Identification of pY654-?-catenin as a critical co-factor in hypoxia-inducible factor-1? signaling and tumor responses to hypoxia.

ABSTRACT: 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 ?-catenin to HIF1? signaling and HIF1?-mediated tumor EMT. Primary human lung adenocarcinomas accumulate pY654-?-catenin and HIF1?. All pY654-?-catenin, and only the tyrosine phosphorylated form, was found complexed with HIF1? 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 ?-catenin to interact with HIF1? and Src, to promote HIF1? transcriptional activity, and for hypoxia-induced EMT. Mice bearing hypoxic pancreatic islet adenomas, generated by treatment with anti-vascular endothelial growth factor antibodies, accumulate HIF1?/pY654-?-catenin complexes and develop an invasive phenotype. Concurrent administration of the ROS inhibitor N-acetylcysteine abrogated ?-catenin/HIF pathway activity and restored adenoma architecture. Collectively, the findings implicate accumulation of pY654-?-catenin specifically complexed to HIF1? and Src kinase as critically involved in HIF1? signaling and tumor invasion. The findings also suggest that targeting ROS-dependent aspects of the pY654-?-catenin/ HIF1? pathway may attenuate untoward biological effects of anti-angiogenic agents and tumor hypoxia.

SUBMITTER: Xi Y 

PROVIDER: S-EPMC3871884 | biostudies-literature | 2013 Oct

REPOSITORIES: biostudies-literature