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

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.

• Authors: 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
• Journal: Molecular cell (Mol Cell) Vol. 60 Issue 2 Pg. 307-18 (Oct 15 2015) ISSN: 1097-4164 [Electronic] United States
• PMID: 26455392 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2015 Elsevier Inc. All rights reserved.

Chemical References

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

Topics

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