Epidermal growth factor receptor signaling synergizes with Hedgehog/GLI in oncogenic transformation via activation of the MEK/ERK/JUN pathway.
Persistent activation of the Hedgehog (HH)/GLI signaling pathway has been implicated in the development of a number of human cancers. The GLI zinc finger transcription factors act at the end of the HH signaling cascade to control gene expression, and recent studies have shown that the activity of GLI proteins can be additionally modified by integration of distinct signals, such as the MEK/extracellular signal-regulated kinase (ERK) and phosphinositide-3 kinase (PI3K)/AKT pathway. However, little is known about the identity of the upstream activators of these HH/GLI interacting signaling pathways in cancer. Here, we provide evidence that integration of the HH/GLI and epidermal growth factor receptor (EGFR) pathway synergistically induces oncogenic transformation, which depends on EGFR-mediated activation of the RAS/RAF/MEK/ERK but not of the PI3K/AKT pathway. EGFR/MEK/ERK signaling induces JUN/activator protein 1 activation, which is essential for oncogenic transformation, in combination with the GLI activator forms GLI1 and GLI2. Furthermore, pharmacologic inhibition of EGFR and HH/GLI efficiently reduces growth of basal cell carcinoma (BCC) cell lines derived from mice with activated HH/GLI signaling. The results identify the synergistic integration of GLI activator function and EGFR signaling as a critical step in oncogenic transformation and provide a molecular basis for therapeutic opportunities relying on combined inhibition of the HH/GLI and EGFR/MEK/ERK/JUN pathway in BCC.
Schnidar
Harald
H
Department of Molecular Biology, University of Salzburg, Salzburg, Austria.
Eberl
Markus
M
Klingler
Stefan
S
Mangelberger
Doris
D
Kasper
Maria
M
Hauser-Kronberger
Cornelia
C
Regl
Gerhard
G
Kroismayr
Renate
R
Moriggl
Richard
R
Sibilia
Maria
M
Aberger
Fritz
F
D019943:Amino Acid Substitution; D000818:Animals; D002455:Cell Division / Q000235:genetics; D002471:Cell Transformation, Neoplastic / Q000473:pathology*; D066246:ErbB Receptors / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D005347:Fibroblasts / Q000502:physiology; D053823:Hedgehog Proteins / Q000502:physiology; D006801:Humans; D015603:Keratinocytes / Q000166:cytology; D051741:Kruppel-Like Transcription Factors / Q000235:genetics; D020930:MAP Kinase Kinase Kinases / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D009369:Neoplasms / Q000201:enzymology / Q000473:pathology* / Q000503:physiopathology; D016755:Proto-Oncogene Proteins c-jun / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D014157:Transcription Factors / Q000235:genetics / Q000502:physiology*; D000071676:Zinc Finger Protein GLI1
C400551:GLI1 protein, human; C498520:Gli1 protein, mouse; D053823:Hedgehog Proteins; D051741:Kruppel-Like Transcription Factors; D016755:Proto-Oncogene Proteins c-jun; D014157:Transcription Factors; D000071676:Zinc Finger Protein GLI1; D066246:ErbB Receptors; D048049:Extracellular Signal-Regulated MAP Kinases; D020930:MAP Kinase Kinase Kinases