Advertisement

Reciprocal Modulation of Terminal Sialylation and Bisecting N-Glycans: A New Axis of Cancer-Cell Glycome Regulation?

  • Ana Magalhães
    Affiliations
    i3S-Instituto de Investigação e Inovação em Saúde, Porto, Portugal

    Institute of Molecular Pathology and Immunology, University of Porto-IPATIMUP, Porto, Portugal
    Search for articles by this author
  • Stefan Mereiter
    Affiliations
    i3S-Instituto de Investigação e Inovação em Saúde, Porto, Portugal

    Institute of Molecular Pathology and Immunology, University of Porto-IPATIMUP, Porto, Portugal

    Institute of Biomedical Sciences of Abel Salazar-ICBAS, Porto, Portugal
    Search for articles by this author
  • Celso Reis
    Affiliations
    i3S-Instituto de Investigação e Inovação em Saúde, Porto, Portugal

    Institute of Molecular Pathology and Immunology, University of Porto-IPATIMUP, Porto, Portugal

    Institute of Biomedical Sciences of Abel Salazar-ICBAS, Porto, Portugal

    Medical Faculty, University of Porto, Porto, Portugal
    Search for articles by this author
Open AccessPublished:April 08, 2016DOI:https://doi.org/10.1074/jbc.L116.722462
      Lu et al. (
      • Lu J.
      • Isaji T.
      • Im S.
      • Fukuda T.
      • Kameyama A.
      • Gu J.
      Expression of N-acetylglucosaminyltransferase III suppresses α2,3-sialylation and its distinctive functions in cell migration are attributed to α2,6-sialylation levels.
      ) have investigated the influence of cellular sialylation on the GnT-III-mediated regulation of cancer cell metastatic potential. The authors demonstrated that GnT-III (GlcNAc-bisecting glycosyltransferase) overexpression results in a significant reduction of α2,3-sialylation, with no major alteration of α2,6-sialylation (
      • Lu J.
      • Isaji T.
      • Im S.
      • Fukuda T.
      • Kameyama A.
      • Gu J.
      Expression of N-acetylglucosaminyltransferase III suppresses α2,3-sialylation and its distinctive functions in cell migration are attributed to α2,6-sialylation levels.
      ). Interestingly, a reciprocal correlation between terminal α2,3-sialylation and bisected N-glycans has also been recently reported (
      • Mereiter S.
      • Magalhães A.
      • Adamczyk B.
      • Jin C.
      • Almeida A.
      • Drici L.
      • Ibáñez-Vea M.
      • Gomes C.
      • Ferreira J.A.
      • Afonso L.P.
      • Santos L.L.
      • Larsen M.R.
      • Kolarich D.
      • Karlsson N.G.
      • Reis C.A.
      Glycomic analysis of gastric carcinoma cells discloses glycans as modulators of RON receptor tyrosine kinase activation in cancer.
      ). Glycomic analysis of cancer cells overexpressing the α2,3-sialyltransferase ST3GAL4 showed that increased terminal α2,3-sialylation is accompanied by a substantial loss of bisected N-glycans (
      • Mereiter S.
      • Magalhães A.
      • Adamczyk B.
      • Jin C.
      • Almeida A.
      • Drici L.
      • Ibáñez-Vea M.
      • Gomes C.
      • Ferreira J.A.
      • Afonso L.P.
      • Santos L.L.
      • Larsen M.R.
      • Kolarich D.
      • Karlsson N.G.
      • Reis C.A.
      Glycomic analysis of gastric carcinoma cells discloses glycans as modulators of RON receptor tyrosine kinase activation in cancer.
      ).
      This coordinated regulation of α2,3-sialylation by bisecting N-glycans and vice versa adds a new level of complexity to the regulation of the cancer cell glycome and raises new questions about the molecular mechanisms underlying these glycosylation shifts. Noteworthy,the down-regulation of bisected N-glycans and α2,3-sialylation by ST3GAL4 and GnT-III, respectively, do not stem from alterations at the glycosyltransferase transcript levels (
      • Lu J.
      • Isaji T.
      • Im S.
      • Fukuda T.
      • Kameyama A.
      • Gu J.
      Expression of N-acetylglucosaminyltransferase III suppresses α2,3-sialylation and its distinctive functions in cell migration are attributed to α2,6-sialylation levels.
      ,
      • Mereiter S.
      • Magalhães A.
      • Adamczyk B.
      • Jin C.
      • Almeida A.
      • Drici L.
      • Ibáñez-Vea M.
      • Gomes C.
      • Ferreira J.A.
      • Afonso L.P.
      • Santos L.L.
      • Larsen M.R.
      • Kolarich D.
      • Karlsson N.G.
      • Reis C.A.
      Glycomic analysis of gastric carcinoma cells discloses glycans as modulators of RON receptor tyrosine kinase activation in cancer.
      ). The supramolecular organization of the Golgi glycosylation pathways is plastic and can be altered in cancer cells (
      • Hassinen A.
      • Pujol F.M.
      • Kokkonen N.
      • Pieters C.
      • Kihlström M.
      • Korhonen K.
      • Kellokumpu S.
      Functional organization of Golgi N- and O-glycosylation pathways involves pH-dependent complex formation that is impaired in cancer cells.
      ); thus, we can hypothesize that altered localization of the overexpressed glycosyltransferases could functionally impact the sequential glycan biosynthetic pathways and therefore interfere with bisecting N-glycans and terminal sialylation.
      Increased α2,3-sialylation is associated with malignancy and patients' poorer prognosis, whereas bisected N-glycans suppress metastization (
      • Pinho S.S.
      • Reis C.A.
      Glycosylation in cancer: mechanisms and clinical implications.
      ). Moreover, N-glycan branching and sialylation patterns determine galectin lattice dynamics with critical impact on tumor cell signaling and definition of aggressiveness features (
      • Croci D.O.
      • Cerliani J.P.
      • Dalotto-Moreno T.
      • Méndez-Huergo S.P.
      • Mascanfroni I.D.
      • Dergan-Dylon S.
      • Toscano M.A.
      • Caramelo J.J.
      • García-Vallejo J.J.
      • Ouyang J.
      • Mesri E.A.
      • Junttila M.R.
      • Bais C.
      • Shipp M.A.
      • Salatino M.
      • Rabinovich G.A.
      Glycosylation-dependent lectin-receptor interactions preserve angiogenesis in anti-VEGF refractory tumors.
      ). Therefore, deciphering the mechanisms underlying reciprocal regulation of terminal sialylation and bisecting N-glycans is fundamental for our understanding of tumor cell biology.

      References

        • Lu J.
        • Isaji T.
        • Im S.
        • Fukuda T.
        • Kameyama A.
        • Gu J.
        Expression of N-acetylglucosaminyltransferase III suppresses α2,3-sialylation and its distinctive functions in cell migration are attributed to α2,6-sialylation levels.
        J. Biol. Chem. 2016; 291: 5708-5720
        • Mereiter S.
        • Magalhães A.
        • Adamczyk B.
        • Jin C.
        • Almeida A.
        • Drici L.
        • Ibáñez-Vea M.
        • Gomes C.
        • Ferreira J.A.
        • Afonso L.P.
        • Santos L.L.
        • Larsen M.R.
        • Kolarich D.
        • Karlsson N.G.
        • Reis C.A.
        Glycomic analysis of gastric carcinoma cells discloses glycans as modulators of RON receptor tyrosine kinase activation in cancer.
        Biochim. Biophys. Acta. 2015;
        • Hassinen A.
        • Pujol F.M.
        • Kokkonen N.
        • Pieters C.
        • Kihlström M.
        • Korhonen K.
        • Kellokumpu S.
        Functional organization of Golgi N- and O-glycosylation pathways involves pH-dependent complex formation that is impaired in cancer cells.
        J. Biol. Chem. 2011; 286: 38329-38340
        • Pinho S.S.
        • Reis C.A.
        Glycosylation in cancer: mechanisms and clinical implications.
        Nat. Rev. Cancer. 2015; 15: 540-555
        • Croci D.O.
        • Cerliani J.P.
        • Dalotto-Moreno T.
        • Méndez-Huergo S.P.
        • Mascanfroni I.D.
        • Dergan-Dylon S.
        • Toscano M.A.
        • Caramelo J.J.
        • García-Vallejo J.J.
        • Ouyang J.
        • Mesri E.A.
        • Junttila M.R.
        • Bais C.
        • Shipp M.A.
        • Salatino M.
        • Rabinovich G.A.
        Glycosylation-dependent lectin-receptor interactions preserve angiogenesis in anti-VEGF refractory tumors.
        Cell. 2014; 156: 744-758