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

ABSTRACT We investigated the intersection of epidermal growth factor receptor (EGFR) and CCAAT enhancer binding protein (C/EBP)‐β 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 ChIPbased 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 inwhich 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.—Selagea, L., Mishra, A., Anand, M., Ross, J., Tucker‐Burden, C., Kong, J., Brat, D. J. EGFR and C/EBP‐β oncogenic signaling is bidirectional in human glioma and varieswith theC/EBP‐β isoform. FASEB J. 30, 4098–4108 (2016). www.fasebj.org