The 10q25.3-26.1 G protein-coupled receptor gene GPR26 is epigenetically silenced in human gliomas.
Loss of heterozygosity (LOH) of the entire chromosome 10 is the most frequent genetic alteration in human glioblastoma (GBM). In addition to PTEN/MMAC1 on 10q23.3, clustering of partial deletion break-points on 10q25.3-26.1 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-deoxycytidine 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 O6-methylguanine-DNA methyl transferase (MGMT), a DNA repair gene co-localized on 10q25.3-26.1 (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.
Boulay
Jean-Louis
JL
Laboratory of Molecular Neuro-Oncology, Department of Biomedicine, University Hospital, CH-4031 Basel. jean-louis.boulay@unibas.ch
Ionescu
Mihai-Constantin S
MC
Sivasankaran
Balasubramanian
B
Labuhn
Martin
M
Dolder-Schlienger
Béatrice
B
Taylor
Elisabeth
E
Morin
Pier
P
Hemmings
Brian A
BA
Lino
Maria Maddalena
MM
Jones
Graham
G
Maier
Daniel
D
Merlo
Adrian
A
D000595:Amino Acid Sequence; D001483:Base Sequence; D015152:Blotting, Northern; D001932:Brain Neoplasms / Q000235:genetics*; D002879:Chromosomes, Human, Pair 10 / Q000235:genetics*; D005434:Flow Cytometry; D020868:Gene Silencing; D005910:Glioma / Q000235:genetics*; D006801:Humans; D008969:Molecular Sequence Data; D020411:Oligonucleotide Array Sequence Analysis; D043562:Receptors, G-Protein-Coupled / Q000235:genetics*; D020133:Reverse Transcriptase Polymerase Chain Reaction
C489011:GPR26 protein, human; D043562:Receptors, G-Protein-Coupled