The 10q25.3-26.1 G protein-coupled receptor gene GPR26 is epigenetically silenced in human gliomas
| Autor: | Pier Morin, Daniel Maier, Brian A. Hemmings, Mihai-Constantin S. Ionescu, Martin Labuhn, Graham Jones, Béatrice Dolder-Schlienger, Jean-Louis Boulay, Maria Maddalena Lino, Balasubramanian Sivasankaran, Elisabeth Taylor, Adrian Merlo |
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| Rok vydání: | 2009 |
| Předmět: |
Cancer Research
medicine.drug_class Molecular Sequence Data Biology medicine.disease_cause Receptors G-Protein-Coupled Loss of heterozygosity Glioma medicine Gene silencing Humans Epigenetics Cancer epigenetics Amino Acid Sequence Gene Silencing neoplasms Oligonucleotide Array Sequence Analysis Genetics Base Sequence Brain Neoplasms Chromosomes Human Pair 10 Reverse Transcriptase Polymerase Chain Reaction Histone deacetylase inhibitor HEK 293 cells medicine.disease Blotting Northern Flow Cytometry Oncology Cancer research Carcinogenesis |
| Zdroj: | International journal of oncology. 35(5) |
| ISSN: | 1791-2423 |
| Popis: | Loss of heterozygosity (LOH) of the entire chromosome 10 is the most frequent genetic alteration in human glioblastoma (GBM). In addition to PTENlMMAC 1 on 10q23.3, clustering of partial deletion break-points on 1Oq25.3- 26.1 points to a second suppressor locus. The proposed target gene DMBT1 was not confirmed. By somatic deletion mapping of this region, we identified the complementary DNA encoding the human homologue of rat orphan G protein-coupled receptor GPR26. GPR26 is highly expressed in fetal and adult brain, but frequently reduced or absent in glioma cells and biopsies, due to de novo methylation of its 5' CpG island. Silencing of GPR26 was reversed with 5-aza-deoxy-cytidine and the histone deacetylase inhibitor trichostatin A. Furthermore, overexpression of GPR26 in HEK and in U87 glioma cells increased intracellular cAMP concentration which is considered to induce astrocytic differentiation. Interestingly, we observed concomitant silencing of GPR26 with 0 6 -methylguanine-DNA methyl transferase (MGMT), a DNA repair gene co-localized on 1Oq25.3-26.1 (p=0.0001). We conclude that epigenetic silencing is a common mechanism in malignant gliomas that simultaneously inactivates MGMT and GPR26. The 10q25.3-26.1 region may contain an important epigenetic pathway in brain tumorigenesis. |
| Databáze: | OpenAIRE |
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