Journal
JOURNAL OF NEURO-ONCOLOGY
Volume 142, Issue 3, Pages 423-434Publisher
SPRINGER
DOI: 10.1007/s11060-019-03126-x
Keywords
Glioblastoma; CpG island methylation; SPINT2; Tumor suppressor; HGF; c-Met
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Funding
- Bradley Zankel Foundation
- National Institutes of Health/National Cancer Institute [R01CA179071]
- UCLA SPORE in Brain Cancer [P50 CA211015]
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PurposeBoth IDH1-mutated and wild-type gliomas abundantly display aberrant CpG island hypermethylation. However, the potential role of hypermethylation in promoting gliomas, especially the most aggressive form, glioblastoma (GBM), remains poorly understood.MethodsWe analyzed RRBS-generated methylation profiles for 11 IDH1(WT) gliomas (including 7 GBMs), 24 IDH1(MUT) gliomas (including 6 GBMs), and 5 normal brain samples and employed TCGA GBM methylation profiles as a validation set. Upon classification of differentially methylated CpG islands by IDH1 status, we used integrated analysis of methylation and gene expression to identify SPINT2 as a top cancer related gene. To explore functional consequences of SPINT2 methylation in GBM, we validated SPINT2 methylation status using targeted bisulfite sequencing in a large cohort of GBM samples. We assessed DNA methylation-mediated SPINT2 gene regulation using 5-aza-2-deoxycytidine treatment, DNMT1 knockdown and luciferase reporter assays. We conducted functional analyses of SPINT2 in GBM cell lines in vitro and in vivo.ResultsWe identified SPINT2 as a candidate tumor-suppressor gene within a group of CpG islands (designated G(T)-CMG) that are hypermethylated in both IDH1(MUT) and IDH1(WT) gliomas but not in normal brain. We established that SPINT2 downregulation results from promoter hypermethylation, and that restoration of SPINT2 expression reduces c-Met activation and tumorigenic properties of GBM cells.ConclusionsWe defined a previously under-recognized group of coordinately methylated CpG islands common to both IDH1(WT) and IDH1(MUT) gliomas (G(T)-CMG). Within G(T)-CMG, we identified SPINT2 as a top cancer-related candidate and demonstrated that SPINT2 suppressed GBM via down-regulation of c-Met activation.
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