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

Cell Metab. 2013 Jun 4;17(6):1000-8. doi: 10.1016/j.cmet.2013.04.013. Epub 2013 May 23.

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