TY - JOUR
T1 - EGFR and C/EBP-β oncogenic signaling is bidirectional in human glioma and varies with the C/EBP-β isoform
AU - Selagea, Ligia
AU - Mishra, Alok
AU - Anand, Monika
AU - Ross, James
AU - Tucker-Burden, Carol
AU - Kong, Jun
AU - Brat, Daniel J.
N1 - Funding Information:
The authors thank the Tissue Procurement Service and the Research Pathology Laboratory of the Cancer Tissue and Pathology Shared Resource at the Winship Cancer Institute. The U.S. Public Health Service supported this work through U.S. National Institutes of Health, National Cancer Institute (NCI) Grants R01CA176659 (to D.J.B.), K25CA181503 (to J.K.), and the Winship Cancer Institute NCI Cancer Center Support Grant P30CA138292. The authors declare no conflicts of interest.
Publisher Copyright:
© 2016 FASEB.
PY - 2016/12
Y1 - 2016/12
N2 - 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.
AB - 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.
KW - Cell signaling
KW - Glioblastoma
KW - LAP
KW - LIP
UR - http://www.scopus.com/inward/record.url?scp=85002397992&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85002397992&partnerID=8YFLogxK
U2 - 10.1096/fj.201600550R
DO - 10.1096/fj.201600550R
M3 - Article
C2 - 27572958
AN - SCOPUS:85002397992
SN - 0892-6638
VL - 30
SP - 4098
EP - 4108
JO - FASEB Journal
JF - FASEB Journal
IS - 12
ER -