title: EGFR mutation-induced alternative splicing of Max contributes to growth of glycolytic tumors in brain cancer.
abstract: Alternative splicing contributes to diverse aspects of cancer pathogenesis including altered cellular metabolism, but the specificity of the process or its consequences are not well understood. We characterized genome-wide alternative splicing induced by the activating EGFRvIII mutation in glioblastoma (GBM). EGFRvIII upregulates the heterogeneous nuclear ribonucleoprotein (hnRNP) A1 splicing factor, promoting glycolytic gene expression and conferring significantly shorter survival in patients. HnRNPA1 promotes splicing of a transcript encoding the Myc-interacting partner Max, generating Delta Max, an enhancer of Myc-dependent transformation. Delta Max, but not full-length Max, rescues Myc-dependent glycolytic gene expression upon induced EGFRvIII loss, and correlates with hnRNPA1 expression and downstream Myc-dependent gene transcription in patients. Finally, Delta Max is shown to promote glioma cell proliferation in vitro and augment EGFRvIII expressing GBM growth in vivo. These results demonstrate an important role for alternative splicing in GBM and identify Delta Max as a mediator of Myc-dependent tumor cell metabolism.
authors.affiliation: Ludwig Institute for Cancer Research, University of California, San Diego, La Jolla, CA 92093, USA.
authors.forename: Ivan
authors.initials: I
authors.lastname: Babic
authors.affiliation: Department of Microbiology, Immunology, and Molecular Genetics, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA; UCLA Molecular Biology Interdepartmental Graduate Program, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA; UCLA Medical Scientist Training Program, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA.
authors.forename: Erik S
authors.initials: ES
authors.lastname: Anderson
authors.affiliation: Department of Neurosurgery, Kobe University, Kobe 650-0017, Japan.
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Tanaka
authors.affiliation: Department of Radiation Oncology, James Comprehensive Cancer Center, The Ohio State University Medical Center, Columbus, OH 43210, USA.
authors.forename: Deliang
authors.initials: D
authors.lastname: Guo
authors.affiliation: Ludwig Institute for Cancer Research, University of California, San Diego, La Jolla, CA 92093, USA.
authors.forename: Kenta
authors.initials: K
authors.lastname: Masui
authors.affiliation: Department of Biological Chemistry, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA.
authors.forename: Bing
authors.initials: B
authors.lastname: Li
authors.affiliation: Department of Molecular and Medical Pharmacology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA.
authors.forename: Shaojun
authors.initials: S
authors.lastname: Zhu
authors.affiliation: Ludwig Institute for Cancer Research, University of California, San Diego, La Jolla, CA 92093, USA; Department of Molecular and Medical Pharmacology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA.
authors.forename: Yuchao
authors.initials: Y
authors.lastname: Gu
authors.affiliation: Ludwig Institute for Cancer Research, University of California, San Diego, La Jolla, CA 92093, USA; Department of Molecular and Medical Pharmacology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA; UCLA Medical Scientist Training Program, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA.
authors.forename: Genaro R
authors.initials: GR
authors.lastname: Villa
authors.affiliation: Department of Molecular and Medical Pharmacology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA; UCLA Medical Scientist Training Program, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA.
authors.forename: David
authors.initials: D
authors.lastname: Akhavan
authors.affiliation: Department of Molecular and Medical Pharmacology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA.
authors.forename: David
authors.initials: D
authors.lastname: Nathanson
authors.affiliation: Ludwig Institute for Cancer Research, University of California, San Diego, La Jolla, CA 92093, USA.
authors.forename: Beatrice
authors.initials: B
authors.lastname: Gini
authors.affiliation: Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA.
authors.forename: Sergey
authors.initials: S
authors.lastname: Mareninov
authors.affiliation: Department of Molecular and Medical Pharmacology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA.
authors.forename: Rui
authors.initials: R
authors.lastname: Li
authors.affiliation: Department of Molecular and Medical Pharmacology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA.
authors.forename: Carolina Espindola
authors.initials: CE
authors.lastname: Camacho
authors.affiliation: Department of Biological Chemistry, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA.
authors.forename: Siavash K
authors.initials: SK
authors.lastname: Kurdistani
authors.affiliation: Department of Human Genetics, David Geffen School of Medicine, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA.
authors.forename: Ascia
authors.initials: A
authors.lastname: Eskin
authors.affiliation: Department of Human Genetics, David Geffen School of Medicine, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA.
authors.forename: Stanley F
authors.initials: SF
authors.lastname: Nelson
authors.affiliation: Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA.
authors.forename: William H
authors.initials: WH
authors.lastname: Yong
authors.affiliation: Ludwig Institute for Cancer Research, University of California, San Diego, La Jolla, CA 92093, USA; Moores Cancer Center, University of California, San Diego, La Jolla, CA 92093, USA.
authors.forename: Webster K
authors.initials: WK
authors.lastname: Cavenee
authors.affiliation: Department of Neurology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA.
authors.forename: Timothy F
authors.initials: TF
authors.lastname: Cloughesy
authors.affiliation: Department of Molecular and Medical Pharmacology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA.
authors.forename: Heather R
authors.initials: HR
authors.lastname: Christofk
authors.affiliation: Howard Hughes Medical Institute, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA; Department of Microbiology, Immunology, and Molecular Genetics, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA.
authors.forename: Douglas L
authors.initials: DL
authors.lastname: Black
authors.affiliation: Ludwig Institute for Cancer Research, University of California, San Diego, La Jolla, CA 92093, USA; Moores Cancer Center, University of California, San Diego, La Jolla, CA 92093, USA; Department of Pathology, University of California, San Diego, La Jolla, CA 92093, USA. Electronic address: pmischel@ucsd.edu.
authors.forename: Paul S
authors.initials: PS
authors.lastname: Mischel
mesh_terms: D017398:Alternative Splicing / Q000235:genetics*; D000818:Animals; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / Q000235:genetics*; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D066246:ErbB Receptors / Q000235:genetics*; D015972:Gene Expression Regulation, Neoplastic; D005909:Glioblastoma / Q000235:genetics* / Q000378:metabolism*; D006019:Glycolysis / Q000235:genetics; D000076245:Heterogeneous Nuclear Ribonucleoprotein A1; D034481:Heterogeneous-Nuclear Ribonucleoprotein Group A-B / Q000378:metabolism; D064593:Heterografts; D006801:Humans; D051379:Mice; D016513:Mice, SCID; D009368:Neoplasm Transplantation; D034622:RNA Interference; D034741:RNA, Small Interfering
chemical_list: D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; D000076245:Heterogeneous Nuclear Ribonucleoprotein A1; D034481:Heterogeneous-Nuclear Ribonucleoprotein Group A-B; C000619657:Hnrnpa1 protein, mouse; C499330:MAX protein, human; D034741:RNA, Small Interfering; C000619656:hnRNPA1 protein, human; C512478:EGFR protein, human; D066246:ErbB Receptors