Notch signaling mediates hypoxia-induced tumor cell migration and invasion

Cecilia Sahlgren, Maria V. Gustafsson, Shaobo Jin, Lorenz Poellinger, Urban Lendahl*

*Corresponding author for this work

Research output: Contribution to journalArticleScientificpeer-review

567 Citations (Scopus)

Abstract

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 upregulated Snail-1 expression by recruitment of the Notch intracellular domain to the Snail-1 promoter, and second, Notch potentiated hypoxia-inducible factor 1α (HIF-1α) recruitment to the lysyl oxidase (LOX) promoter and elevated the hypoxia-induced upregulation 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 hypoxia induced EMT and cell invasiveness in tumors.

Original languageEnglish
Pages (from-to)6392-6397
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume105
Issue number17
DOIs
Publication statusPublished - 29 Apr 2008
Externally publishedYes
MoE publication typeA1 Journal article-refereed

Keywords

  • E-cadherin
  • Lysyl oxidase
  • Snail

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