EGFR Mutation Promotes Glioblastoma through Epigenome and Transcription Factor Network Remodeling

Feng Liu, Gary C. Hon, Genaro R. Villa, Kristen M. Turner, Shiro Ikegami, Huijun Yang, Zhen Ye, Bin Li, Samantha Kuan, Ah Young Lee, Ciro Zanca, Bowen Wei, Greg Lucey, David Jenkins, Wei Zhang, Cathy L. Barr, Frank B. Furnari, Timothy F. Cloughesy, William H. Yong, Timothy C. GahmanAndrew K. Shiau, Webster K. Cavenee, Bing Ren, Paul S. Mischel

Research output: Contribution to journalArticle

83 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)307-318
Number of pages12
JournalMolecular Cell
Volume60
Issue number2
DOIs
StatePublished - Oct 15 2015

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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    Liu, F., Hon, G. C., Villa, G. R., Turner, K. M., Ikegami, S., Yang, H., Ye, Z., Li, B., Kuan, S., Lee, A. Y., Zanca, C., Wei, B., Lucey, G., Jenkins, D., Zhang, W., Barr, C. L., Furnari, F. B., Cloughesy, T. F., Yong, W. H., ... Mischel, P. S. (2015). EGFR Mutation Promotes Glioblastoma through Epigenome and Transcription Factor Network Remodeling. Molecular Cell, 60(2), 307-318. https://doi.org/10.1016/j.molcel.2015.09.002