|
|
Shared epigenetic mechanisms in human and mouse gliomas
inactivate expression of the growth suppressor SLC5A8
Hong C, Maunakea A, Jun P, Bollen AW, Hodgson JG, Goldenberg DD, Weiss
WA, Costello JF
Department of Neurological Surgery, Brain Tumor Research Center, University
of California-San Francisco, San Francisco, California 94143-0875, USA.
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.
PMID: 15867356 [PubMed - in process]
|
