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.

Suppression of TRPM7 Inhibited Hypoxia-Induced Migration and Invasion of Androgen-Independent Prostate Cancer Cells by Enhancing RACK1-Mediated Degradation of HIF-1α

“…In contrast, N-Cad as a mesenchymal cell-cell adhesion protein, as well as vimentin protein expression, are increased [41]. EMT is stimulated by various signals, including hypoxia, which was shown to prompted EMT in prostate cancer cells [22]. Here, our study also verified hypoxia insult caused a decrease of E-Cad protein expression, whereas an increase of N-Cad and vimentin protein expression.…”

“…These results indicated that TRPM7 knockdown promoted the degradation of HIF-1α of androgen-independent prostate cancer cells in hypoxic conditions. HIF-1α is involved in EMT of prostate cancer cells [22]. Our western blot results showed that knockdown of HIF-1α inhibited EMT change of androgen-independent prostate cancer cells induced by hypoxia in both PC3 and DU145 cells.…”

“…Expression, and HIF-1α Regulated the EMT in Hypoxia-Insulted Androgen-Independent Prostate Cancer Cells. HIF-1α accumulation is associated with hypoxia-induced EMT in prostate cancer cells [22]. Next, we determined whether the level of HIF-1α protein expression was affected by TRPM7.…”

Hypoxia-Induced Epithelial-Mesenchymal Transition in Cancers: HIF-1α and Beyond

“…HIF-1α may also act on some EMT transcription factors indirectly through FoxM1 signaling pathway in prostate cancer cell lines (76) and through PAFAH1B2 gene in pancreatic cancer (77). HIF-1α also facilitated the regulatory loop with integrin-linked kinase (ILK) to promote epithelial-mesenchymal transition in breast and prostate cancer cell lines (78).…”

Integrative Analysis of Breast Cancer Cells Reveals an Epithelial-Mesenchymal Transition Role in Adaptation to Acidic Microenvironment

“…It has been shown that growth factors, such as epidermal growth factor (EGF), transforming growth factorβ (TGF-β), and basic fibroblast growth factor (bFGF/FGF2) are also able to induce EMT (14,15). It has also recently reported that tumor microenvironment conditions such as hypoxia and acidosis can induce EMT (16,17).…”