Abstract
Aberrant CpG methylations play important roles in cancer development and progression. In this study, aberrant methylations in human breast cancer were searched for using methylation-sensitive representational difference analysis (MS-RDA). A CpG island (CGI) in the 5′ region of the heparan sulfate D -glucosaminyl 3-O-sulfotransferase-2 (3-OST-2) gene was found to be hypermethylated, while its exon 2 was hypomethylated. In seven breast cancer cell lines, hypermethylation of the 5′ region and loss of 3-OST-2 expression were observed. Treatment with a demethylating agent, 5-aza-2′-deoxycytidine, removed the methylation of the CGI in the 5′ region and restored its expression, demonstrating silencing of the 3-OST-2 gene. Methylation-specific PCR (MSP) analysis in 85 primary breast cancers showed that the hypermethylation of the CGI in the 5′ region was present in 75 (88%) of them. Quantitative reverse transcriptase-PCR (RT–PCR) analysis in 37 primary breast cancers showed that the average expression level was decreased in them. Further, MSP analysis in primary colon, lung and pancreatic cancers showed that hypermethylation of the CGI in the 5′ region was present in the colon (8/10, 80%), lung (7/10, 70%) and pancreatic (10/10, 100%) cancers. These results showed that silencing of 3-OST-2 was present in a wide range of human cancers. The 3-OST-2 gene encodes an enzyme involved in the final modification step of heparan sulfate proteoglycans (HSPGs), and its silencing is expected to result in abnormal modification of HSPGs and abnormal signal transduction. From the high incidence, silencing of the 3-OST-2 gene is expected to have high diagnostic, and potentially therapeutic, values.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 50 print issues and online access
$259.00 per year
only $5.18 per issue
Rent or buy this article
Prices vary by article type
from$1.95
to$39.95
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
Accession codes
References
Asada K, Miyamoto K, Fukutomi T, Tsuda H, Yagi Y, Wakazono K, Oishi S, Fukui H, Sugimura T and Ushijima T . Oncology (in press).
Baylin SB, Esteller M, Rountree MR, Bachman KE, Schuebel K and Herman JG . (2001). Hum. Mol. Genet., 10, 687–692.
Bernfield M, Gotte M, Park PW, Reizes O, Fitzgerald ML, Lincecum J and Zako M . (1999). Annu. Rev. Biochem., 68, 729–777.
Bird A . (2002). Genes Dev., 16, 6–21.
Clark SJ, Harrison J, Paul CL and Frommer M . (1994). Nucleic Acids Res., 22, 2990–2997.
Clark SJ and Melki J . (2002). Oncogene, 21, 5380–5387.
Eads CA, Danenberg KD, Kawakami K, Saltz LB, Blake C, Shibata D, Danenberg PV and Laird PW . (2000). Nucleic Acids Res., 28, E32.
Esko JD and Lindahl U . (2001). J. Clin. Invest., 108, 169–173.
Esteller M, Corn PG, Baylin SB and Herman JG . (2001). Cancer Res., 61, 3225–3229.
Esteller M, Sanchez-Cespedes M, Rosell R, Sidransky D, Baylin SB and Herman JG . (1999). Cancer Res., 59, 67–70.
Feinberg AP . (2001). Nat. Genet., 27, 9–10.
Gardiner-Garden M and Frommer M . (1987). J. Mol. Biol., 196, 261–282.
Gonzalgo ML, Hayashida T, Bender CM, Pao MM, Tsai YC, Gonzales FA, Nguyen HD, Nguyen TT and Jones PA . (1998). Cancer Res., 58, 1245–1252.
Herman JG, Graff JR, Myohanen S, Nelkin BD and Baylin SB . (1996). Proc. Natl. Acad. Sci. USA., 93, 9821–9826.
Jones PA . (1999). Trends Genet., 15, 34–37.
Jones PA and Baylin SB . (2002). Nat. Rev. Genet., 3, 415–428.
Jones PA and Laird PW . (1999). Nat. Genet., 21, 163–167.
Kaneda A, Kaminishi M, Nakanishi Y, Sugimura T and Ushijima T . (2002). Int. J. Cancer, 100, 57–62.
Kaneda A, Kaminishi M, Yanagihara K, Sugimura T and Ushijima T . Cancer Res. (in press).
Kawakami K, Brabender J, Lord RV, Groshen S, Greenwald BD, Krasna MJ, Yin J, Fleisher AS, Abraham JM, Beer DG, Sidransky D, Huss HT, Demeester TR, Eads C, Laird PW, Ilson DH, Kelsen DP, Harpole D, Moore MB, Danenberg KD, Danenberg PV and Meltzer SJ . (2000). J. Natl. Cancer Inst., 92, 1805–1811.
Kelsey G, Bodle D, Miller HJ, Beechey CV, Coombes C, Peters J and Williamson CM . (1999). Genomics, 62, 129–138.
Lisitsyn N, Lisitsyn N and Wigler M . (1993). Science, 259, 946–951.
Matsuda K, Maruyama H, Guo F, Kleeff J, Itakura J, Matsumoto Y, Lander AD and Korc M . (2001). Cancer Res., 61, 5562–5569.
Muller K, Heller H and Doerfler W . (2001). J. Biol. Chem., 276, 14271–14278.
Perrimon N and Bernfield M . (2000). Nature, 404, 725–728.
Rein T, Zorbas H and DePamphilis ML . (1997). Mol. Cell. Biol., 17, 416–426.
Sambrook J, Fritsch EF and Maniatis T . (eds). (1989). Molecular Cloning, Vol. 2. Cold Spring Harbor Laboratory Press: Cold Spring Harbor, New York, pp 1914–1923.
Shapiro B, Chakrabarty M, Cohn EM and Leon SA . (1983). Cancer, 51, 2116–2120.
Shworak NW, Liu J, Petros LM, Zhang L, Kobayashi M, Copeland NG, Jenkins NA and Rosenberg RD . (1999). J. Biol. Chem., 274, 5170–5184.
Silva JM, Dominguez G, Villanueva MJ, Gonzalez R, Garcia JM, Corbacho C, Provencio M, Espana P and Bonilla F . (1999). Br. J. Cancer, 80, 1262–1264.
Stanley MJ, Stanley MW, Sanderson RD and Zera R . (1999). Am. J. Clin. Pathol., 112, 377–383.
Stroun M, Anker P, Maurice P, Lyautey J, Lederrey C and Beljanski M . (1989). Oncology, 46, 318–322.
Surani MA . (2001). Nature, 414, 122–128.
Takai D, Yagi Y, Wakazono K, Ohishi N, Morita Y, Sugimura T and Ushijima T . (2001). Oncogene, 20, 7505–7513.
Ushijima T, Morimura K, Hosoya Y, Okonogi H, Tatematsu M, Sugimura T and Nagao M . (1997). Proc. Natl. Acad. Sci. USA., 94, 2284–2289.
Acknowledgements
We are grateful to Dr Masatsugu Yano for providing tumor samples. This study was supported by Grants-in-Aid for the second term 10-year Comprehensive Strategy for Cancer Control and for Human Genome and Tissue Regeneration from the Ministry of Health, Labour, and Welfare, Japan.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Miyamoto, K., Asada, K., Fukutomi, T. et al. Methylation-associated silencing of heparan sulfate D-glucosaminyl 3-O-sulfotransferase-2 (3-OST-2) in human breast, colon, lung and pancreatic cancers. Oncogene 22, 274–280 (2003). https://doi.org/10.1038/sj.onc.1206146
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/sj.onc.1206146
Keywords
This article is cited by
-
Changes in heparan sulfate sulfotransferases and cell-surface heparan sulfate during SKM-1 cells granulocytic differentiation and A549 cells epithelial-mesenchymal transition
Glycoconjugate Journal (2020)
-
CpG Islands Methylation Analysis of CDH11, EphA5, and HS3ST2 Genes in Gastric Adenocarcinoma Patients
Journal of Gastrointestinal Cancer (2020)
-
Incorporating genetic networks into case-control association studies with high-dimensional DNA methylation data
BMC Bioinformatics (2019)
-
Heparan sulfate proteoglycans undergo differential expression alterations in left sided colorectal cancer, depending on their metastatic character
BMC Cancer (2018)
-
Biomolecular analysis of matrix proteoglycans as biomarkers in non small cell lung cancer
Glycoconjugate Journal (2018)