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SGNE1/7B2 is epigenetically altered and transcriptionally downregulated in human medulloblastomas

Oncogene volume 26, pages 5662–5668 (2007)Cite this article

Abstract

In a genome-wide screen using differential methylation hybridization (DMH), we have identified a CpG island within the 5′ region and untranslated first exon of the secretory granule neuroendocrine protein 1 gene (SGNE1/7B2) that showed hypermethylation in medulloblastomas compared to fetal cerebellum. Bisulfite sequencing and combined bisulfite restriction assay were performed to confirm the methylation status of this CpG island in primary medulloblastomas and medulloblastoma cell lines. Hypermethylation was detected in 16/23 (70%) biopsies and 7/8 (87%) medulloblastoma cell lines, but not in non-neoplastic fetal (n=8) cerebellum. Expression of SGNE1 was investigated by semi-quantitative competitive reverse transcription–polymerase chain reaction and found to be significantly downregulated or absent in all, but one primary medulloblastomas and all cell lines compared to fetal cerebellum. After treatment of medulloblastoma cell lines with 5-aza-2′-deoxycytidine, transcription of SGNE1 was restored. No mutation was found in the coding region of SGNE1 by single-strand conformation polymorphism analysis. Reintroduction of SGNE1 into the medulloblastoma cell line D283Med led to a significant growth suppression and reduced colony formation. In summary, we have identified SGNE1 as a novel epigenetically silenced gene in medulloblastomas. Its frequent inactivation, as well as its inhibitory effect on tumor cell proliferation and focus formation strongly argues for a significant role in medulloblastoma development.

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References

  • Biegel JA, Rorke LB, Packer RJ, Sutton LN, Schut L, Bonner K et al. (1989). Isochromosome 17q in primitive neuroectodermal tumors of the central nervous system. Genes Chromosomes Cancer 1: 139–147.

    Article  CAS  PubMed  Google Scholar 

  • Bigner SH, Friedman HS, Vogelstein B, Oakes WJ, Bigner DD . (1990). Amplification of the c-myc gene in human medulloblastoma cell lines and xenografts. Cancer Res 50: 2347–2350.

    CAS  PubMed  Google Scholar 

  • Bock C, Reither S, Mikeska T, Paulsen M, Walter J, Lengauer T . (2005). BiQ Analyzer: visualization and quality control for DNA methylation data from bisulfite sequencing. Bioinformatics 21: 4067–4068.

    Article  CAS  PubMed  Google Scholar 

  • Braks JA, Broers CA, Danger JM, Martens GJ . (1996). Structural organization of the gene encoding the neuroendocrine chaperone 7B2. Eur J Biochem 236: 60–67.

    Article  CAS  PubMed  Google Scholar 

  • Braks JA, Martens GJ . (1994). 7B2 is a neuroendocrine chaperone that transiently interacts with prohormone convertase PC2 in the secretory pathway. Cell 78: 263–273.

    Article  CAS  PubMed  Google Scholar 

  • Cassidy SB . (1997). Prader–Willi syndrome. J Med Genet 34: 917–923.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Collini P, Sampietro G, Luksch R, Migliorini L, Boracchi P, Scopsi L . (1998). Differentiation in paediatric peripheral primitive neuroectodermal tumours of bone. A critical contribution to its assessment. Virchows Arch 432: 505–513.

    Article  CAS  PubMed  Google Scholar 

  • Frühwald MC, O'Dorisio MS, Dai Z, Tanner SM, Balster DA, Gao X et al. (2001). Aberrant promoter methylation of previously unidentified target genes is a common abnormality in medulloblastomas—implications for tumor biology and potential clinical utility. Oncogene 20: 5033–5042.

    Article  PubMed  Google Scholar 

  • Gardiner-Garden M, Frommer M . (1987). CpG islands in vertebrate genomes. J Mol Biol 196: 261–282.

    Article  CAS  PubMed  Google Scholar 

  • Hartmann W, Digon-Söntgerath B, Koch A, Waha A, Endl E, Dani I et al. (2006). Phosphatidylinositol 3′-kinase/AKT signaling is activated in medulloblastoma cell proliferation and is associated with reduced expression of PTEN. Clin Cancer Res 12: 3019–3027.

    Article  CAS  PubMed  Google Scholar 

  • Hsi KL, Seidah NG, de Serres G, Chretien M . (1982). Isolation and NH2-terminal sequence of a novel porcine anterior pituitary polypeptide. Homology to proinsulin, secretin and Rous sarcoma virus transforming protein TVFV60. FEBS Lett 147: 261–266.

    Article  CAS  PubMed  Google Scholar 

  • Iguchi H, Chan JS, Seidah NG, Chretien M . (1984). Tissue distribution and molecular forms of a novel pituitary protein in the rat. Neuroendocrinology 39: 453–458.

    Article  CAS  PubMed  Google Scholar 

  • Jeannotte R, Paquin J, Petit-Turcotte C, Day R . (1997). Convertase PC2 and the neuroendocrine polypeptide 7B2 are co-induced and processed during neuronal differentiation of P19 embryonal carcinoma cells. DNA Cell Biol 16: 1175–1187.

    Article  CAS  PubMed  Google Scholar 

  • Kleihues P, Louis DN, Scheithauer BW, Rorke LB, Reifenberger G, Burger PC et al. (2002). The WHO classification of tumors of the nervous system. J Neuropathol Exp Neurol 61: 215–225 discussion 226-9.

    Article  PubMed  Google Scholar 

  • Kobayashi I, Jin L, Ruebel KH, Bayliss JM, Hidehiro O, Lloyd RV . (2003). Regulation of cell growth and expression of 7B2, PC2, and PC1/3 by TGFbeta 1 and sodium butyrate in a human pituitary cell line (HP75). Endocrine 22: 285–292.

    Article  CAS  PubMed  Google Scholar 

  • Koch A, Tonn J, Kraus JA, Sörensen N, Albrecht NS, Wiestler OD et al. (1996). Molecular analysis of the lissencephaly gene 1 (LIS-1) in medulloblastomas. Neuropathol Appl Neurobiol 22: 233–242.

    Article  CAS  PubMed  Google Scholar 

  • Kraus JA, Koch A, Albrecht S, von Deimling A, Wiestler OD, Pietsch T . (1996). Loss of heterozygosity at locus F13B on chromosome 1q in human medulloblastoma. Int J Cancer 67: 11–15.

    Article  CAS  PubMed  Google Scholar 

  • Lindsey JC, Anderton JA, Lusher ME, Clifford SC . (2005). Epigenetic events in medulloblastoma development. Neurosurg Focus 19: E10.

    Article  PubMed  Google Scholar 

  • Mattei MG, Mbikay M, Sylla BS, Lenoir G, Mattei JF, Seidah NG et al. (1990). Assignment of the gene for neuroendocrine protein 7B2 (SGNE1 locus) to mouse chromosome region 2[E3-F3] and to human chromosome region 15q11-q15. Genomics 6: 436–440.

    Article  CAS  PubMed  Google Scholar 

  • Mbikay M, Seidah NG, Chretien M . (2001). Neuroendocrine secretory protein 7B2: structure, expression and functions. Biochem J 357: 329–342.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Mercapide J, Lopez de Cicco R, Bassi DE, Castresana JS, Thomas G, Klein-Szanto AJ . (2002). Inhibition of furin-mediated processing results in suppression of astrocytoma cell growth and invasiveness. Clin Cancer Res 8: 1740–1746.

    CAS  PubMed  Google Scholar 

  • Pietsch T, Scharmann T, Fonatsch C, Schmidt D, Ockler R, Freihoff D et al. (1994). Characterization of five new cell lines derived from human primitive neuroectodermal tumors of the central nervous system. Cancer Res 54: 3278–3287.

    CAS  PubMed  Google Scholar 

  • Pomeroy SL, Tamayo P, Gaasenbee KM, Sturla LM, Angelo M, McLaughlin ME et al. (2002). Prediction of central nervous system embryonal tumour outcome based on gene expression. Nature 415: 436–442.

    Article  CAS  PubMed  Google Scholar 

  • Reardon DA, Michalkiewicz E, Boyett JM, Sublett JE, Entrekin RE, Ragsdale ST et al. (1997). Extensive genomic abnormalities in childhood medulloblastoma by comparative genomic hybridization. Cancer Res 57: 4042–4047.

    CAS  PubMed  Google Scholar 

  • Roebroek AJ, Martens GJ, Duits AJ, Schalken JA, van Bokhoven A, Wagenaar SS et al. (1989). Differential expression of the gene encoding the novel pituitary polypeptide 7B2 in human lung cancer cells. Cancer Res 49: 4154–4158.

    CAS  PubMed  Google Scholar 

  • Russo C, Pellarin M, Tingby O, Bollen AW, Lamborn KR, Mohapatra G et al. (1999). Comparative genomic hybridization in patients with supratentorial and infratentorial primitive neuroectodermal tumors. Cancer 86: 331–339.

    Article  CAS  PubMed  Google Scholar 

  • Schmidt G, Sirois F, Anini Y, Kauri LM, Gyamera-Acheampong C, Fleck E et al. (2006). Differences of pancreatic expression of 7B2 between C57BL/6J and C3H/HeJ mice and genetic polymorphisms at its locus (Sgne1). Diabetes 55: 452–459.

    Article  CAS  PubMed  Google Scholar 

  • Seidah NG, Hsi KL, de Serres G, Rochemont J, Hamelin J, Antakly T et al. (1983). Isolation and NH2-terminal sequence of a highly conserved human and porcine pituitary protein belonging to a new superfamily. Immunocytochemical localization in pars distalis and pars nervosa of the pituitary and in the supraoptic nucleus of the hypothalamus. Arch Biochem Biophys 225: 525–534.

    Article  CAS  PubMed  Google Scholar 

  • Seidel B, Dong W, Savaria D, Zheng M, Pintar JE, Day R . (1998). Neuroendocrine protein 7B2 is essential for proteolytic conversion and activation of proprotein convertase 2 in vivo. DNA Cell Biol 17: 1017–1029.

    Article  CAS  PubMed  Google Scholar 

  • Strausberg RL, Feingold EA, Grouse LH, Derge JG, Klausner RD, Collins FS et al. (2002). Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences. Proc Natl Acad Sci USA 99: 16899–16903.

    Article  PubMed  Google Scholar 

  • Uziel T, Zindy F, Sherr CJ, Roussel MF . (2006). The CDK inhibitor p18Ink4c is a tumor suppressor in medulloblastoma. Cell Cycle 5: 363–365.

    Article  CAS  PubMed  Google Scholar 

  • Waha A, Güntner S, Huang TH, Yan PS, Arslan B, Pietsch T et al. (2005). Epigenetic silencing of the protocadherin family member PCDH-gamma-A11 in astrocytomas. Neoplasia 7: 193–199.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Waha A, Koch A, Meyer-Puttlitz B, Weggen S, Sörensen N, Tonn JC et al. (2003). Epigenetic silencing of the HIC-1 gene in human medulloblastomas. J Neuropathol Exp Neurol 62: 1192–1201.

    Article  CAS  PubMed  Google Scholar 

  • Waha A, Watzka M, Koch A, Pietsch T, Przkora R, Peters N et al. (1998). A rapid and sensitive protocol for competitive reverse transcriptase (cRT) PCR analysis of cellular genes. Brain Pathol 8: 13–18.

    Article  CAS  PubMed  Google Scholar 

  • Waldbieser GC, Aimi J, Dixon JE . (1991). Cloning and characterization of the rat complementary deoxyribonucleic acid and gene encoding the neuroendocrine peptide 7B2. Endocrinology 128: 3228–3236.

    Article  CAS  PubMed  Google Scholar 

  • Westphal CH, Muller L, Zhou A, Zhu X, Bonner-Weir S, Schambelan M et al. (1999). The neuroendocrine protein 7B2 is required for peptide hormone processing in vivo and provides a novel mechanism for pituitary Cushing's disease. Cell 96: 689–700.

    Article  CAS  PubMed  Google Scholar 

  • Yan PS, Chen CM, Shi H, Rahmatpanah F, Wei SH, Caldwell CW et al. (2001). Dissecting complex epigenetic alterations in breast cancer using CpG island microarrays. Cancer Res 61: 8375–8380.

    CAS  PubMed  Google Scholar 

  • Zhu X, Lindberg I . (1995). 7B2 facilitates the maturation of proPC2 in neuroendocrine cells and is required for the expression of enzymatic activity. J Cell Biol 129: 1641–1650.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We thank Dr G J Riggins and Dr D Bigner, Duke University Medical Center, Durham, NC, USA for kindly providing the cell lines D425Med and D556Med and Ulrich Klatt for photographic work. This work was supported by the Lise-Meitner-Habilitationsprogramm, NGFN Brain Tumor Network (N3KR-S09T02; N3KR-S04T06) and SMP-Epigenetics (PEG-S04T02), the Comprehensive Network Pediatric Oncology, the BONFOR-Progamm of the medical faculty of Bonn and the Children's Cancer Foundation Bonn.

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Authors and Affiliations

  1. Department of Neuropathology, University of Bonn, Germany

    A Waha, A Koch, W Hartmann, U Milde, J Felsberg, A Hübner, T Mikeska, T Pietsch & A Waha

  2. Montreal Children's Hospital Research Institute, McGill University, Montreal, Canada

    C G Goodyer

  3. Department of Pediatric Neurosurgery, University of Würzburg, Germany

    N Sörensen

  4. Department of Biochemistry and Molecular Biology, Louisiana State University, Medical Center, New Orleans, LA, USA

    I Lindberg

  5. German Cancer Research Center (DKFZ), Heidelberg, Germany

    O D Wiestler

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Correspondence to A Waha.

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Supplementary Information accompanies the paper on the Oncogene website (http://www.nature.com/onc).

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Waha, A., Koch, A., Hartmann, W. et al. SGNE1/7B2 is epigenetically altered and transcriptionally downregulated in human medulloblastomas. Oncogene 26, 5662–5668 (2007). https://doi.org/10.1038/sj.onc.1210338

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