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

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 journal › Article

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 language	English (US)
Pages (from-to)	307-318
Number of pages	12
Journal	Molecular Cell
Volume	60
Issue number	2
DOIs	https://doi.org/10.1016/j.molcel.2015.09.002
State	Published - 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

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

Liu, F, Hon, GC, Villa, GR, Turner, KM, Ikegami, S, Yang, H, Ye, Z, Li, B, Kuan, S, Lee, AY, Zanca, C, Wei, B, Lucey, G, Jenkins, D, Zhang, W, Barr, CL, Furnari, FB, Cloughesy, TF, Yong, WH, Gahman, TC, Shiau, AK, Cavenee, WK, Ren, B & Mischel, PS 2015, 'EGFR Mutation Promotes Glioblastoma through Epigenome and Transcription Factor Network Remodeling', Molecular Cell, vol. 60, no. 2, pp. 307-318. https://doi.org/10.1016/j.molcel.2015.09.002

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. / EGFR Mutation Promotes Glioblastoma through Epigenome and Transcription Factor Network Remodeling. In: Molecular Cell. 2015 ; Vol. 60, No. 2. pp. 307-318.

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title = "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.",

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

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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.

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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.

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