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 language | English (US) |
|---|---|
| Pages (from-to) | 307-318 |
| Number of pages | 12 |
| Journal | Molecular Cell |
| Volume | 60 |
| Issue number | 2 |
| DOIs | |
| State | Published - Oct 15 2015 |
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ASJC Scopus subject areas
- Molecular Biology
- Cell Biology
Cite this
EGFR Mutation Promotes Glioblastoma through Epigenome and Transcription Factor Network Remodeling. / 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.
In: Molecular Cell, Vol. 60, No. 2, 15.10.2015, p. 307-318.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - EGFR Mutation Promotes Glioblastoma through Epigenome and Transcription Factor Network Remodeling
AU - Liu, Feng
AU - Hon, Gary C.
AU - Villa, Genaro R.
AU - Turner, Kristen M.
AU - Ikegami, Shiro
AU - Yang, Huijun
AU - Ye, Zhen
AU - Li, Bin
AU - Kuan, Samantha
AU - Lee, Ah Young
AU - Zanca, Ciro
AU - Wei, Bowen
AU - Lucey, Greg
AU - Jenkins, David
AU - Zhang, Wei
AU - Barr, Cathy L.
AU - Furnari, Frank B.
AU - Cloughesy, Timothy F.
AU - Yong, William H.
AU - Gahman, Timothy C.
AU - Shiau, Andrew K.
AU - Cavenee, Webster K.
AU - Ren, Bing
AU - Mischel, Paul S.
PY - 2015/10/15
Y1 - 2015/10/15
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=84944896282&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84944896282&partnerID=8YFLogxK
U2 - 10.1016/j.molcel.2015.09.002
DO - 10.1016/j.molcel.2015.09.002
M3 - Article
C2 - 26455392
AN - SCOPUS:84944896282
VL - 60
SP - 307
EP - 318
JO - Molecular Cell
JF - Molecular Cell
SN - 1097-2765
IS - 2
ER -