising anticancer drugs. However, preclinical and clinical studies have shown that many types of human cancers are resistant to TRAIL agonists. We previously reported that a deficiency of fucosylation, which is one of the most common oligosaccharide modifications, leads to resistance to TRAIL-induced apoptosis. In contrast, DNA methylation is associated with silencing of various tumor suppressor genes and resistance of cancer cells to anticancer drugs. The aim of this study is to clarify the involvement of DNA methylation in the regulation of cellular fucosylation and the susceptibility to TRAIL-induced apoptosis. When nineteen cancer cell lines with relatively low fucosylation levels were treated with a novel methyltransferase inhibitor, zebularine, an increase in the fucosylation level was observed in many cancer cell lines. The expression of fucosylation-related genes, such as the FX, GDP-fucose transporter, and Fut4 genes, was significantly increased after the treatment with zebularine. Moreover, a synergistic effect of zebularine on TRAIL-induced apoptosis was observed in several cancer cell lines, in which fucosylation was increased by treatment with zebularine. This synergistic effect was independent of the expression of TRAIL receptors and caspase-8. These results indicate that cellular fucosylation is regulated through DNA methylation in many cancer cells. Moreover, zebularine might be useful as a combination drug with TRAIL-based therapies in patients with TRAIL-resistant cancer.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6

Similar content being viewed by others

Abbreviations

TRAIL:

Tumor necrosis factor-related apoptosis-inducing ligand

AAL:

Aleuria aurantia lectin

GMDS:

GDP-mannose-4,6-dehydratase

AFP:

alpha-fetoprotein

GDP-fucose:

guanosin 5′-diphosphate-fucose

GDP-Fuc Tr:

GDP-fucose transporter

References

  1. Ohtsubo, K., Marth, J.D.: Glycosylation in cellular mechanisms of health and disease. Cell 126, 855–867 (2006)

    Article  CAS  PubMed  Google Scholar 

  2. Haltiwanger, R.S., Lowe, J.B.: Role of glycosylation in development. Annu. Rev. Biochem. 73, 491–537 (2004)

    Article  CAS  PubMed  Google Scholar 

  3. Hakomori, S.: Aberrant glycosylation in tumors and tumor-associated carbohydrate antigens. Adv. Cancer Res. 52, 257–331 (1989)

    Article  CAS  PubMed  Google Scholar 

  4. Miyoshi, E., Moriwaki, K., Nakagawa, T.: Biological function of fucosylation in cancer biology. J. Biochem. 143, 725–729 (2008)

    Article  CAS  PubMed  Google Scholar 

  5. Alpert, M.E., Uriel, J., de Nechaud, B.: Alpha-1 fetoglobulin in the diagnosis of human hepatoma. N. Engl. J. Med. 278, 984–986 (1968)

    Article  CAS  PubMed  Google Scholar 

  6. Aoyagi, Y., Isemura, M., Suzuki, Y., Sekine, C., Soga, K., Ozaki, T., Ichida, F.: Fucosylated alpha-fetoprotein as marker of early hepatocellular carcinoma. Lancet 2, 1353–1354 (1985)

    Article  CAS  PubMed  Google Scholar 

  7. Aoyagi, Y., Isemura, M., Suzuki, Y., Sekine, C., Soga, K., Ozaki, T., Ichida, F.: Change in fucosylation of alpha-fetoprotein on malignant transformation of liver cells. Lancet 1, 210 (1986)

    Article  CAS  PubMed  Google Scholar 

  8. Food and Drug Administration, HHS: Medical devices; immunology and microbiology devices; classification of AFP-L3% immunological test systems. Final rule. Fed. Regist. 70, 57748–57750 (2005)

    Google Scholar 

  9. Ohyama, C., Smith, P.L., Angata, K., Fukuda, M.N., Lowe, J.B., Fukuda, M.: Molecular cloning and expression of GDP-D-mannose-4, 6-dehydratase, a key enzyme for fucose metabolism defective in Lec13 cells. J. Biol. Chem. 273, 14582–14587 (1998)

    Article  CAS  PubMed  Google Scholar 

  10. Sullivan, F.X., Kumar, R., Kriz, R., Stahl, M., Xu, G.Y., Rouse, J., Chang, X.J., Boodhoo, A., Potvin, B., Cumming, D.A.: Molecular cloning of human GDP-mannose 4, 6-dehydratase and reconstitution of GDP-fucose biosynthesis in vitro. J. Biol. Chem. 273, 8193–8202 (1998)

    Article  CAS  PubMed  Google Scholar 

  11. Tonetti, M., Sturla, L., Bisso, A., Benatti, U., De Flora, A.: Synthesis of GDP-L-fucose by the human FX protein. J. Biol. Chem. 271, 27274–27279 (1996)

    Article  CAS  PubMed  Google Scholar 

  12. Smith, P.L., Myers, J.T., Rogers, C.E., Zhou, L., Petryniak, B., Becker, D.J., Homeister, J.W., Lowe, J.B.: Conditional control of selectin ligand expression and global fucosylation events in mice with a targeted mutation at the FX locus. J. Cell Biol. 158, 801–815 (2002)

    Article  CAS  PubMed  Google Scholar 

  13. Lübke, T., Marquardt, T., Etzioni, A., Hartmann, E., von Figura, K., Körner, C.: Complementation cloning identifies CDG-IIc, a new type of congenital disorders of glycosylation, as a GDP-fucose transporter deficiency. Nat. Genet. 28, 73–76 (2001)

    Article  PubMed  Google Scholar 

  14. Lühn, K., Wild, M.K., Eckhardt, M., Gerardy-Schahn, R., Vestweber, D.: The gene defective in leukocyte adhesion deficiency II encodes a putative GDP-fucose transporter. Nat. Genet. 28, 69–72 (2001)

    Article  PubMed  Google Scholar 

  15. Noda, K., Miyoshi, E., Gu, J., Gao, C.X., Nakahara, S., Kitada, T., Honke, K., Suzuki, K., Yoshihara, H., Yoshikawa, K., Kawano, K., Tonetti, M., Kasahara, A., Hori, M., Hayashi, N., Taniguchi, N.: Relationship between elevated FX expression and increased production of GDP-L-fucose, a common donor substrate for fucosylation in human hepatocellular carcinoma and hepatoma cell lines. Cancer Res. 63, 6282–6289 (2003)

    CAS  PubMed  Google Scholar 

  16. Moriwaki, K., Noda, K., Nakagawa, T., Asahi, M., Yoshihara, H., Taniguchi, N., Hayashi, N., Miyoshi, E.: A high expression of GDP-fucose transporter in hepatocellular carcinoma is a key factor for increases in fucosylation. Glycobiology 17, 1311–1320 (2007)

    Article  CAS  PubMed  Google Scholar 

  17. Okuyama, N., Ide, Y., Nakano, M., Nakagawa, T., Yamanaka, K., Moriwaki, K., Murata, K., Ohigashi, H., Yokoyama, S., Eguchi, H., Ishikawa, O., Ito, T., Kato, M., Kasahara, A., Kawano, S., Gu, J., Taniguchi, N., Miyoshi, E.: Fucosylated haptoglobin is a novel marker for pancreatic cancer: a detailed analysis of the oligosaccharide structure and a possible mechanism for fucosylation. Int. J. Cancer 118, 2803–2808 (2006)

    Article  CAS  PubMed  Google Scholar 

  18. Narisada, M., Kawamoto, S., Kuwamoto, K., Moriwaki, K., Nakagawa, T., Matsumoto, H., Asahi, M., Koyama, N., Miyoshi, E.: Identification of an inducible factor secreted by pancreatic cancer cell lines that stimulates the production of fucosylated haptoglobin in hepatoma cells. Biochem. Biophys. Res. Commun. 377, 792–796 (2008)

    Article  CAS  PubMed  Google Scholar 

  19. Wiley, S.R., Schooley, K., Smolak, P.J., Din, W.S., Huang, C.P., Nicholl, J.K., Sutherland, G.R., Smith, T.D., Rauch, C., Smith, C.A., et al.: Identification and characterization of a new member of the TNF family that induces apoptosis. Immunity 3, 673–682 (1995)

    Article  CAS  PubMed  Google Scholar 

  20. Takeda, K., Hayakawa, Y., Smyth, M.J., Kayagaki, N., Yamaguchi, N., Kakuta, S., Iwakura, Y., Yagita, H., Okumura, K.: Involvement of tumor necrosis factor-related apoptosis-inducing ligand in surveillance of tumor metastasis by liver natural killer cells. Nat. Med. 7, 94–100 (2001)

    Article  CAS  PubMed  Google Scholar 

  21. Ashkenazi, A., Herbst, R.S.: To kill a tumor cell: the potential of proapoptotic receptor agonists. J. Clin. Invest. 118, 1979–1990 (2008)

    Article  CAS  PubMed  Google Scholar 

  22. Ashkenazi, A.: Directing cancer cells to self-destruct with pro-apoptotic receptor agonists. Nat. Rev. Drug Discov. 7, 1001–1012 (2008)

    Article  CAS  PubMed  Google Scholar 

  23. Johnstone, R.W., Frew, A.J., Smyth, M.J.: The TRAIL apoptotic pathway in cancer onset, progression and therapy. Nat. Rev. Cancer 8, 782–798 (2008)

    Article  CAS  PubMed  Google Scholar 

  24. Moriwaki, K., Noda, K., Furukawa, Y., Ohshima, K., Uchiyama, A., Nakagawa, T., Taniguchi, N., Daigo, Y., Nakamura, Y., Hayashi, N., Miyoshi, E.: Deficiency of GMDS leads to escape from NK cell-mediated tumor surveillance through modulation of TRAIL signaling. Gastroenterology 137, 188–198 (2009)

    Article  CAS  PubMed  Google Scholar 

  25. Herman, J.G., Baylin, S.B.: Gene silencing in cancer in association with promoter hypermethylation. N Engl. J. Med. 349, 2042–2054 (2003)

    Article  CAS  PubMed  Google Scholar 

  26. Jones, P.A., Baylin, S.B.: The epigenomics of cancer. Cell 128, 683–692 (2007)

    Article  CAS  PubMed  Google Scholar 

  27. Kannagi, R., Yin, J., Miyazaki, K., Izawa, M.: Current relevance of incomplete synthesis and neo-synthesis for cancer-associated alteration of carbohydrate determinants–Hakomori’s concepts revisited. Biochim. Biophys. Acta 1780, 525–531 (2008)

    CAS  PubMed  Google Scholar 

  28. Kawamura, Y.I., Toyota, M., Kawashima, R., Hagiwara, T., Suzuki, H., Imai, K., Shinomura, Y., Tokino, T., Kannagi, R., Dohi, T.: DNA hypermethylation contributes to incomplete synthesis of carbohydrate determinants in gastrointestinal cancer. Gastroenterology 135, 142–151 (2008)

    Article  CAS  PubMed  Google Scholar 

  29. Cheng, J.C., Yoo, C.B., Weisenberger, D.J., Chuang, J., Wozniak, C., Liang, G., Marquez, V.E., Greer, S., Orntoft, T.F., Thykjaer, T., Jones, P.A.: Preferential response of cancer cells to zebularine. Cancer Cell 6, 151–158 (2004)

    Article  CAS  PubMed  Google Scholar 

  30. Elias, A., Siegelin, M.D., Steinmüller, A., von Deimling, A., Lass, U., Korn, B., Mueller, W.: Epigenetic silencing of death receptor 4 mediates tumor necrosis factor-related apoptosis-inducing ligand resistance in gliomas. Clin. Cancer Res. 15, 5457–5465 (2009)

    Article  CAS  PubMed  Google Scholar 

  31. Bae, S.I., Cheriyath, V., Jacobs, B.S., Reu, F.J., Borden, E.C.: Reversal of methylation silencing of Apo2L/TRAIL receptor 1 (DR4) expression overcomes resistance of SK-MEL-3 and SK-MEL-28 melanoma cells to interferons (IFNs) or Apo2L/TRAIL. Oncogene 27, 490–498 (2008)

    Article  CAS  PubMed  Google Scholar 

  32. Horak, P., Pils, D., Haller, G., Pribill, I., Roessler, M., Tomek, S., Horvat, R., Zeillinger, R., Zielinski, C., Krainer, M.: Contribution of epigenetic silencing of tumor necrosis factor-related apoptosis inducing ligand receptor 1 (DR4) to TRAIL resistance and ovarian cancer. Mol. Cancer Res. 3, 335–343 (2005)

    Article  CAS  PubMed  Google Scholar 

  33. Fulda, S., Debatin, K.M.: 5-Aza-2′-deoxycytidine and IFN-gamma cooperate to sensitize for TRAIL-induced apoptosis by upregulating caspase-8. Oncogene 25, 5125–5133 (2006)

    Article  CAS  PubMed  Google Scholar 

  34. Hopkins-Donaldson, S., Ziegler, A., Kurtz, S., Bigosch, C., Kandioler, D., Ludwig, C., Zangemeister-Wittke, U., Stahel, R.: Silencing of death receptor and caspase-8 expression in small cell lung carcinoma cell lines and tumors by DNA methylation. Cell Death Differ. 10, 356–364 (2003)

    Article  CAS  PubMed  Google Scholar 

  35. Fulda, S., Küfer, M.U., Meyer, E., van Valen, F., Dockhorn-Dworniczak, B., Debatin, K.M.: Sensitization for death receptor- or drug-induced apoptosis by re-expression of caspase-8 through demethylation or gene transfer. Oncogene 20, 5865–5877 (2001)

    Article  CAS  PubMed  Google Scholar 

  36. Eggert, A., Grotzer, M.A., Zuzak, T.J., Wiewrodt, B.R., Ho, R., Ikegaki, N., Brodeur, G.M.: Resistance to tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-induced apoptosis in neuroblastoma cells correlates with a loss of caspase-8 expression. Cancer Res. 61, 1314–1319 (2001)

    CAS  PubMed  Google Scholar 

  37. Grotzer, M.A., Eggert, A., Zuzak, T.J., Janss, A.J., Marwaha, S., Wiewrodt, B.R., Ikegaki, N., Brodeur, G.M., Phillips, P.C.: Resistance to TRAIL-induced apoptosis in primitive neuroectodermal brain tumor cells correlates with a loss of caspase-8 expression. Oncogene 19, 4604–4610 (2000)

    Article  CAS  PubMed  Google Scholar 

  38. Stresemann, C., Brueckner, B., Musch, T., Stopper, H., Lyko, F.: Functional diversity of DNA methyltransferase inhibitors in human cancer cell lines. Cancer Res. 66, 2794–2800 (2006)

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

This study was performed by a grant from the New Energy and Industrial Technology Development Organization (NEDO) as a part of the developing technology project on implementing sugar chain functions in Japan, a Grant-in-Aid for Scientific Research (A), No. 21249038, from the Japan Society for the Promotion of Science, a Grant-in-Aid for Cancer Research and Scientific Research on Priority Areas, No. 20014011, from the Ministry of Education, Science, and the Global COE program of Osaka University funded by the Ministry of Education, Culture, Sports, Science, and Technology of Japan.

Author information

Authors and Affiliations

  1. Department of Molecular Biochemistry and Clinical Investigation, Osaka University Graduate School of Medicine, 1-7 Yamada-oka, Suita, 565-0871, Japan

    Kenta Moriwaki, Megumi Narisada, Taku Imai, Shinichiro Shinzaki & Eiji Miyoshi

Authors
  1. Kenta Moriwaki
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Megumi Narisada
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Taku Imai
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Shinichiro Shinzaki
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Eiji Miyoshi
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Eiji Miyoshi.

Electronic Supplementary Material

Below is the link to the electronic supplementary material.

ESM 1

(PDF 855 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Moriwaki, K., Narisada, M., Imai, T. et al. The effect of epigenetic regulation of fucosylation on TRAIL-induced apoptosis. Glycoconj J 27, 649–659 (2010). https://doi.org/10.1007/s10719-010-9310-5

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10719-010-9310-5

Keywords

Search

Navigation