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Regulatory mechanism for the human glioblastoma cell-specific expression of the human GD1c/GT1a/GQ1b synthase (hST8Sia V) gene

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Abstract

In this study we observed that human GD1c/GT1a/GQ1b synthase (hST8Sia V) is particularly expressed in human glioblastoma cells. To address the mechanism regulating human glioblastoma-specific gene expression of the hST8Sia V, after the transcription start site (TSS) was identified by the 5’-rapid amplification of cDNA end with total RNA from human glioblastoma U87MG cells, the 5’-flanking region (2.5 kb) of the hST8Sia V gene was isolated and its promoter activity was examined. By luciferase reporter assay, this 5’-flanking region revealed strong promoter activity in only U-87MG cells, but not in other tissue-derived cancer cells. 5’-deletion mutant analysis showed that the region from -1140 to -494 is crucial for transcription of the hST8Sia V gene in U87MG cells. This region contains the activator protein-1 (AP-1) binding site, the main target of the c-Jun N-terminal kinase (JNK) downstream. The AP-1 binding site at -1043/-1037 was proved to be indispensable for the hST8Sia V gene-specific expression in U87MG cells by site-directed mutagenesis. Moreover, the transcriptional activation of hST8Sia V gene in U87MG cells was strongly inhibited by a specific JNK inhibitor, SP600125. These results suggest that the hST8Sia V gene-specific expression in U87MG cells is controlled by JNK/AP-1 signaling pathway.

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Data availability

The datasets used in this study are available from the corresponding authors upon request.

References

  1. Ledeen, R.W., Wu, G.: Gangliosides of the nervous system. Methods Mol. Biol. 1804, 19–55 (2018)

    Article  PubMed  CAS  Google Scholar 

  2. Sipione, S., Monyror, J., Galleguillos, D., Steinberg, N., Kadam, V.: Gangliosides in the Brain: Physiology, Pathophysiology and Therapeutic Applications. Front. Neurosci. 14, 572965 (2020)

    Article  PubMed  PubMed Central  Google Scholar 

  3. Schnaar, R.L., Gerardy-Schahn, R., Hildebrandt, H.: Sialic Acids in the brain: gangliosides and polysialic acid in nervous system development, stability, disease, and regeneration. Physiol. Rev. 94, 461–518 (2014)

    Article  PubMed  PubMed Central  Google Scholar 

  4. Ogawa-Goto, K., Abe, T.: Gangliosides and glycosphingolipids of peripheral nervous Ssstem myelins—a minireview. Neurochem. Res. 23, 305–310 (1998)

    Article  PubMed  CAS  Google Scholar 

  5. Palmano, K., Rowan, A., Guillermo, R., Guan, J., McJarrow, P.: The role of gangliosides in neurodevelopment. Nutrients 7, 3891–3913 (2015)

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  6. Schengrund, C.L.: Gangliosides: glycosphingolipids essential for normal neural development and function. Trends Biochem. Sci. 40, 397–406 (2015)

    Article  PubMed  CAS  Google Scholar 

  7. Hakomori, S.: Bifunctional role of glycosphingolipids. Modulators for transmembrane signaling and mediators for cellular interactions. J. Biol. Chem. 265, 18713–18716 (1990)

  8. Zella, C.B., Marchase, R.B.: Gangliosides as modulators of cell function. Am. J. Physiol. 262, C1341–C1355 (1992)

    Article  Google Scholar 

  9. Lopez, P.H.H., Schnaar, R.L.: Gangliosides in cell recognition and membrane protein regulation. Curr. Opin. Struct. Biol. 19, 549–557 (2009)

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  10. Schnaar, R.L.: Glycosphingolipids in cell surface recognition. Glycobiology 1, 477–485 (1991)

    Article  PubMed  CAS  Google Scholar 

  11. Schnaar, R.L.: Glycolipid-mediated cell–cell recognition in inflammation and nerve regeneration. Arch. Biochem. Biophys. 426, 163–172 (2004)

    Article  PubMed  CAS  Google Scholar 

  12. Regina Todeschini, A., Hakomori, S.: Functional role of glycosphingolipids and gangliosides in control of cell adhesion, motility, and growth, through glycosynaptic microdomains. Biochim. Biophys. Acta 1780, 421–433 (2008)

    Article  PubMed  CAS  Google Scholar 

  13. Potapenko, M., Shurin, G.V., de León, J.: Gangliosides as immunomodulators. Adv. Exp. Med. Biol. 601, 195–203 (2007)

    Article  PubMed  Google Scholar 

  14. Iwabuchi, K.: Gangliosides in the immune system: role of glycosphingolipids and glycosphingolipid-enriched lipid rafts in immunological functions. Methods Mol. Biol. 1804, 83–95 (2018)

    Article  PubMed  CAS  Google Scholar 

  15. Birkle, S., Zeng, G., Gao, L., Yu, R.K., Aubry, J.: Role of tumor-associated gangliosides in cancer progression. Biochimie 85, 455–463 (2003)

    Article  PubMed  CAS  Google Scholar 

  16. Daniotti, J.L., Vilcaes, A.A., Torres, Demichelis, V., Ruggiero, F.M., Rodriguez-Walker, M.: Glycosylation of glycolipids in cancer: basis for development of novel therapeutic approaches. Front. Oncol. 3, 306 (2013)

  17. Groux-Degroote, S., Guerardel, Y., Delannoy, P.: Gangliosides: structures, biosynthesis, analysis, and roles in cancer. ChemBioChem. 18, 1146–1154 (2017)

    Article  PubMed  CAS  Google Scholar 

  18. Tsuchida, T., Saxton, R.E., Morton, D.L., Irie, R.F.: Gangliosides of human melanoma. Cancer 63, 1166–1174 (1989)

    Article  PubMed  CAS  Google Scholar 

  19. Wikstrand, C.J., Fredman, P., McLendon, R.R.: Altered expression of ganglioside phenotypes of human gliomas in vivo and in vitro. Mol. Chem. Neuropathol. 21, 129–138 (1994)

    Article  PubMed  CAS  Google Scholar 

  20. Schengrund, C.L.: Gangliosides and neuroblastomas. Int. J. Mol. Sci. 21, 5313 (2020)

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  21. Fuentes, R., Allman, R., Mason, M.D.: Ganglioside expression in lung cancer cell lines. Lung Cancer 18, 21–33 (1997)

    Article  PubMed  CAS  Google Scholar 

  22. Groux-Degroote, S., Guérardel, Y., Julien, S., Delannoy, P.: Gangliosides in breast cancer: new perspectives. Biochemistry(Moscow). 80, 808–819 (2015)

  23. Hakomori, S.: Tumor malignancy defined by aberrant glycosylation and sphingo(glyco)lipid metabolism. Cancer Res. 56, 5309–5318 (1996)

    PubMed  CAS  Google Scholar 

  24. Hettmer, S., Malott, C., Woods, W., Ladisch, S., Kaucic, K.: Biological stratification of human neuroblastoma by complex “B” pathway ganglioside expression. Cancer Res. 63, 7270–7276 (2003)

    PubMed  CAS  Google Scholar 

  25. Hettmer, S., Ladisch, S., Kaucic, K.: Low complex ganglioside expression characterizes human neuroblastoma cell lines. Cancer Lett. 225, 141–149 (2005)

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  26. Mizutani, A., Kuroda, Y., Muramoto, K., Kobayashi, K., Yamagishi, K., Inokuchi, J.: Effects of glucosylceramide synthase inhibitor and ganglioside GQ1b on synchronous oscillations of intracellular Ca2+ in cultured cortical neurons. Biochem. Biophys. Res. Commun. 222, 494–498 (1996)

    Article  PubMed  CAS  Google Scholar 

  27. Jung, W.R., Kim, H.G., Kim, K.L.: Ganglioside GQ1b improves spatial learning and memory of rats as measured by the Y-maze and the Morris water maze tests. Neurosci. Lett. 439, 220–225 (2008)

    Article  PubMed  CAS  Google Scholar 

  28. Chiba, A., Kusunoki, S., Obata, H., Machinami, R., Kanazawa, I.: Serum anti-GQ1b IgG antibody is associated with ophthalmoplegia in Miller Fisher syndrome and Guillain–Barre´ syndrome. clinical and immunohistochemical studies. Neurology. 43, 1911–1917 (1993)

  29. Liu, J.X., Willison, H.J., Pedrosa-Domellof, F.: Immunolocalization of GQ1b and related gangliosides in human extraocular neuromuscular junctions and muscle spindles. Invest. Ophthalmol. Vis. Sci. 50, 3226–3232 (2009)

    Article  PubMed  Google Scholar 

  30. Kitagawa, H., Paulson, J.C.: Differential expression of five sialyltransferase genes in human tissues. J. Biol. Chem. 269, 17872–17878 (1994)

    Article  PubMed  CAS  Google Scholar 

  31. Harduin-Lepers, A., Vallejo-Ruiz, V., Krzewinski-Recchi, M.A., Samyn-Petit, B., Julien, S., Delannoy, P.: The human sialyltransferase family. Biochimie 83, 727–737 (2001)

    Article  PubMed  CAS  Google Scholar 

  32. Yu, R.K., Zeng, G.: Cloning and transcriptional regulation of genes responsible for synthesis of gangliosides. Curr. Drug Targets 9, 317–324 (2008)

    Article  PubMed  PubMed Central  Google Scholar 

  33. Kim, S.W., Lee, S.H., Kim, K.S., Kim, C.H., Choo, Y.K., Lee, Y.C.: Isolation and characterization of the promoter region of the human GM3 synthase gene. Biochim. Biophys. Acta 1578, 84–89 (2002)

    Article  PubMed  CAS  Google Scholar 

  34. Choi, H.J., Chung, T.W., Kang, N.Y., Kim, K.S., Lee, Y.C., Kim, C.H.: Transcriptional regulation of the human GM3 synthase (hST3Gal V) gene during monocytic differentiation of HL-60 cells. FEBS Lett. 555, 204–208 (2003)

    Article  PubMed  CAS  Google Scholar 

  35. Choi, H.J., Chung, T.W., Lee, Y.C., Kim, C.H.: Molecular mechanism for transcriptional activation of ganglioside GM3 synthase and its function in differentiation of HL-60 cells. Glycobiology 15, 233–244 (2005)

    PubMed  Google Scholar 

  36. Choi, H.J., Chung, T.W., Kang, N.Y., Kim, K.S., Lee, Y.C., Kim, C.H.: Involvement of CREB in the transcriptional regulation of the human GM3 synthase (hST3Gal V) gene during megakaryocytoid differentiation of human leukemia K562 cells. Biochem. Biophys. Res. Commun. 313, 142–147 (2004)

    Article  PubMed  CAS  Google Scholar 

  37. Kwon, H.Y., Kang, N.Y., Dae, H.M., Kim, K.S., Kim, C.H., Do, S.I., Lee, Y.C.: Valproic acid-mediated transcriptional regulation of human GM3 synthase (hST3Gal V) in SK-N-BE(2)-C human neuroblastoma cells. Acta Pharmacol. Sin. 29, 999–1005 (2008)

    Article  PubMed  CAS  Google Scholar 

  38. Song, N., Kim, S.J., Kwon, H.Y., Son, S.W., Kim, K.S., Ahn, H.B., Lee, Y.C.: Transcriptional activation of human GM3 synthase (hST3Gal V) gene by valproic acid in ARPE-19 human retinal pigment epithelial cells. BMB Rep. 44, 405–409 (2011)

    Article  PubMed  CAS  Google Scholar 

  39. Yoon, H.K., Lee, J.W., Kim, K.S., Mun, S.W., Ki, D.H., Kim, H.J., Kim, C.H., Lee, Y.C.: Serum deprivation-induced human GM3 synthase (hST3Gal V) gene expression is mediated by Runx2 in human osteoblastic MG-63 cells. Int. J. Mol. Sci. 17, E35 (2015)

    Article  Google Scholar 

  40. Lee, M., Choi, H., Kim, K.S., Kim, D.H., Kim, C.H., Lee, Y.C.: Curcumin downregulates human GM3 synthase (hST3Gal V) gene expression with autophagy induction in human colon carcinoma HCT116 cells. Evid. Based Complement. Alternat. Med. 2018, 6746412 (2018)

  41. Kang, N.Y., Kang, S.K., Lee, Y.C., Choi, H.J., Lee, Y.S., Cho, S.Y., Ko, J.H., Kim, C.H.: Transcriptional regulation of the human GD3 synthase gene expression in Fas-induced Jurkat T cells: a critical role of transcription factor NF-kB in regulated expression. Glycobiology 16, 375–389 (2006)

    Article  PubMed  CAS  Google Scholar 

  42. Kang, N.Y., Kim, C.H., Kim. K.S,, Ko, J.H., Jeong, Y.K., Lee, Y.C.: Expression of the human CMP-NeuAc:GM3 α2,8-sialyltransferase (GD3 synthase) gene through the NF-κB activation in human melanoma SK-MEL-2 cells. Biochim. Biophys. Acta. 1769, 622–630 (2007)

  43. Dae, H.M., Kwon, H.Y., Kang, N.Y., Song, N.R., Kim, K.S., Kim, C.H., Lee, J.H., Lee, Y.C.: Isolation and functional analysis of the human glioblastoma-specific promoter region of the human GD3 synthase (hST8Sia I) gene. Acta Biochim. Biophys. Sin. 41, 237–245 (2009)

    Article  PubMed  CAS  Google Scholar 

  44. Kwon, H.Y., Dae, H.M., Song, N.R., Kim, K.S., Kim, C.H., Lee, Y.C.: Valproic acid induces transcriptional activation of human GD3 synthase (hST8Sia I) in SK-N-BE(2)-C human neuroblastoma cells. Mol. Cells 27, 113–118 (2009)

    Article  PubMed  CAS  Google Scholar 

  45. Kwon, H.Y., Kim, S.J., Kim, C.H., Son, S.W., Kim, K.S., Lee, J.H., Do, S.I., Lee, Y.C.: Triptolide downregulates human GD3 synthase (hST8Sia I) gene expression in SK-MEL-2 human melanoma cells. Exp. Mol. Med. 42, 849–855 (2010)

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  46. Baik, J.S., Kim, K.S., Moon, H.I., An, H.K., Park, S.J., Kim, C.H., Lee, Y.C.: Cordycepin-mediated transcriptional regulation of human GD3 synthase (hST8Sia I) in human neuroblastoma SK-N-BE(2)-C cells. Acta Biochim. Biophys. Sin. 46, 65–71 (2014)

    Article  PubMed  CAS  Google Scholar 

  47. Lee, M., Kim, K.S., Fukushi, A., Kim, D.H., Kim, C.H., Lee, Y.C.: Transcriptional activation of human GD3 synthase (hST8Sia I) gene in curcumin-induced autophagy in A549 human lung carcinoma cells. Int. J. Mol. Sci. 19, 1943 (2018)

    Article  PubMed  PubMed Central  Google Scholar 

  48. Bobowski, M., Vincent, A., Steenackers, A., Colomb, F., Van Seuningen, I., Julien, S., Delannoy, P.: Estradiol represses the GD3 synthase gene ST8SIA1 expression in human breast cancer cells by preventing NFkB binding to ST8SIA1 promoter. PLoS ONE 8, e62559 (2013)

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  49. An, S.Y., Lee, M., Yoon, H.K., Abekura, F., Kim, K.S., Kim, D.H., Kim, H.J., Lee, K., Kim, C.H., Lee, Y.C.: Regulation of human β-galactoside α2, 6-sialyltransferase (hST6Gal I) gene expression during differentiation of human osteoblastic MG-63 cells. Glycoconj. J. 37, 681–690 (2020)

    Article  PubMed  CAS  Google Scholar 

  50. An, S.Y., Kim, K.S., Kim, H.D., Cho, J.H., Kim, C.H., Lee, Y.C.: Curcumin-mediated transcriptional regulation of human N-acetylgalactosamine-α2,6-sialyltransferase (hST6GalNAc I) which synthesizes sialyl-Tn antigen in HCT116 human colon cancer cells. Front. Mol. Biosci. 9, 985648 (2022)

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  51. Kim, Y.J., Kim, K.S., Do, S., Kim, C.H., Kim, S.K., Lee, Y.C.: Molecular cloning and expression of human α2,8-sialyltransferase (hST8Sia V). Biochem. Biophys. Res. Commun. 235, 327–330 (1997)

    Article  PubMed  CAS  Google Scholar 

  52. Yoon, H.K., An, H.K., Ko, M.J., Kim, K.S., Mun, S.W., Kim, D.H., Kim, C.M., Kim, C.H., Choi, Y.W., Lee, Y.C.: Upregulation of human ST8Sia VI (α2,8-sialyltransferase) gene expression by physcion in human neuroblastoma SK-N-BE(2)-C cells. Int. J. Mol. Sci. 17, E1246 (2016)

    Article  Google Scholar 

  53. Bogoyevitch, M.A., Kobe, B.: Uses for JNK: the many and varied substrates of the c-Jun N-terminal kinases. Microbiol. Mol. Biol. Rev. 70, 1061–1095 (2006)

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  54. Gustems, M., Woellmer, A., Rothbauer, U., Eck, S.H., Wieland, T., Lutter, D., Hammerschmidt, W.: c-Jun/c-Fos heterodimers regulate cellular genes via a newly identified class of methylated DNA sequence motifs. Nucleic Acids Res. 42, 3059–3072 (2014)

    Article  PubMed  CAS  Google Scholar 

  55. Ashkani, J., Naidoo, K.J.: Glycosyltransferase gene expression profiles classify cancer types and propose prognostic subtypes. Sci. Rep. 6, 26451 (2016)

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  56. Meany, D.W., Chan, D.L.: Aberrant glycosylation associated with enzymes as cancer biomarkers. Clin. Proteomics 8, 1–14 (2011)

    Article  Google Scholar 

  57. Davis, R.J.: Signal transduction by the JNK group of MAP kinases. Cell 103, 239–252 (2000)

    Article  PubMed  CAS  Google Scholar 

  58. Bubici, C., Papa, S.: JNK signalling in cancer: in need of new, smarter therapeutic targets. Br. J. Pharmacol. 171, 24–37 (2014)

    Article  PubMed  CAS  Google Scholar 

  59. Antonyak, M.A., Kenyon, L.C., Godwin, A.K., James, D.C., Emlet, D.R., Okamoto, I., Tnani, M., Holgado-Madruga, M., Moscatello, D.K., Wong, A.J.: Elevated JNK activation contributes to the pathogenesis of human brain tumors. Oncogene 21, 5038–5046 (2002)

    Article  PubMed  CAS  Google Scholar 

  60. Li, J.Y., Wang, H., May, S., Song, X., Fueyo, J., Fuller, G.N., Wang, H.: Constitutive activation of c-Jun N-terminal kinase correlates with histologic grade and EGFR expression in diffuse gliomas. J. Neurooncol. 88, 11–17 (2008)

    Article  PubMed  CAS  Google Scholar 

  61. de los Reyes Corrales, T., Losada-Pérez, M.: JNK pathway in CNS pathologies. Int. J. Mol. Sci. 22, 3883 (2021)

  62. Karin, M., Liu, Z., Zandi, E.: AP-1 function and regulation. Curr. Opin. Cell Biol. 9, 240–246 (1997)

    Article  PubMed  CAS  Google Scholar 

  63. Hess, J., Angel, P., Schorpp-Kistner, M.: AP-1 subunits: quarrel and harmony among siblings. J. Cell Sci. 117, 5965–5973 (2004)

    Article  PubMed  CAS  Google Scholar 

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Acknowledgements

This work was supported by the Dong-A University research fund.

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Authors and Affiliations

  1. Department of Medicinal Biotechnology, College of Health Sciences, Dong-A University, Busan, 49315, South Korea

    So-Young An, Ji-Won Lee, Kyoung-Sook Kim, Jong-Hyun Cho & Young-Choon Lee

  2. Molecular and Cellular Glycobiology Unit, Department of Biological Sciences, SungKyunKwan University, Kyunggi-Do, 16419, South Korea

    Hee-Do Kim & Cheorl-Ho Kim

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Contributions

Conceived and designed the experiments: SA, CK, YL. Performed the experiments: SA, KK, HK, CK, YL. Contributed reagents/materials/analysis tools: JC, HK, YL, CK. SA, YL.

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Correspondence to Cheorl-Ho Kim or Young-Choon Lee.

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An, SY., Lee, JW., Kim, HD. et al. Regulatory mechanism for the human glioblastoma cell-specific expression of the human GD1c/GT1a/GQ1b synthase (hST8Sia V) gene. Glycoconj J 40, 621–630 (2023). https://doi.org/10.1007/s10719-023-10136-5

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