Notch signaling mediates hypoxia-induced tumor cell migration and invasion.
Tumor hypoxia is linked to increased metastatic potential, but the molecular mechanisms coupling hypoxia to metastasis are poorly understood. Here, we show that Notch signaling is required to convert the hypoxic stimulus into epithelial-mesenchymal transition (EMT), increased motility, and invasiveness. Inhibition of Notch signaling abrogated hypoxia-induced EMT and invasion, and, conversely, an activated form of Notch could substitute for hypoxia to induce these processes. Notch signaling deploys two distinct mechanisms that act in synergy to control the expression of Snail-1, a critical regulator of EMT. First, Notch directly up-regulated Snail-1 expression by recruitment of the Notch intracellular domain to the Snail-1 promoter, and second, Notch potentiated hypoxia-inducible factor 1alpha (HIF-1alpha) recruitment to the lysyl oxidase (LOX) promoter and elevated the hypoxia-induced up-regulation of LOX, which stabilizes the Snail-1 protein. In sum, these data demonstrate a complex integration of the hypoxia and Notch signaling pathways in regulation of EMT and open up perspectives for pharmacological intervention with hypoxiainduced EMT and cell invasiveness in tumors.
Sahlgren
Cecilia
C
Department of Cell and Molecular Biology, Medical Nobel Institute, Karolinska Institutet, SE-171 77 Stockholm, Sweden.
Gustafsson
Maria V
MV
Jin
Shaobo
S
Poellinger
Lorenz
L
Lendahl
Urban
U
D015820:Cadherins / Q000235:genetics; D015687:Cell Hypoxia; D045744:Cell Line, Tumor; D002465:Cell Movement; D015536:Down-Regulation / Q000235:genetics; D004848:Epithelium / Q000473:pathology; D016326:Extracellular Matrix Proteins / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008024:Ligands; D008648:Mesoderm / Q000473:pathology; D009361:Neoplasm Invasiveness / Q000473:pathology*; D009369:Neoplasms / Q000235:genetics / Q000473:pathology*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051880:Receptors, Notch / Q000378:metabolism*; D015398:Signal Transduction; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D015854:Up-Regulation / Q000235:genetics
D015820:Cadherins; D016326:Extracellular Matrix Proteins; D008024:Ligands; D012333:RNA, Messenger; D051880:Receptors, Notch; C000604407:SNAI1 protein, human; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors