Transcriptional regulation of FoxM1 by HIF-1α mediates hypoxia-induced EMT in prostate cancer
Transcriptional regulation of FoxM1 by HIF-1α mediates hypoxia-induced EMT in prostate cancer
复制标题
HIF-1 α 对 FoxM1 的转录调节介导前列腺癌缺氧诱导的 EMT
DOI：
10.3892/or.2019.7248
复制
发表时间：
2019-10-01
期刊：
影响因子：
4.2
通讯作者：
Zeng, Jin
中科院分区：
文献类型：
--
作者：
Tang, Cong;Liu, Tianjie;Zeng, Jin
低氧是一种与肿瘤发生相关的微环境改变，通常发生在前列腺癌(Pca)发展的早期阶段。越来越多的证据表明，低氧/低氧诱导因子(HIF)参与了PCa上皮-间充质转化(EMT)的诱导和转移潜能的增加。然而，低氧/缺氧诱导因子调节EMT的机制尚不清楚。在本研究中，我们从HIF-1α/Forkhead box M1(FOXM1)信号通路方面探讨了低氧诱导PCa内EMT的分子机制。以PCAPC3和DU145细胞为体外模型系统。我们的结果表明，低氧诱导了PCa细胞的EMT。生物信息学分析证实了HIF-1α和FOXM1之间可能的关联。此外，FOXM1与PCa的发展和Gleason评分显著相关。缺氧可导致HIF-1α和FOXM1表达增加。基因敲除FOXM1可阻断低氧诱导的PCa内EMT，而外源性过表达FOXM1则促进低氧诱导的PCa内EMT。此外，缺氧时FOXM1的表达增加是由于HIF-1α对FOXM1启动子的转录调控所致。我们还通过不同长度的启动子序列证实了HIF-1α与FOXM1启动子的结合部位。这些发现为低氧应激下前列腺癌中EMT的调控提供了新的见解。未来值得研究的是，抑制FOXM1作为一个潜在的靶点可能是一种有效的治疗PCa的策略。
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-1 alpha/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-1 alpha 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-1 alpha 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-1 alpha. We also confirmed the binding site of HIF-1 alpha 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.