Human tumors arise 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 (epigenetic) and copy number (genetic) analyses, we identified SLC5A8 on chromosome 12q23.1 and PRKWNK2 on chromosome 9q22.31 that were affected primarily by aberrant methylation in human astrocytomas and oligodendrogliomas. SLC5A8 encodes a sodium/monocarboxylate cotransporter and PRKWNK2 encodes a putative serine/threonine kinase. Both genes are highly expressed in normal brain but significant down-regulated in primary gliomas. Bisulfite sequencing analysis showed that their promoter CpG islands were unmethylated in normal brain, but extensively methylated in brain tumors, consistent with the tumor-specific loss of gene expression. In glioma cell lines, SLC5A8 and PRKWNK2 expression was also suppressed but could be reactivated with a methylation inhibitor. Expression of exogenous SLC5A8 or PRKWNK2 in glioma cells inhibited colony formation, suggesting they may function as growth suppressors in vitro. Remarkably, 9 of 10 murine oligodendroglial tumors (from p53+/− or ink4a/arf+/− animals transgenic for S100β-v-erbB) demonstrated a similar tumor-specific down-regulation of mSCL5A8, the highly conserved mouse homologue of SLC5A8. Similarly, the murine PRKWNK2 was also methylated and downregulated in a proportion of the mouse gliomas. Taken together, these data suggest that SLC5A8 and PRKWNK2 function as growth suppressors in vitro, and that epigenetic mechanisms are their primary cause of gene silencing in human gliomas. The shared epigenetic inactivation of both SCL5A8 and PRKWNK2 in mouse and human 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.

[Proc Amer Assoc Cancer Res, Volume 46, 2005]