Hypoxia is linked to epithelial-mesenchymal transition (EMT) and
tumor progression in numerous
carcinomas. Responses to
hypoxia are thought to operate via
hypoxia-inducible factors (HIFs), but the importance of co-factors that regulate HIF signaling within
tumors is not well understood. Here, we elucidate a signaling pathway that physically and functionally couples
tyrosine phosphorylation of β-
catenin to HIF1α signaling and HIF1α-mediated
tumor EMT. Primary human
lung adenocarcinomas accumulate pY654-β-catenin and HIF1α. All pY654-β-catenin, and only the
tyrosine phosphorylated form, was found complexed with HIF1α and active Src, both within the human
tumors and in lung tumor cell lines exposed to
hypoxia. Phosphorylation of Y654, generated by
hypoxia mediated,
reactive oxygen species (ROS)-dependent
Src kinase activation, was required for β-
catenin to interact with HIF1α and Src, to promote HIF1α transcriptional activity, and for
hypoxia-induced EMT. Mice bearing hypoxic pancreatic islet
adenomas, generated by treatment with anti-
vascular endothelial growth factor antibodies, accumulate HIF1α/pY654-β-
catenin complexes and develop an invasive phenotype. Concurrent administration of the ROS inhibitor
N-acetylcysteine abrogated β-
catenin/HIF pathway activity and restored
adenoma architecture. Collectively, the findings implicate accumulation of pY654-β-catenin specifically complexed to HIF1α and
Src kinase as critically involved in HIF1α signaling and
tumor invasion. The findings also suggest that targeting ROS-dependent aspects of the pY654-β-
catenin/ HIF1α pathway may attenuate untoward biological effects of anti-angiogenic agents and tumor hypoxia.