Abstract
Prostate cancer is the most common cancer in American men and the second leading cause of cancer-related death. Most of these deaths are associated with metastasis, a process involving the epithelial-to-mesenchymal (EMT) transition. Furthermore, growing evidence suggests that partial-EMT (p-EMT) may lead to more aggressive disease than complete EMT. In this study, the EMT-inducing transcription factor Zeb1 was knocked down in mesenchymal PC-3 prostate cancer cells (Zeb1KD) and resulting changes in cellular phenotype were assessed using protein and RNA analysis, invasion and migration assays, cell morphology assays, and DNA methylation chip analysis. Inducible knockdown of Zeb1 resulted in a p-EMT phenotype including co-expression of epithelial and mesenchymal markers, a mixed epithelial/mesenchymal morphology, increased invasion and migration, and enhanced expression of p-EMT markers relative to PC-3 mesenchymal controls (p ≤ 0.05). Treatment of Zeb1KD cells with the global de-methylating drug 5-azacytidine (5-aza) mitigated the observed aggressive p-EMT phenotype (p ≤ 0.05). DNA methylation chip analysis revealed 10 potential targets for identifying and/or targeting aggressive p-EMT prostate cancer in the future. These findings provide a framework to enhance prognostic and/or therapeutic options for aggressive prostate cancer in the future by identifying new p-EMT biomarkers to classify patients with aggressive disease who may benefit from 5-aza treatment.
Highlights
Prostate cancer is the second leading cause of cancer related deaths in American men [1]
Metastasis is associated with an epithelialto mesenchymal transition (EMT), where epithelial cells lose their epithelial characteristics and gain a mesenchymal phenotype, which aids in the process of metastasis [2,3,4,5,6,7,8]
Master EMT-inducing transcription factors upregulate mesenchymal genes and/or inhibit epithelial genes, which can cause the cell to undergo EMT [10]. An example of this is zinc finger E-box-binding homeobox 1 (Zeb1), which binds to the E-box promoter sequence, regulates neuronal differentiation, and has important roles in promoting EMT to allow for cell movement during gestation [11,12]
Summary
Prostate cancer is the second leading cause of cancer related deaths in American men [1] Most of these deaths are caused by metastasis, which allows cancer to spread beyond the prostate to other parts of the body [2]. Master EMT-inducing transcription factors upregulate mesenchymal genes and/or inhibit epithelial genes, which can cause the cell to undergo EMT [10]. An example of this is zinc finger E-box-binding homeobox 1 (Zeb1), which binds to the E-box promoter sequence, regulates neuronal differentiation, and has important roles in promoting EMT to allow for cell movement during gestation [11,12]. Zeb promotes metastasis and a loss of cell polarity by repressing the epithelial proteins E-Cadherin and EpCAM and promotes tumorigenicity by repressing stemnessinhibiting microRNAs [10,13]
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