SPINT2 is hypermethylated in both IDH1 mutated and wild-type glioblastomas, and exerts tumor suppression via reduction of c-Met activation

Fei Liu, Christopher D. Cox, Reshmi Chowdhury, Laura Dovek, Huytram Nguyen, Tie Li, Sichen Li, Byram Ozer, Arthur Chou, Nhung Nguyen, Bowen Wei, Joseph Antonios, Horacio Soto, Harley Kornblum, Linda Liau, Robert Prins, P. Leia Nghiemphu, William Yong, Timothy Cloughesy, Albert Lai

Research output: Contribution to journalArticle

Abstract

Purpose: Both 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. Methods: We 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. Results: We 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. Conclusions: We 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.

Original languageEnglish (US)
JournalJournal of neuro-oncology
DOIs
Publication statusPublished - Jan 1 2019
Externally publishedYes

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Keywords

  • CpG island methylation
  • Glioblastoma
  • HGF/c-Met
  • SPINT2
  • Tumor suppressor

ASJC Scopus subject areas

  • Oncology
  • Neurology
  • Clinical Neurology
  • Cancer Research

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