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 Gahman; Andrew K Shiau; Webster K Cavenee; Bing Ren; Paul S Mischel

doi:10.1016/j.molcel.2015.09.002

EGFR Mutation Promotes Glioblastoma through Epigenome and Transcription Factor Network Remodeling

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

Authors

Feng Liu¹, Gary C Hon¹, Genaro R Villa², Kristen M Turner¹, Shiro Ikegami¹, Huijun Yang¹, Zhen Ye¹, Bin Li¹, Samantha Kuan¹, Ah Young Lee¹, Ciro Zanca¹, Bowen Wei³, Greg Lucey³, David Jenkins¹, Wei Zhang⁴, Cathy L Barr⁵, Frank B Furnari⁶, Timothy F Cloughesy³, William H Yong³, Timothy C Gahman¹, Andrew K Shiau¹, Webster K Cavenee⁷, Bing Ren⁸, Paul S Mischel⁹

Affiliations

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.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Adult
Animals
Azepines / pharmacology
Brain Neoplasms / genetics*
Brain Neoplasms / metabolism
Brain Neoplasms / pathology
Cell Line, Tumor
Cell Survival / drug effects
Cell Transformation, Neoplastic / genetics
Cell Transformation, Neoplastic / metabolism
Cell Transformation, Neoplastic / pathology
Child
Epigenesis, Genetic*
ErbB Receptors / genetics*
ErbB Receptors / metabolism
Forkhead Transcription Factors / genetics*
Forkhead Transcription Factors / metabolism
Gene Expression Regulation, Neoplastic
Gene Regulatory Networks
Glioblastoma / genetics*
Glioblastoma / metabolism
Glioblastoma / pathology
Humans
Mice
Mice, Nude
Mutation
Neoplasm Transplantation
Nerve Tissue Proteins / genetics*
Nerve Tissue Proteins / metabolism
SOX9 Transcription Factor / genetics*
SOX9 Transcription Factor / metabolism
Signal Transduction
Transcriptome
Triazoles / pharmacology

Substances

(+)-JQ1 compound
Azepines
FOXG1 protein, human
Forkhead Transcription Factors
Nerve Tissue Proteins
SOX9 Transcription Factor
SOX9 protein, human
Triazoles
EGFR protein, human
ErbB Receptors

Associated data

GEO/GSE72468

Abstract

Publication types

MeSH terms

Substances

Associated data

Grants and funding