학술논문
EGFR Mutation Promotes Glioblastoma through Epigenome and Transcription Factor Network Remodeling
Document Type
article
Author
Liu, Feng; Hon, Gary C; Villa, Genaro R; Turner, Kristen M; Ikegami, Shiro; Yang, Huijun; Ye, Zhen; Li, Bin; Kuan, Samantha; Lee, Ah Young; Zanca, Ciro; Wei, Bowen; Lucey, Greg; Jenkins, David; Zhang, Wei; Barr, Cathy L; Furnari, Frank B; Cloughesy, Timothy F; Yong, William H; Gahman, Timothy C; Shiau, Andrew K; Cavenee, Webster K; Ren, Bing; Mischel, Paul S
Source
Molecular Cell. 60(2)
Subject
Language
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.