Journal
INTERNATIONAL JOURNAL OF CANCER
Volume 132, Issue 3, Pages 509-520Publisher
WILEY-BLACKWELL
DOI: 10.1002/ijc.27690
Keywords
nuclear EGFRvIII; EGFR; STAT5b; Bcl-XL; glioma transcriptional regulation
Categories
Funding
- National Cancer Institute of the National Institutes of Health [RO1CA108500, SPORE P50CA127001, PO1 CAO95616]
- University of Texas M. D. Anderson's Cancer Centre [CA016672]
- Goldhirsh Foundation
- American Brain Tumor Association Fellowship
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Aberrant EGFR signaling strongly promotes glioma malignancy and treatment resistance. The most prevalent mutation, ?EGFR/EGFRvIII, is an in-frame deletion of the extracellular domain, which occurs in more than 25% of glioblastomas and enhances growth and survival of tumor cells. Paradoxically, the signaling of the potent oncogene ?EGFR is of low intensity, raising the question of whether it exhibits preferential signaling to key downstream targets. We have observed levels of phosphorylation of STAT5 at position Y699 in cells expressing ?EGFR that are similar or higher than in cells that overexpress EGFR and are acutely stimulated with EGF, prompting us to investigate the role of STAT5 activation in glioblastoma. Here, we show that in human glioblastoma samples, pSTAT5 levels correlated positively with EGFR expression and were associated with reduced survival. Interestingly, the activation of STAT5b downstream of ?EGFR was dependent on SFKs, while the signal from acutely EGF-stimulated EGFR to STAT5b involved other kinases. Phosphorylated STAT5b and ?EGFR associated in the nucleus, bound DNA and were found on promoters known to be regulated by STAT5 including that of the Aurora A gene. ?EGFR cooperated with STAT5b to regulate the Bcl-XL promoter and knockdown of STAT5b suppressed anchorage independent growth, reduced the levels of Bcl-XL and sensitized glioblastoma cells to cisplatin. Together these results delineate a novel association of nuclear ?EGFR with STAT5b, which promotes oncogenesis and treatment resistance in glioblastoma by direct regulation of anti-apoptotic gene, Bcl-XL.
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