Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

ST6GAL1 inhibits metastasis of hepatocellular carcinoma via modulating sialylation of MCAM on cell surface

Oncogene volume 42, pages 516–529 (2023)Cite this article

Subjects

Abstract

The poor prognosis of hepatocellular carcinoma (HCC) is mainly because of its high rate of metastasis. Thus, elucidation of the molecular mechanisms underlying HCC metastasis is of great significance. Glycosylation is an important post-translational modification that is closely associated with tumor progression. Altered glycosylation including the altered sialylation resulting from aberrant expression of β-galactoside α2,6 sialyltransferase 1 (ST6GAL1) has long been considered as an important feature of cancer cells. However, there is limited information on the roles of ST6GAL1 and α2,6 sialylation in HCC metastasis. Here, we found that ST6GAL1 and α2,6 sialylation were negatively correlated with the metastatic potentials of HCC cells. Moreover, ST6GAL1 overexpression inhibited migration and invasion of HCC cells in vitro and suppressed HCC metastasis in vivo. Using a metabolic labeling-based glycoproteomic strategy, we identified a list of sialylated proteins that may be regulated by ST6GAL1. In particular, an increase in α2,6 sialylation of melanoma cell adhesion molecule (MCAM) inhibited its interaction with galectin-3 and decreased its expression on cell surface. In vitro and in vivo analysis showed that ST6GAL1 exerted its function in HCC metastasis by regulating MCAM expression. Finally, we found the relative intensity of sialylated MCAM was negatively correlated with tumor malignancy in HCC patients. Taken together, these results demonstrate that ST6GAL1 may be an HCC metastasis suppressor by affecting sialylation of MCAM on cell surface, which provides a novel insight into the roles of ST6GAL1 in HCC progression and supports the functional complexity of ST6GAL1 in a cancer type- and tissue type-specific manner.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: The expression levels of cell surface α2,6 sialylation and the sialyltransferase ST6GAL1 are negatively correlated with the metastatic potentials of HCC cell lines.
Fig. 2: ST6GAL1 overexpression inhibits HCC metastasis in vivo.
Fig. 3: ST6GAL1 is downregulated in human HCC tissues and its expression is negatively correlated with TNM stages, vascular invasion and tumor differentiation of HCC.
Fig. 4: Discovery of substrate proteins of ST6GAL1 by metabolic labeling-based glycoproteomic analysis.
Fig. 5: ST6GAL1 overexpression decreases the expression of MCAM, impairs its interaction with galectin-3 and dimerization on cell surface.
Fig. 6: ST6GAL1 loss promotes HCC metastasis by up-regulating MCAM.
Fig. 7: Expression and prognostic value of sialylated MCAM in human HCC tissues.

Similar content being viewed by others

Data availability

The datasets generated and/or analysed during the current study are available from the corresponding author on reasonable request.

References

  1. Sung H, Ferlay J, Siegel RL, Laversanne M, Soerjomataram I, Jemal A, et al. Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2021;71:209–49.

    Article  PubMed  Google Scholar 

  2. Chen W, Zheng R, Baade PD, Zhang S, Zeng H, Bray F, et al. Cancer statistics in China, 2015. CA Cancer J Clin. 2016;66:115–32.

    Article  PubMed  Google Scholar 

  3. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2020. CA Cancer J Clin. 2020;70:7–30.

    Article  PubMed  Google Scholar 

  4. Wu C, Ren X, Zhang Q. Incidence, risk factors, and prognosis in patients with primary hepatocellular carcinoma and lung metastasis: a population-based study. Cancer Manag Res. 2019;11:2759–68.

    Article  PubMed  PubMed Central  Google Scholar 

  5. Varki A. Biological roles of glycans. Glycobiology. 2017;27:3–49.

    Article  CAS  PubMed  Google Scholar 

  6. Pinho SS, Reis CA. Glycosylation in cancer: mechanisms and clinical implications. Nat Rev Cancer. 2015;15:540–55.

    Article  CAS  PubMed  Google Scholar 

  7. Mereiter S, Balmana M, Campos D, Gomes J, Reis CA. Glycosylation in the era of cancer-targeted therapy: where are we heading? Cancer Cell. 2019;36:6–16.

    Article  CAS  PubMed  Google Scholar 

  8. Silsirivanit A. Glycosylation markers in cancer. Adv Clin Chem. 2019;89:189–213.

    Article  CAS  PubMed  Google Scholar 

  9. Lu J, Gu J. Significance of beta-galactoside alpha2,6 sialyltranferase 1 in cancers. Molecules. 2015;20:7509–27.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Garnham R, Scott E, Livermore KE, Munkley J. ST6GAL1: a key player in cancer. Oncol Lett. 2019;18:983–9.

    CAS  PubMed  PubMed Central  Google Scholar 

  11. Britain CM, Bhalerao N, Silva AD, Chakraborty A, Buchsbaum DJ, Crowley MR, et al. Glycosyltransferase ST6Gal-I promotes the epithelial to mesenchymal transition in pancreatic cancer cells. J Biol Chem. 2021;296:100034.

    Article  CAS  PubMed  Google Scholar 

  12. Wichert B, Milde-Langosch K, Galatenko V, Schmalfeldt B, Oliveira-Ferrer L. Prognostic role of the sialyltransferase ST6GAL1 in ovarian cancer. Glycobiology 2018;28:898–903.

    Article  CAS  PubMed  Google Scholar 

  13. Lu J, Isaji T, Im S, Fukuda T, Hashii N, Takakura D, et al. beta-Galactoside alpha2,6-sialyltranferase 1 promotes transforming growth factor-beta-mediated epithelial-mesenchymal transition. J Biol Chem. 2014;289:34627–41.

    Article  PubMed  PubMed Central  Google Scholar 

  14. Wang PH, Li YF, Juang CM, Lee YR, Chao HT, Ng HT, et al. Expression of sialyltransferase family members in cervix squamous cell carcinoma correlates with lymph node metastasis. Gynecol Oncol. 2002;86:45–52.

    Article  CAS  PubMed  Google Scholar 

  15. Gessner P, Riedl S, Quentmaier A, Kemmner W. Enhanced activity of CMP-neuAc:Gal beta 1-4GlcNAc:alpha 2,6-sialyltransferase in metastasizing human colorectal tumor tissue and serum of tumor patients. Cancer Lett. 1993;75:143–9.

    Article  CAS  PubMed  Google Scholar 

  16. Gretschel S, Haensch W, Schlag PM, Kemmner W. Clinical relevance of sialyltransferases ST6GAL-I and ST3GAL-III in gastric cancer. Oncology 2003;65:139–45.

    Article  CAS  PubMed  Google Scholar 

  17. Christie DR, Shaikh FM, Lucas JAT, Lucas JA 3rd, Bellis SL. ST6Gal-I expression in ovarian cancer cells promotes an invasive phenotype by altering integrin glycosylation and function. J Ovarian Res. 2008;1:3.

    Article  PubMed  PubMed Central  Google Scholar 

  18. Holdbrooks AT, Britain CM, Bellis SL. ST6Gal-I sialyltransferase promotes tumor necrosis factor (TNF)-mediated cancer cell survival via sialylation of the TNF receptor 1 (TNFR1) death receptor. J Biol Chem. 2018;293:1610–22.

    Article  CAS  PubMed  Google Scholar 

  19. Tang ZY, Ye SL, Liu YK, Qin LX, Sun HC, Ye QH, et al. A decade’s studies on metastasis of hepatocellular carcinoma. J Cancer Res Clin Oncol. 2004;130:187–96.

    Article  PubMed  Google Scholar 

  20. Jiang G, Zhang L, Zhu Q, Bai D, Zhang C, Wang X. CD146 promotes metastasis and predicts poor prognosis of hepatocellular carcinoma. J Exp Clin Cancer Res. 2016;35:38.

    Article  PubMed  PubMed Central  Google Scholar 

  21. Wang J, Tang X, Weng W, Qiao Y, Lin J, Liu W, et al. The membrane protein melanoma cell adhesion molecule (MCAM) is a novel tumor marker that stimulates tumorigenesis in hepatocellular carcinoma. Oncogene. 2015;34:5781–95.

    Article  CAS  PubMed  Google Scholar 

  22. Stalin J, Nollet M, Garigue P, Fernandez S, Vivancos L, Essaadi A, et al. Targeting soluble CD146 with a neutralizing antibody inhibits vascularization, growth and survival of CD146-positive tumors. Oncogene. 2016;35:5489–500.

    Article  CAS  PubMed  Google Scholar 

  23. Zhang Z, Zheng Y, Wang H, Zhou Y, Tai G. CD146 interacts with galectin-3 to mediate endothelial cell migration. FEBS Lett. 2018;592:1817–28.

    Article  CAS  PubMed  Google Scholar 

  24. Colomb F, Wang W, Simpson D, Zafar M, Beynon R, Rhodes JM, et al. Galectin-3 interacts with the cell-surface glycoprotein CD146 (MCAM, MUC18) and induces secretion of metastasis-promoting cytokines from vascular endothelial cells. J Biol Chem. 2017;292:8381–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Zhuo Y, Bellis SL. Emerging role of alpha2,6-sialic acid as a negative regulator of galectin binding and function. J Biol Chem. 2011;286:5935–41.

    Article  CAS  PubMed  Google Scholar 

  26. Hirabayashi J, Hashidate T, Arata Y, Nishi N, Nakamura T, Hirashima M, et al. Oligosaccharide specificity of galectins: a search by frontal affinity chromatography. Biochim Biophys Acta. 2002;1572:232–54.

    Article  CAS  PubMed  Google Scholar 

  27. Dobie C, Skropeta D. Insights into the role of sialylation in cancer progression and metastasis. Br J Cancer. 2021;124:76–90.

    Article  CAS  PubMed  Google Scholar 

  28. Poon TC, Chiu CH, Lai PB, Mok TS, Zee B, Chan AT, et al. Correlation and prognostic significance of beta-galactoside alpha-2,6-sialyltransferase and serum monosialylated alpha-fetoprotein in hepatocellular carcinoma. World J Gastroenterol. 2005;11:6701–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Dall’Olio F, Chiricolo M, D’Errico A, Gruppioni E, Altimari A, Fiorentino M, et al. Expression of beta-galactoside alpha2,6 sialyltransferase and of alpha2,6-sialylated glycoconjugates in normal human liver, hepatocarcinoma, and cirrhosis. Glycobiology. 2004;14:39–49.

    Article  PubMed  Google Scholar 

  30. Antony P, Rose M, Heidenreich A, Knuchel R, Gaisa NT, Dahl E. Epigenetic inactivation of ST6GAL1 in human bladder cancer. BMC Cancer. 2014;14:901.

    Article  PubMed  PubMed Central  Google Scholar 

  31. Yamamoto H, Kaneko Y, Rebbaa A, Bremer EG, Moskal JR. alpha2,6-Sialyltransferase gene transfection into a human glioma cell line (U373 MG) results in decreased invasivity. J Neurochem. 1997;68:2566–76.

    Article  CAS  PubMed  Google Scholar 

  32. Yamamoto H, Oviedo A, Sweeley C, Saito T, Moskal JR. Alpha2,6-sialylation of cell-surface N-glycans inhibits glioma formation in vivo. Cancer Res. 2001;61:6822–9.

    CAS  PubMed  Google Scholar 

  33. Zhu Y, Srivatana U, Ullah A, Gagneja H, Berenson CS, Lance P. Suppression of a sialyltransferase by antisense DNA reduces invasiveness of human colon cancer cells in vitro. Biochim Biophys Acta. 2001;1536:148–60.

    Article  CAS  PubMed  Google Scholar 

  34. Seales EC, Jurado GA, Brunson BA, Wakefield JK, Frost AR, Bellis SL. Hypersialylation of beta1 integrins, observed in colon adenocarcinoma, may contribute to cancer progression by up-regulating cell motility. Cancer Res. 2005;65:4645–52.

    Article  CAS  PubMed  Google Scholar 

  35. Petretti T, Kemmner W, Schulze B, Schlag PM. Altered mRNA expression of glycosyltransferases in human colorectal carcinomas and liver metastases. Gut. 2000;46:359–66.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Jung YR, Park JJ, Jin YB, Cao YJ, Park MJ, Kim EJ, et al. Silencing of ST6Gal I enhances colorectal cancer metastasis by down-regulating KAI1 via exosome-mediated exportation and thereby rescues integrin signaling. Carcinogenesis. 2016;37:1089–97.

    Article  CAS  PubMed  Google Scholar 

  37. Zhou L, Zhang S, Zou X, Lu J, Yang X, Xu Z, et al. The beta-galactoside alpha2,6-sialyltranferase 1 (ST6GAL1) inhibits the colorectal cancer metastasis by stabilizing intercellular adhesion molecule-1 via sialylation. Cancer Manag Res. 2019;11:6185–99.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Oswald DM, Zhou JY, Jones MB, Cobb BA. Disruption of hepatocyte Sialylation drives a T cell-dependent pro-inflammatory immune tone. Glycoconj J. 2020;37:395–407.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Dorsett KA, Marciel MP, Hwang J, Ankenbauer KE, Bhalerao N, Bellis SL. Regulation of ST6GAL1 sialyltransferase expression in cancer cells. Glycobiology 2021;31:530–9.

    Article  CAS  PubMed  Google Scholar 

  40. Kroes RA, Moskal JR. The role of DNA methylation in ST6Gal1 expression in gliomas. Glycobiology. 2016;26:1271–83.

    CAS  PubMed  Google Scholar 

  41. Huang G, Li Z, Li Y, Liu G, Sun S, Gu J, et al. Loss of core fucosylation in both ST6GAL1 and its substrate enhances glycoprotein sialylation in mice. Biochem J. 2020;477:1179–201.

    Article  CAS  PubMed  Google Scholar 

  42. Zhou Y, Fukuda T, Hang Q, Hou S, Isaji T, Kameyama A, et al. Inhibition of fucosylation by 2-fluorofucose suppresses human liver cancer HepG2 cell proliferation and migration as well as tumor formation. Sci Rep. 2017;7:11563.

    Article  PubMed  PubMed Central  Google Scholar 

  43. Shan M, Yang D, Dou H, Zhang L. Fucosylation in cancer biology and its clinical applications. Prog Mol Biol Transl Sci. 2019;162:93–119.

    Article  CAS  PubMed  Google Scholar 

  44. Swindall AF, Bellis SL. Sialylation of the Fas death receptor by ST6Gal-I provides protection against Fas-mediated apoptosis in colon carcinoma cells. J Biol Chem. 2011;286:22982–90.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Wang Z, Xu Q, Zhang N, Du X, Xu G, Yan X. CD146, from a melanoma cell adhesion molecule to a signaling receptor. Signal Transduct Target Ther. 2020;5:148.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Bu P, Zhuang J, Feng J, Yang D, Shen X, Yan X. Visualization of CD146 dimerization and its regulation in living cells. Biochim Biophys Acta. 2007;1773:513–20.

    Article  CAS  PubMed  Google Scholar 

  47. Croci DO, Cerliani JP, Dalotto-Moreno T, Mendez-Huergo SP, Mascanfroni ID, Dergan-Dylon S, et al. Glycosylation-dependent lectin-receptor interactions preserve angiogenesis in anti-VEGF refractory tumors. Cell. 2014;156:744–58.

    Article  CAS  PubMed  Google Scholar 

  48. Zhang S, Lu J, Xu Z, Zou X, Sun X, Xu Y, et al. Differential expression of ST6GAL1 in the tumor progression of colorectal cancer. Biochem Biophys Res Commun. 2017;486:1090–6.

    Article  CAS  PubMed  Google Scholar 

  49. Yi CH, Weng HL, Zhou FG, Fang M, Ji J, Cheng C, et al. Elevated core-fucosylated IgG is a new marker for hepatitis B virus-related hepatocellular carcinoma. Oncoimmunology. 2015;4:e1011503.

    Article  PubMed  PubMed Central  Google Scholar 

  50. Zou X, Yoshida M, Nagai-Okatani C, Iwaki J, Matsuda A, Tan B, et al. A standardized method for lectin microarray-based tissue glycome mapping. Sci Rep. 2017;7:43560.

    Article  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

We thank Dr. Yanmin Yu (Ruijin Hosptial, Shanghai Jiao Tong University School of Medicine) for her help in the pathological interpretation of tissue arrays.

Funding

This work was supported by the by the National Science and Technology Major Project of China (2018ZX10302-205-003-002), the National Natural Science Foundation of China (32071271, 31770850, 31600643 and 81802100), the Innovation Group Project of Shanghai Municipal Health Commission (2019CXJQ03).

Author information

Author notes

  1. These authors contributed equally: Xia Zou, Jishun Lu, Yao Deng.

Authors and Affiliations

  1. Key Laboratory of Systems Biomedicine (Ministry of Education), Shanghai Center for Systems Biomedicine, Shanghai Jiao Tong University, Shanghai, 200240, China

    Xia Zou, Jishun Lu, Yao Deng, Qiannan Liu, Yalu Cui, Fang Yang, Binbin Tan, Xiaoyan Lu & Yan Zhang

  2. SCSB (China)-AIST (Japan) Joint Medical Glycomics Laboratory, Shanghai Jiao Tong University, Shanghai, 200240, China

    Xia Zou, Takashi Sato, Binbin Tan, Atsushi Kuno, Hisashi Narimatsu & Yan Zhang

  3. Department of General Surgery, Shanghai Minimally Invasive Surgery Center, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China

    Xialin Yan & Bo Feng

  4. Clinical Laboratory Medicine Center, Yueyang Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, 200437, China

    Xiao Xiao & Chunfang Gao

  5. Department of Laboratory Medicine, Shanghai Eastern Hepatobiliary Surgery Hospital, Shanghai, 200438, China

    Meng Fang

  6. Molecular and Cellular Glycoproteomics Research Group, Cellular and Molecular Biotechnology Research Institute, National Institute of Advanced Industrial Science and Technology, Tsukuba, Ibaraki, 305-8568, Japan

    Hiromichi Sawaki, Takashi Sato, Atsushi Kuno & Hisashi Narimatsu

Authors
  1. Xia Zou
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Jishun Lu
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Yao Deng
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Qiannan Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Xialin Yan
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Yalu Cui
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Xiao Xiao
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Meng Fang
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Fang Yang
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Hiromichi Sawaki
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Takashi Sato
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Binbin Tan
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Xiaoyan Lu
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Bo Feng
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. Atsushi Kuno
    View author publications

    You can also search for this author in PubMed Google Scholar

  16. Hisashi Narimatsu
    View author publications

    You can also search for this author in PubMed Google Scholar

  17. Chunfang Gao
    View author publications

    You can also search for this author in PubMed Google Scholar

  18. Yan Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

Conception and design: YZ, JL; Development of methodology: XZ, JL, XY, YC; Acquisition of data: XZ, JL, YD, QL, XY, YC, XX, MF, FY, HS, BT, XL; Analysis and interpretation of data: XZ, JL, YD, YZ; Technical or material support: CG, HN, AK, TS, BF; Writing—original draft: XZ, JL; Writing—review and editing: YZ, CG, HN, AK, TS; Study supervision: YZ.

Corresponding author

Correspondence to Yan Zhang.

Ethics declarations

Competing interests

The authors declare no competing interests.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Zou, X., Lu, J., Deng, Y. et al. ST6GAL1 inhibits metastasis of hepatocellular carcinoma via modulating sialylation of MCAM on cell surface. Oncogene 42, 516–529 (2023). https://doi.org/10.1038/s41388-022-02571-9

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41388-022-02571-9

This article is cited by

Search

Advanced search

Quick links