Priority Research Papers:
Epigenetic suppression of EGFR signaling in G-CIMP+ glioblastomas
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Jie Li1,*, Zachary J. Taich1,*,Amit Goyal1, David Gonda1, Johnny Akers1, Bandita Adhikari1, Kunal Patel1, Scott Vandenberg2, Wei Yan3, Zhaoshi Bao3, Bob S. Carter1, Renzhi Wang4, Ying Mao5, Tao Jiang3 and Clark C. Chen1
1 Center for Theoretical and Applied Neuro-Oncology, Division of Neurosurgery, University of California, San Diego
2 Department of Pathology, University of California, San Diego
3 Department of Neurosurgery, Tiantan Hospital, Capital Medical University, Beijing, China
4 Department of Neurosurgery, Peking Union Medical College Hospital, Beijing, China
5 Department of Neurosurgery, Huashan Hospital, Shanghai Medical College, Fudan University, Shanghai, China
* These authors contributed equally to this work
Clark C. Chen, email:
Keywords: G-CIMP, EGFR, Glioblastoma, Epigenetic suppression
Received: August 10, 2014 Accepted: August 15, 2014 Published: August 16, 2014
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.
Zachary J. Taich
Bob S. Carter
Clark C. Chen
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