Notch signaling mediates hypoxia-induced tumor cell migration and invasion

TLDR

Tumor hypoxia is linked to increased metastatic potential, yet the molecular mechanisms connecting hypoxia to metastasis remain poorly understood. Notch signaling promotes EMT by directly up‑regulating Snail‑1 via NICD recruitment to its promoter and by enhancing HIF‑1α–mediated LOX expression, which stabilizes Snail‑1 protein. Inhibition of Notch blocks hypoxia‑induced EMT and invasion, while constitutively active Notch mimics hypoxia, demonstrating that Notch is essential for hypoxia‑driven tumor cell migration and invasion and suggesting a target for therapeutic intervention.

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 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.