Abstract
The intrinsic signaling cascades and cell states associated with the Glioma CpG Island Methylator Phenotype (G-CIMP) remain poorly understood. Using published mRNA signatures associated with EGFR activation, we demonstrate that G-CIMP+ tumors harbor decreased EGFR signaling using three independent datasets, including the Chinese Glioma Genome Atlas(CGGA; n=155), the REMBRANDT dataset (n=288), and The Cancer Genome Atlas (TCGA; n=406). Additionally, an independent collection of 25 fresh-frozen glioblastomas confirmed lowered pERK levels in G-CIMP+ specimens (p<0.001), indicating suppressed EGFR signaling. Analysis of TCGA glioblastomas revealed that G-CIMP+ glioblastomas harbored lowered mRNA levels for EGFR and H-Ras. Induction of G-CIMP+ state by exogenous expression of a mutated isocitrate dehydrogenase 1, IDH1-R132H, suppressed EGFR and H-Ras protein expression as well as pERK accumulation in independent glioblastoma models. These suppressions were associated with increased deposition of the repressive histone markers, H3K9me3 and H3K27me3, in the EGFR and H-Ras promoter regions. The IDH1-R132H expression-induced pERK suppression can be reversed by exogenous expression of H-RasG12V. Finally, the G-CIMP+ Ink4a-Arf-/- EGFRvIII glioblastoma line was more resistant to the EGFR inhibitor, Gefitinib, relative to its isogenic G-CIMP- counterpart. These results suggest that G-CIMP epigenetically regulates EGFR signaling and serves as a predictive biomarker for EGFR inhibitors in glioblastoma patients.
Highlights
Glioblastoma is the most common form of primary brain cancer and remains one of the most devastating of human diseases [1]
We showed the Epidermal Growth Factor Receptor (EGFR) signaling was suppressed in Glioma CpG island methylator phenotype (G-CIMP)+ glioblastomas
The The Cancer Genome Atlas (TCGA) efforts have identified three pathways that are aberrantly regulated in glioblastomas, including those mediated by receptor tyrosine kinase (RTK), p53, and Rb
Summary
Glioblastoma is the most common form of primary brain cancer and remains one of the most devastating of human diseases [1]. The aggregate of laboratory and clinical investigations spanning the past four decades has led to the understanding that glioblastomas, like most cancers, are defined by a unifying set of phenotypes, including self-sufficiency in growth signaling and altered DNA damage response [2, 3]. The underlying molecular events responsible for these phenotypes are diverse, and they vary among different glioblastomas. The term glioblastoma captures a wide spectrum of molecular physiologies [4]. One of the recurrent physiologic states in glioblastoma is the Glioma CpG island methylator phenotype (G-CIMP) [6]. Glioblastoma with this phenotype harbors extensive methylation in the www.impactjournals.com/oncotarget
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