Epigenetic suppression of EGFR signaling in G-CIMP+ glioblastomas

Jie Li, Zachary J. Taich, Amit Goyal, David Gonda, Johnny Akers, Bandita Adhikari, Kunal Patel, Scott Vandenberg, Wei Yan, Zhaoshi Bao, Bob S. Carter, Renzhi Wang, Ying Mao, Tao Jiang, Clark C. Chen

Research output: Contribution to journalArticle

15 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)7342-7356
Number of pages15
JournalOncotarget
Volume5
Issue number17
DOIs
StatePublished - Jan 1 2014

Keywords

  • EGFR
  • Epigenetic suppression
  • G-CIMP
  • Glioblastoma

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    Li, J., Taich, Z. J., Goyal, A., Gonda, D., Akers, J., Adhikari, B., Patel, K., Vandenberg, S., Yan, W., Bao, Z., Carter, B. S., Wang, R., Mao, Y., Jiang, T., & Chen, C. C. (2014). Epigenetic suppression of EGFR signaling in G-CIMP+ glioblastomas. Oncotarget, 5(17), 7342-7356. https://doi.org/10.18632/oncotarget.2350