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.
authors.affiliation: Ludwig Institute for Cancer Research, La Jolla, CA 92093, USA.
authors.forename: Feng
authors.initials: F
authors.lastname: Liu
authors.affiliation: Ludwig Institute for Cancer Research, La Jolla, CA 92093, USA.
authors.forename: Gary C
authors.initials: GC
authors.lastname: Hon
authors.affiliation: Ludwig Institute for Cancer Research, La Jolla, CA 92093, USA; David Geffen UCLA School of Medicine, Los Angeles, CA 90095, USA.
authors.forename: Genaro R
authors.initials: GR
authors.lastname: Villa
authors.affiliation: Ludwig Institute for Cancer Research, La Jolla, CA 92093, USA.
authors.forename: Kristen M
authors.initials: KM
authors.lastname: Turner
authors.affiliation: Ludwig Institute for Cancer Research, La Jolla, CA 92093, USA.
authors.forename: Shiro
authors.initials: S
authors.lastname: Ikegami
authors.affiliation: Ludwig Institute for Cancer Research, La Jolla, CA 92093, USA.
authors.forename: Huijun
authors.initials: H
authors.lastname: Yang
authors.affiliation: Ludwig Institute for Cancer Research, La Jolla, CA 92093, USA.
authors.forename: Zhen
authors.initials: Z
authors.lastname: Ye
authors.affiliation: Ludwig Institute for Cancer Research, La Jolla, CA 92093, USA.
authors.forename: Bin
authors.initials: B
authors.lastname: Li
authors.affiliation: Ludwig Institute for Cancer Research, La Jolla, CA 92093, USA.
authors.forename: Samantha
authors.initials: S
authors.lastname: Kuan
authors.affiliation: Ludwig Institute for Cancer Research, La Jolla, CA 92093, USA.
authors.forename: Ah Young
authors.initials: AY
authors.lastname: Lee
authors.affiliation: Ludwig Institute for Cancer Research, La Jolla, CA 92093, USA.
authors.forename: Ciro
authors.initials: C
authors.lastname: Zanca
authors.affiliation: David Geffen UCLA School of Medicine, Los Angeles, CA 90095, USA.
authors.forename: Bowen
authors.initials: B
authors.lastname: Wei
authors.affiliation: David Geffen UCLA School of Medicine, Los Angeles, CA 90095, USA.
authors.forename: Greg
authors.initials: G
authors.lastname: Lucey
authors.affiliation: Ludwig Institute for Cancer Research, La Jolla, CA 92093, USA.
authors.forename: David
authors.initials: D
authors.lastname: Jenkins
authors.affiliation: Department of Pathology, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Wei
authors.initials: W
authors.lastname: Zhang
authors.affiliation: 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.
authors.forename: Cathy L
authors.initials: CL
authors.lastname: Barr
authors.affiliation: Ludwig Institute for Cancer Research, La Jolla, CA 92093, USA; Department of Pathology, UCSD School of Medicine, La Jolla, CA 92093, USA.
authors.forename: Frank B
authors.initials: FB
authors.lastname: Furnari
authors.affiliation: David Geffen UCLA School of Medicine, Los Angeles, CA 90095, USA.
authors.forename: Timothy F
authors.initials: TF
authors.lastname: Cloughesy
authors.affiliation: David Geffen UCLA School of Medicine, Los Angeles, CA 90095, USA.
authors.forename: William H
authors.initials: WH
authors.lastname: Yong
authors.affiliation: Ludwig Institute for Cancer Research, La Jolla, CA 92093, USA.
authors.forename: Timothy C
authors.initials: TC
authors.lastname: Gahman
authors.affiliation: Ludwig Institute for Cancer Research, La Jolla, CA 92093, USA.
authors.forename: Andrew K
authors.initials: AK
authors.lastname: Shiau
authors.affiliation: 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.
authors.forename: Webster K
authors.initials: WK
authors.lastname: Cavenee
authors.affiliation: 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.
authors.forename: Bing
authors.initials: B
authors.lastname: Ren
authors.affiliation: 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.
authors.forename: Paul S
authors.initials: PS
authors.lastname: Mischel
mesh_terms: D000328:Adult; D000818:Animals; D001381:Azepines / Q000494:pharmacology; D001932:Brain Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D002648:Child; D044127:Epigenesis, Genetic; D066246:ErbB Receptors / Q000235:genetics* / Q000378:metabolism; D051858:Forkhead Transcription Factors / Q000235:genetics* / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D053263:Gene Regulatory Networks; D005909:Glioblastoma / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D009154:Mutation; D009368:Neoplasm Transplantation; D009419:Nerve Tissue Proteins / Q000235:genetics* / Q000378:metabolism; D055758:SOX9 Transcription Factor / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction; D059467:Transcriptome; D014230:Triazoles / Q000494:pharmacology
chemical_list: C561695:(+)-JQ1 compound; D001381:Azepines; C090173:FOXG1 protein, human; D051858:Forkhead Transcription Factors; D009419:Nerve Tissue Proteins; D055758:SOX9 Transcription Factor; C527932:SOX9 protein, human; D014230:Triazoles; C512478:EGFR protein, human; D066246:ErbB Receptors