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Mol Cell. 2015 Oct 15;60(2):307-18. doi: 10.1016/j.molcel.2015.09.002. Epub 2015 Oct 8.

EGFR Mutation Promotes Glioblastoma through Epigenome and Transcription Factor Network Remodeling.

Author information

1
Ludwig Institute for Cancer Research, La Jolla, CA 92093, USA.
2
Ludwig Institute for Cancer Research, La Jolla, CA 92093, USA; David Geffen UCLA School of Medicine, Los Angeles, CA 90095, USA.
3
David Geffen UCLA School of Medicine, Los Angeles, CA 90095, USA.
4
Department of Pathology, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
5
Toronto Western Research Institute, University Health Network, Toronto, ON M5T 2S8, Canada; Program in Neurosciences and Mental Health, Hospital for Sick Children, Toronto, ON M5T 2S8, Canada.
6
Ludwig Institute for Cancer Research, La Jolla, CA 92093, USA; Department of Pathology, UCSD School of Medicine, La Jolla, CA 92093, USA.
7
Ludwig Institute for Cancer Research, La Jolla, CA 92093, USA; Department of Medicine, UCSD School of Medicine, La Jolla, CA 92093, USA; Moores Cancer Center, UCSD School of Medicine, La Jolla, CA 92093, USA.
8
Ludwig Institute for Cancer Research, La Jolla, CA 92093, USA; Department of Cellular and Molecular Medicine, Institute of Genomic Medicine, UCSD School of Medicine, La Jolla, CA 92093, USA; Moores Cancer Center, UCSD School of Medicine, La Jolla, CA 92093, USA. Electronic address: biren@ucsd.edu.
9
Ludwig Institute for Cancer Research, La Jolla, CA 92093, USA; Department of Pathology, UCSD School of Medicine, La Jolla, CA 92093, USA; Moores Cancer Center, UCSD School of Medicine, La Jolla, CA 92093, USA. Electronic address: pmischel@ucsd.edu.

Abstract

Epidermal growth factor receptor (EGFR) gene amplification and mutations are the most common oncogenic events in glioblastoma (GBM), but the mechanisms by which they promote aggressive tumor growth are not well understood. Here, through integrated epigenome and transcriptome analyses of cell lines, genotyped clinical samples, and TCGA data, we show that EGFR mutations remodel the activated enhancer landscape of GBM, promoting tumorigenesis through a SOX9 and FOXG1-dependent transcriptional regulatory network in vitro and in vivo. The most common EGFR mutation, EGFRvIII, sensitizes GBM cells to the BET-bromodomain inhibitor JQ1 in a SOX9, FOXG1-dependent manner. These results identify the role of transcriptional/epigenetic remodeling in EGFR-dependent pathogenesis and suggest a mechanistic basis for epigenetic therapy.

PMID:
26455392
PMCID:
PMC4609298
DOI:
10.1016/j.molcel.2015.09.002
[Indexed for MEDLINE]
Free PMC Article

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