Shared epigenetic mechanisms in human and mouse gliomas inactivate expression of the growth suppressor SLC5A8.
Tumors arise in part from the deleterious effects of genetic and epigenetic mechanisms on gene expression. In several mouse models of human tumors, the tumorigenic phenotype is reversible, suggesting that epigenetic mechanisms also contribute significantly to tumorigenesis in mice. It is not known whether these are the same epigenetic mechanisms in human and mouse tumors or whether they affect homologous genes. Using an integrated approach for genome-wide methylation and copy number analyses, we identified SLC5A8 on chromosome 12q23.1 that was affected frequently by aberrant methylation in human astrocytomas and oligodendrogliomas. SLC5A8 encodes a sodium monocarboxylate cotransporter that was highly expressed in normal brain but was significant down-regulated in primary gliomas. Bisulfite sequencing analysis showed that the CpG island was unmethylated in normal brain but frequently localized methylated in brain tumors, consistent with the tumor-specific loss of gene expression. In glioma cell lines, SLC5A8 expression was also suppressed but could be reactivated with a methylation inhibitor. Expression of exogenous SLC5A8 in LN229 and LN443 glioma cells inhibited colony formation, suggesting that it may function as a growth suppressor in normal brain cells. Remarkably, 9 of 10 murine oligodendroglial tumors (from p53+/- or ink4a/arf+/- animals transgenic for S100beta-v-erbB) showed a similar tumor-specific down-regulation of mSLC5A8, the highly conserved mouse homologue. Taken together, these data suggest that SLC5A8 functions as a growth suppressor gene in vitro and that it is silenced frequently by epigenetic mechanisms in primary gliomas. The shared epigenetic inactivation of mSLC5A8 in mouse gliomas indicates an additional degree of commonality in the origin and/or pathway to tumorigenesis between primary human tumors and these mouse models of gliomas.
Hong
Chibo
C
Department of Neurological Surgery, Brain Tumor Research Center, University of California-San Francisco, San Francisco, California 94143-0875, USA.
Maunakea
Alika
A
Jun
Peter
P
Bollen
Andrew W
AW
Hodgson
J Graeme
JG
Goldenberg
David D
DD
Weiss
William A
WA
Costello
Joseph F
JF
D000818:Animals; D001254:Astrocytoma / Q000235:genetics* / Q000378:metabolism; D001932:Brain Neoplasms / Q000235:genetics* / Q000378:metabolism; D027682:Cation Transport Proteins / Q000096:biosynthesis / Q000235:genetics*; D045744:Cell Line, Tumor; D018899:CpG Islands / Q000235:genetics; D019175:DNA Methylation; D004195:Disease Models, Animal; D015536:Down-Regulation; D015972:Gene Expression Regulation, Neoplastic; D020868:Gene Silencing; D016147:Genes, Tumor Suppressor; D005822:Genetic Vectors / Q000235:genetics; D006801:Humans; D051379:Mice; D008811:Mice, Inbred DBA; D008822:Mice, Transgenic; D027501:Monocarboxylic Acid Transporters; D009837:Oligodendroglioma / Q000235:genetics* / Q000378:metabolism; D012190:Retroviridae / Q000235:genetics
D027682:Cation Transport Proteins; D027501:Monocarboxylic Acid Transporters; C476760:SLC5A8 protein, human