Nuclear EGFRvIII-STAT5b complex contributes to glioblastoma cell survival by direct activation of the Bcl-XL promoter.
Aberrant EGFR signaling strongly promotes glioma malignancy and treatment resistance. The most prevalent mutation, ΔEGFR/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 ΔEGFR 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 ΔEGFR 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 ΔEGFR was dependent on SFKs, while the signal from acutely EGF-stimulated EGFR to STAT5b involved other kinases. Phosphorylated STAT5b and ΔEGFR associated in the nucleus, bound DNA and were found on promoters known to be regulated by STAT5 including that of the Aurora A gene. ΔEGFR 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 ΔEGFR with STAT5b, which promotes oncogenesis and treatment resistance in glioblastoma by direct regulation of anti-apoptotic gene, Bcl-XL.
Department of Neurosurgery, University of Texas MD Anderson Cancer Center, TX, USA. klatha@mdanderson.org
Khatri
K
Latha
Ming
M
Li
Vaibhav
V
Chumbalkar
Anupama
A
Gururaj
YeoHyeon
Y
Hwang
Sumana
S
Dakeng
Raymond
R
Sawaya
Kenneth
K
Aldape
Webster K
WK
Cavenee
Oliver
O
Bogler
Frank B
FB
Furnari
D000818:Animals; D017209:Apoptosis / Q000235:genetics; D064096:Aurora Kinase A; D064127:Aurora Kinases; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000378:metabolism; D002470:Cell Survival; D002945:Cisplatin / Q000494:pharmacology; D066246:ErbB Receptors / Q000378:metabolism*; D005909:Glioblastoma / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D006801:Humans; D051379:Mice; D010766:Phosphorylation; D011401:Promoter Regions, Genetic; D017346:Protein Serine-Threonine Kinases / Q000235:genetics; D034622:RNA Interference; D034741:RNA, Small Interfering; D050799:STAT5 Transcription Factor / Q000235:genetics / Q000378:metabolism*; D017384:Sequence Deletion; D015398:Signal Transduction / Q000235:genetics; D051020:bcl-X Protein / Q000235:genetics*; D019061:src-Family Kinases / Q000378:metabolism
C494811:BCL2L1 protein, human; D034741:RNA, Small Interfering; D050799:STAT5 Transcription Factor; C494095:STAT5B protein, human; D051020:bcl-X Protein; C410723:epidermal growth factor receptor VIII; D066246:ErbB Receptors; D019061:src-Family Kinases; C576918:Aurka protein, mouse; D064096:Aurora Kinase A; D064127:Aurora Kinases; D017346:Protein Serine-Threonine Kinases; D002945:Cisplatin