EGFR and C/EBP-β oncogenic signaling is bidirectional in human glioma and varies with the C/EBP-β isoform

Ligia Selagea, Alok Mishra, Monika Anand, James Ross, Carol Tucker-Burden, Jun Kong, Daniel J. Brat

Research output: Contribution to journalArticle

Abstract

We investigated the intersection of epidermal growth factor receptor (EGFR) and CCAAT enhancer binding protein (C/EBP)-b signaling in glioblastoma (GBM), given that both gene products strongly influence neoplastic behavior. C/EBP-β is known to drive themesenchymal transcriptional signature inGBM, likely through strong microenvironmental influences, whereas the genetic contributions to its up-regulation in this disease are not well described. We demonstrated that stable overexpression and activation of WT EGFR (U87MG-WT) led to elevated C/EBP-β expression, as well as enhanced nuclear translocation and DNA-binding activity, leading to upregulation of C/EBP-β transcription and translation. Deeper investigation identified bidirectional regulation, with C/EBP-β also causing up-regulation of EGFR that was at least partially dependent on the STAT3. Based on ChIP-based studies, we also found that that the translational isoforms of C/EBP-β [liver-enriched transcription-activating protein (LAP)-1/2 and liver inhibitory protein (LIP)] have differential occupancy on STAT3 promoter and opposing roles in transcriptional regulation of STAT3 and EGFR. We further demonstrated that the shorter C/EBP-β isoform, LIP, promoted proliferation and migration of U87MG glioma cells, potentially via induction of cytokine IL-6. Our molecular dissection of EGFR and C/EBP-β pathway interactions uncovered a complex signaling network in which increased activity of either EGFRorC/EBP-β leads to the up-regulation of the other, enhancing oncogenic signaling. Disrupting the EGFR-C/EBP-β signaling axis could attenuate malignant behavior of glioblastoma.

Original languageEnglish (US)
Pages (from-to)4098-4108
Number of pages11
JournalFASEB Journal
Volume30
Issue number12
DOIs
StatePublished - Dec 2016

Keywords

  • Cell signaling
  • Glioblastoma
  • LAP
  • LIP

ASJC Scopus subject areas

  • Biotechnology
  • Biochemistry
  • Molecular Biology
  • Genetics

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