HIF-2α Enhances β-Catenin/TCF-Driven Transcription by Interacting with β-Catenin

The tumor-promoting factors beta-catenin and hypoxia-inducible factor (HIF) are often found to be coactivated in rapidly growing tumors. Recently, it was shown that HIF-1 alpha negatively regulates Wnt/beta-catenin signaling by sequestering beta-catenin from beta-catenin/T-cell factor (TCF). However, no investigation has been undertaken on the involvement of HIF-2 alpha in beta-catenin regulation. In this study, it was found that, like HIF-1 alpha, HIF-2 alpha interacts with beta-catenin, but at a different site. Furthermore, HIF-2 alpha was found to assemble with beta-catenin/TCF and facilitate gene transcription. Mutational analyses revealed that transactivation domains of HIF-2 alpha promote p300 coactivator recruitment by beta-catenin. Furthermore, HIF-2 alpha and beta-catenin were found to associate in the nuclei of 786-0 renal cell carcinoma cells, and HIF-2 alpha was found to be required for beta-catenin activation in these cells and for their proliferation. These results suggest that this interaction contributes to the unrestrained growth of tumor cells containing coactivated HIF-2 alpha and beta-catenin. Interestingly, these actions of HIF-2 alpha oppose those of HIF-1 alpha on beta-catenin and cell growth, and this suggests that HIF-1 alpha/HIF-2 alpha balance may importantly determine cell growth when hypoxia and Wnt stimulation coexist. Cancer Res; 70(24); 10101-11. (C) 2010 AACR.