New Biomarker for Castration-Resistant Prostate Cancer: A Glycobiological Perspective

  • Shingo HatakeyamaEmail author
  • Tohru Yoneyama
  • Hayato Yamamoto
  • Yuki Tobisawa
  • Shin-Ichiro Nishimura
  • Chikara Ohyama


Cancer-associated glycan aberrations are frequently observed in tumors. Glycan alterations are reported to have potential as cancer biomarkers. An aberrant glycosylation and glycosyl epitope have been known to be tumor-associated antigens. In addition, changes in glycosyltransferase could be associated with the signal pathways. Detecting in aberrant glycosylation on prostate-specific antigen (α2,3-linked sialylation) may improve specificity in detection of prostate cancer. However, a practical procedure to analyze a large number of glycan samples quickly is not available for serum due to methodological problems. Recent progress in mass spectrometry has led to new challenges in glycan analysis including a chemo-selective glycan enrichment technology called glycoblotting to purify oligosaccharides from a crude glycoprotein mixture. Previous study suggested that triand tetra-antennary N-glycans were significantly higher in CRPC patients than in non-CRPC patients, and the expression of N-glycan branching enzyme genes was significantly upregulated in CRPC cell lines. These results suggest that the overexpression of triand tetra-antennary N-glycans may be associated with the castration-resistant status in prostate cancer and may be a potential predictive biomarker for CRPC. The incorporation of glycan biomarkers appears to be a promising approach for improving CRPC detection.


Prostate cancer Castration-resistant prostate cancer N-glycan Glycobiology 



This work was supported by a Grant-in-Aid for Scientific Research (No. 15H02563 15 K15579, 17 K11118, 17 K11119, 17 K16768, 17 K16770, and 17 K16771) from the Japan Society for the Promotion of Science.


  1. 1.
    Ishibashi Y, Tobisawa Y, Hatakeyama S, Ohashi T, Tanaka M, Narita S, et al. Serum triand tetra-antennary N-glycan is a potential predictive biomarker for castration-resistant prostate cancer. Prostate. 2014;74(15):1521–9. Scholar
  2. 2.
    Tsuboi S, Hatakeyama S, Ohyama C, Fukuda M. Two opposing roles of O-glycans in tumor metastasis. Trends Mol Med. 2012;18(4):224–32. Scholar
  3. 3.
    Kyan A, Kamimura N, Hagisawa S, Hatakeyama S, Koie T, Yoneyama T, et al. Positive expressions of N-acetylglucosaminyltransferase-V (GnT-V) and beta1-6 branching N-linked oligosaccharides in human testicular germ cells diminish during malignant transformation and progression. Int J Oncol. 2008;32(1):129–34.PubMedGoogle Scholar
  4. 4.
    Hatakeyama S, Amano M, Tobisawa Y, Yoneyama T, Tsushima M, Hirose K, et al. Serum N-glycan profiling predicts prognosis in patients undergoing hemodialysis. ScientificWorldJournal. 2013;2013:268407. Scholar
  5. 5.
    Sato T, Yoneyama T, Tobisawa Y, Hatakeyama S, Yamamoto H, Kojima Y, et al. Core 2 beta-1, 6-N-acetylglucosaminyltransferase-1 expression in prostate biopsy specimen is an indicator of prostate cancer aggressiveness. Biochem Biophys Res Commun. 2016;470(1):150–6. Scholar
  6. 6.
    Hatakeyama S, Yoneyama T, Tobisawa Y, Ohyama C. Recent progress and perspectives on prostate cancer biomarkers. Int J Clin Oncol. 2017;22(2):214–21. Scholar
  7. 7.
    Narita T, Hatakeyama S, Yoneyama T, Narita S, Yamashita S, Mitsuzuka K, et al. Clinical implications of serum N-glycan profiling as a diagnostic and prognostic biomarker in germ-cell tumors. Cancer Med. 2017;6(4):739–48. Scholar
  8. 8.
    Oikawa M, Hatakeyama S, Narita T, Yoneyama T, Tobisawa Y, Yamamoto H, et al. Significance of serum N-glycan profiling as a diagnostic biomarker in urothelial carcinoma. Eur Urol Focus. 2017.
  9. 9.
    Kita Y, Miura Y, Furukawa J, Nakano M, Shinohara Y, Ohno M, et al. Quantitative glycomics of human whole serum glycoproteins based on the standardized protocol for liberating N-glycans. Mol Cell Proteomics. 2007;6(8):1437–45. Scholar
  10. 10.
    Furukawa J, Shinohara Y, Kuramoto H, Miura Y, Shimaoka H, Kurogochi M, et al. Comprehensive approach to structural and functional glycomics based on chemoselective glycoblotting and sequential tag conversion. Anal Chem. 2008;80(4):1094–101. Scholar
  11. 11.
    Miura Y, Hato M, Shinohara Y, Kuramoto H, Furukawa J, Kurogochi M, et al. BlotGlycoABCTM, an integrated glycoblotting technique for rapid and large scale clinical glycomics. Mol Cell Proteomics. 2008;7(2):370–7. Scholar
  12. 12.
    Hakomori S. Tumor malignancy defined by aberrant glycosylation and sphingo(glyco)lipid metabolism. Cancer Res. 1996;56(23):5309–18.PubMedGoogle Scholar
  13. 13.
    Kyselova Z, Mechref Y, Al Bataineh MM, Dobrolecki LE, Hickey RJ, Vinson J, et al. Alterations in the serum glycome due to metastatic prostate cancer. J Proteome Res. 2007;6(5):1822–32. Scholar
  14. 14.
    Lee SH, Hatakeyama S, Yu SY, Bao X, Ohyama C, Khoo KH, et al. Core3 O-glycan synthase suppresses tumor formation and metastasis of prostate carcinoma PC3 and LNCaP cells through down-regulation of alpha2beta1 integrin complex. J Biol Chem. 2009;284(25):17157–69. Scholar
  15. 15.
    Hagisawa S, Ohyama C, Takahashi T, Endoh M, Moriya T, Nakayama J, et al. Expression of core 2 beta1,6-N-acetylglucosaminyltransferase facilitates prostate cancer progression. Glycobiology. 2005;15(10):1016–24. Scholar
  16. 16.
    Prakash S, Robbins PW. Glycotyping of prostate specific antigen. Glycobiology. 2000;10(2):173–6.CrossRefPubMedGoogle Scholar
  17. 17.
    Ohyama C, Hosono M, Nitta K, Oh-eda M, Yoshikawa K, Habuchi T, et al. Carbohydrate structure and differential binding of prostate specific antigen to Maackia Amurensis lectin between prostate cancer and benign prostate hypertrophy. Glycobiology. 2004;14(8):671–9. Scholar
  18. 18.
    Tsuchiya N, Ohyama C, Habuchi T. Tumor markers in prostate cancer—clinical significance and future prospect of prostate specific antigen (PSA). Gan To Kagaku Ryoho. 2005;32(2):275–80.Google Scholar
  19. 19.
    Tajiri M, Ohyama C, Wada Y. Oligosaccharide profiles of the prostate specific antigen in free and complexed forms from the prostate cancer patient serum and in seminal plasma: a glycopeptide approach. Glycobiology. 2008;18(1):2–8. Scholar
  20. 20.
    Yoneyama T, Ohyama C, Hatakeyama S, Narita S, Habuchi T, Koie T, et al. Measurement of aberrant glycosylation of prostate specific antigen can improve specificity in early detection of prostate cancer. Biochem Biophys Res Commun. 2014;448(4):390–6. Scholar
  21. 21.
    Ishikawa T, Yoneyama T, Tobisawa Y, Hatakeyama S, Kurosawa T, Nakamura K, et al. An automated micro-total immunoassay system for measuring cancer-associated alpha2,3-linked Sialyl N-Glycan-carrying prostate-specific antigen may improve the accuracy of prostate cancer diagnosis. Int J Mol Sci. 2017;18(2):E470. Scholar
  22. 22.
    Nishimura S, Niikura K, Kurogochi M, Matsushita T, Fumoto M, Hinou H, et al. High-throughput protein glycomics: combined use of chemoselective glycoblotting and MALDI-TOF/TOF mass spectrometry. Angew Chem Int Ed Engl. 2004;44(1):91–6. Scholar
  23. 23.
    Hatakeyama S, Amano M, Tobisawa Y, Yoneyama T, Tsuchiya N, Habuchi T, et al. Serum N-glycan alteration associated with renal cell carcinoma detected by high throughput glycan analysis. J Urol. 2014;191(3):805–13. Scholar
  24. 24.
    Tsui KH, Chang PL, Feng TH, Chung LC, Sung HC, Juang HH. Evaluating the function of matriptase and N-acetylglucosaminyltransferase V in prostate cancer metastasis. Anticancer Res. 2008;28(4A):1993–9.PubMedGoogle Scholar
  25. 25.
    Bennun SV, Yarema KJ, Betenbaugh MJ, Krambeck FJ. Integration of the transcriptome and glycome for identification of glycan cell signatures. PLoS Comput Biol. 2013;9(1):e1002813. Scholar
  26. 26.
    Taniguchi N, Kizuka Y. Glycans and cancer: role of N-glycans in cancer biomarker, progression and metastasis, and therapeutics. Adv Cancer Res. 2015;126:11–51. Scholar
  27. 27.
    Demetriou M, Granovsky M, Quaggin S, Dennis JW. Negative regulation of T-cell activation and autoimmunity by Mgat5 N-glycosylation. Nature. 2001;409(6821):733–9. Scholar

Copyright information

© Springer Nature Singapore Pte Ltd. 2018

Authors and Affiliations

  • Shingo Hatakeyama
    • 1
    Email author
  • Tohru Yoneyama
    • 1
  • Hayato Yamamoto
    • 1
  • Yuki Tobisawa
    • 1
  • Shin-Ichiro Nishimura
    • 2
  • Chikara Ohyama
    • 1
  1. 1.Department of UrologyHirosaki University Graduate School of MedicineHirosakiJapan
  2. 2.Graduate School of Life ScienceFrontier Research Centre for Advanced Material and Life Science, Hokkaido UniversitySapporoJapan

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