EGFR mutation-induced alternative splicing of Max contributes to growth of glycolytic tumors in brain cancer

Ivan Babic; Erik S Anderson; Kazuhiro Tanaka; Deliang Guo; Kenta Masui; Bing Li; Shaojun Zhu; Yuchao Gu; Genaro R Villa; David Akhavan; David Nathanson; Beatrice Gini; Sergey Mareninov; Rui Li; Carolina Espindola Camacho; Siavash K Kurdistani; Ascia Eskin; Stanley F Nelson; William H Yong; Webster K Cavenee; Timothy F Cloughesy; Heather R Christofk; Douglas L Black; Paul S Mischel

doi:10.1016/j.cmet.2013.04.013

EGFR mutation-induced alternative splicing of Max contributes to growth of glycolytic tumors in brain cancer

Cell Metab. 2013 Jun 4;17(6):1000-1008. doi: 10.1016/j.cmet.2013.04.013. Epub 2013 May 23.

Authors

Ivan Babic¹, Erik S Anderson², Kazuhiro Tanaka³, Deliang Guo⁴, Kenta Masui¹, Bing Li⁵, Shaojun Zhu⁶, Yuchao Gu⁷, Genaro R Villa⁸, David Akhavan⁹, David Nathanson⁶, Beatrice Gini¹, Sergey Mareninov¹⁰, Rui Li⁶, Carolina Espindola Camacho⁶, Siavash K Kurdistani⁵, Ascia Eskin¹¹, Stanley F Nelson¹¹, William H Yong¹⁰, Webster K Cavenee¹², Timothy F Cloughesy¹³, Heather R Christofk⁶, Douglas L Black¹⁴, Paul S Mischel¹⁵

Affiliations

¹ Ludwig Institute for Cancer Research, University of California, San Diego, La Jolla, CA 92093, USA.
² 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.
³ Department of Neurosurgery, Kobe University, Kobe 650-0017, Japan.
⁴ Department of Radiation Oncology, James Comprehensive Cancer Center, The Ohio State University Medical Center, Columbus, OH 43210, USA.
⁵ Department of Biological Chemistry, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA.
⁶ Department of Molecular and Medical Pharmacology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA.
⁷ 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.
⁸ 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.
⁹ 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.
¹⁰ Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA.
¹¹ Department of Human Genetics, David Geffen School of Medicine, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA.
¹² 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.
¹³ Department of Neurology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA.
¹⁴ 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.
¹⁵ 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.

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.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Alternative Splicing / genetics*
Animals
Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / genetics*
Cell Line, Tumor
Cell Proliferation
ErbB Receptors / genetics*
Gene Expression Regulation, Neoplastic
Glioblastoma / genetics*
Glioblastoma / metabolism*
Glycolysis / genetics
Heterogeneous Nuclear Ribonucleoprotein A1
Heterogeneous-Nuclear Ribonucleoprotein Group A-B / metabolism
Heterografts
Humans
Mice
Mice, SCID
Neoplasm Transplantation
RNA Interference
RNA, Small Interfering

Substances

Basic Helix-Loop-Helix Leucine Zipper Transcription Factors
Heterogeneous Nuclear Ribonucleoprotein A1
Heterogeneous-Nuclear Ribonucleoprotein Group A-B
Hnrnpa1 protein, mouse
MAX protein, human
RNA, Small Interfering
hnRNPA1 protein, human
EGFR protein, human
ErbB Receptors

Associated data

GEO/GSE46028

Abstract

Publication types

MeSH terms

Substances

Associated data

Grants and funding