Human Molecular Genetics Advance Access originally published online on September 22, 2004
Human Molecular Genetics 2004 13(22):2753-2765; doi:10.1093/hmg/ddh298
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Human Molecular Genetics, Vol. 13, No. 22 © Oxford University Press 2004; all rights reserved
Epigenetic loss of the familial tumor-suppressor gene exostosin-1 (EXT1) disrupts heparan sulfate synthesis in cancer cells
1Cancer Epigenetics Laboratory, Spanish National Cancer Centre (CNIO), Melchor Fernandez Almagro 3, 28029 Madrid, Spain, 2Department of Clinical Chemistry and Transfusion Medicine, Research Center for Endocrinology and Metabolism, Institution of Laboratory Medicine, Sahlgrenska University Hospital, Goteborg, Sweden, 3Laboratory of Oncologic Research, Department of Musculoskeletal Oncology, Rizzoli Orthopedic Institute, Bologna, Italy, 4Department of Human Pathology and Oncology, Universita Degli Studi di Firenze, Italy, 5Department of Pediatrics, Clinica Universitaria de Navarra, Pamplona, Spain, 6Laboratory of Molecular Genetics of Cancer—GEMOCA, School of Medicine, Sao Paulo, Brazil, 7Department of Pathology, Leiden University Medical Center, Leiden, The Netherlands, 8Cytogenetics Laboratory, Spanish National Cancer Centre (CNIO), Melchor Fernandez Almagro 3, 28029 Madrid, Spain and 9Department of Medical Genetics, University of Antwerp, Universiteitsplein 1, Building T, 6th floor, 2610 Antwerp, Belgium
Received June 28, 2004; Accepted September 11, 2004
Germline mutations in the Exostoses-1 gene (EXT1) are found in hereditary multiple exostoses syndrome, which is characterized by the formation of osteochondromas and an increased risk of chondrosarcomas and osteosarcomas. However, despite its putative tumor-suppressor function, little is known of the contribution of EXT1 to human sporadic malignancies. Here, we report that EXT1 function is abrogated in human cancer cells by transcriptional silencing associated with CpG island promoter hypermethylation. We also show that, at the biochemical and cellular levels, the epigenetic inactivation of EXT1, a glycosyltransferase, leads to the loss of heparan sulfate (HS) synthesis. Reduced HS production can be reversed by the use of a DNA demethylating agent. Furthermore, the re-introduction of EXT1 into cancer cell lines displaying methylation-dependent silencing of EXT1 induces tumor-suppressor-like features, e.g. reduced colony formation density and tumor growth in nude mouse xenograft models. Screening a large collection of human cancer cell lines (n=79) and primary tumors (n=454) from different cell types, we found that EXT1 CpG island hypermethylation was common in leukemia, especially acute promyelocytic leukemia and acute lymphoblastic leukemia, and non-melanoma skin cancer. These findings highlight the importance of EXT1 epigenetic inactivation, leading to an abrogation of HS biosynthesis, in the processes of tumor onset and progression.
* To whom correspondence should be addressed. Tel: +34 912246940; Fax: +34 912246923; Email: mesteller{at}cnio.es
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