Role of Hypoxia-Inducible Factor-a and prolyl-4 hydroxylases in prostate cancer development and progression

Hypoxia is characterized as a common and fundamental feature of solid tumor. Clinical investigation shows that activation of Hypoxia-Inducible Factor-a (HIF1? ) is closely associated with prostate cancer progression and resistance to therapy. A wide range of cross-talk exists between HIF1? and prostate cancer, but the exact molecular mechanism of how HIF1? contributes to prostate cancer progression and resistance to therapy is not well known. Here we show that HIF1? interacts with FOXA1 and hypoxic stimulation leads to a dramatic change in genome-wide transcription factor binding sites between HIF1? and FOXA1. Further investigation shows hypoxia alters FOXA1 protein stability and FOXA1 is shown to interacts PHD1 and subsequently undergoes hydroxylation of proline residues. The C-terminal domains of FOXA1 is shown to interact with PHD1, which further confirms the hydroxylation mediated stability of FOXA1 in prostate cancer cell lines. Functional assays showed reduced proliferation and migration of LNCAP 1F5 in HIF1? and PHD1 knockdown cell lines. These results provide a clear mechanistic role of prolyl-4 hydroxylases and HIF1? in prostate cancer metastasis.