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DNMT1 regulates IL-6- and TGF-?1-induced epithelial mesenchymal transition in prostate epithelial cells.

ABSTRACT: Multiple factors have been considered to play a role in the development of benign prostatic hyperplasia (BPH), including chronic inflammation, hormones, and epithelial-mesenchymal transition (EMT). Inflammation is regarded as one of the potential inducers of EMT. However, the mechanisms, modulating pro-inflammatory factors (IL-6 and TGF-?1) induce EMT features, have not yet been studied in BPH. In this study, we investigated whether DNA methyltransferases1 (DNMT1) could regulate IL-6 and TGF-?1 induce EMT. The expression of EMT features was analyzed in normal prostate epithelial cells (PrECs) and BPH1 cells. Real-time RT-PCR and western blotting were used to examine the expression of EMT features in IL-6- and TGF-?1-treated PrECs. Next, bisulfite sequencing PCR (BSP) methods were used to examine the DNA methylation level of the Cdh1 promoter region. The results showed that EMT features were increased in BPH1 cells, compared to PrECs. IL-6 and TGF-?1 treatment induced EMT features, including decreased E-cadherin expression. The results of BSP revealed significant DNA hypermethylation at the promoter region of Cdh1 after IL-6 and TGF-?1 exposure, which was rescued when pretreated with 5-Aza or TGF-?1 antibody. Moreover, the protein expression and methyltransferase activity of DNMT1 were also increased after IL-6 and TGF-?1 induction. Collectively, our study showed that IL-6 and TGF-?1 could activate DNMT1 and directly regulate the expression of E-cadherin in PrECs, providing a potential therapeutic candidate for BPH.

SUBMITTER: Xu H

PROVIDER: S-EPMC5432940 | biostudies-literature | 2017 May

REPOSITORIES: biostudies-literature

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DNMT1 regulates IL-6- and TGF-β1-induced epithelial mesenchymal transition in prostate epithelial cells.

Xu Hui H Chen Yanbo Y Chen Qi Q Xu Huan H Wang Yanxia Y Yu Jiao J Zhou Juan J Wang Zhong Z Xu Bing B

European journal of histochemistry : EJH 20170503 2

Multiple factors have been considered to play a role in the development of benign prostatic hyperplasia (BPH), including chronic inflammation, hormones, and epithelial-mesenchymal transition (EMT). Inflammation is regarded as one of the potential inducers of EMT. However, the mechanisms, modulating pro-inflammatory factors (IL-6 and TGF-β1) induce EMT features, have not yet been studied in BPH. In this study, we investigated whether DNA methyltransferases1 (DNMT1) could regulate IL-6 and TGF-β1 ...[more]

PMID: 28735516

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Project description:A growing body of evidence supports that the epithelial-to-mesenchymal transition (EMT), which occurs during cancer development and progression, has a crucial role in metastasis by enhancing the motility of tumor cells. Transforming growth factor-β (TGF-β) is known to induce EMT in a number of cancer cell types; however, the mechanism underlying this transition process is not fully understood. In this study we have demonstrated that TGF-β upregulates the expression of tumor suppressor protein Par-4 (prostate apoptosis response-4) concomitant with the induction of EMT. Mechanistic investigations revealed that exogenous treatment with each TGF-β isoform upregulates Par-4 mRNA and protein levels in parallel levels of phosphorylated Smad2 and IκB-α increase. Disruption of TGF-β signaling by using ALK5 inhibitor, neutralizing TGF-β antibody or phosphoinositide 3-kinase inhibitor reduces endogenous Par-4 levels, suggesting that both Smad and NF-κB pathways are involved in TGF-β-mediated Par-4 upregulation. NF-κB-binding sites in Par-4 promoter have previously been reported; however, using chromatin immunoprecipitation assay we showed that Par-4 promoter region also contains Smad4-binding site. Furthermore, TGF-β promotes nuclear localization of Par-4. Prolonged TGF-β3 treatment disrupts epithelial cell morphology, promotes cell motility and induces upregulation of Snail, vimentin, zinc-finger E-box binding homeobox 1 and N-Cadherin and downregulation of Claudin-1 and E-Cadherin. Forced expression of Par-4, results in the upregulation of vimentin and Snail expression together with increase in cell migration. In contrast, small interfering RNA-mediated silencing of Par-4 expression results in decrease of vimentin and Snail expression and prevents TGF-β-induced EMT. We have also uncovered a role of X-linked inhibitor of apoptosis protein in the regulation of endogenous Par-4 levels through inhibition of caspase-mediated cleavage. In conclusion, our findings suggest that Par-4 is a novel and essential downstream target of TGF-β signaling and acts as an important factor during TGF-β-induced EMT.

Dataset Information

DNMT1 regulates IL-6- and TGF-?1-induced epithelial mesenchymal transition in prostate epithelial cells.

Publications

DNMT1 regulates IL-6- and TGF-β1-induced epithelial mesenchymal transition in prostate epithelial cells.

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