Transcriptional regulation of FoxM1 by HIF‑1α mediates hypoxia‑induced EMT in prostate cancer.

Abstract

Hypoxia is a tumorigenesis-related microenvironment change which usually occurs in the earliest stage of prostate cancer (PCa) development. Accumulating evidence has demonstrated that hypoxia/hypoxia-inducing factor (HIF) is involved in the induction of epithelial-mesenchymal transition (EMT) and increased metastatic potential in PCa. However, the mechanism by which hypoxia/HIF regulates EMT remains unclear. In the present study, we demonstrated the molecular mechanisms of hypoxia-induced EMT in PCa, focusing on HIF-1α/Forkhead box M1 (FoxM1) signaling pathway. PCa PC3 and DU145 cell lines were used as the model system in vitro. Our data revealed that hypoxia induced EMT in PCa cells. Bioinformatics analysis identified the possible association between HIF-1α and FoxM1. Additionally, FoxM1 was significantly associated with PCa development and Gleason scores of PCa. Exposure to hypoxia resulted in the increased expression of HIF-1α and FoxM1. Genetic knockdown FoxM1 abolished hypoxia-induced EMT in PCa, while exogenous overexpression of FoxM1 facilitated hypoxia-induced EMT. Furthermore, the increase of FoxM1 during hypoxia was due to the transcriptional regulation on the FoxM1 promoter by HIF-1α. We also confirmed the binding site of HIF-1α on the FoxM1 promoter by different lengths promoter sequences. These findings provide new insights into how EMT is regulated in PCa under hypoxic stress. It is worthwhile to investigate in future that inhibition of FoxM1 as a potential target may be an effective therapeutic strategy against PCa.