Dataset Information

TET1-mediated DNA hydroxymethylation activates inhibitors of the Wnt/β-catenin signaling pathway to suppress EMT in pancreatic tumor cells.

ABSTRACT:

Background

Ten-eleven translocation 1 (TET1) is a dioxygenase that converts 5-methylcytosine (5-mC) to 5-hydroxymethylcytosine (5-hmC) to induce DNA demethylation. TET1 has been reported to be absent in cancers, and to influence various oncogenes and anti-oncogenes. However the function of TET1 in pancreatic tumor remains poorly understood. In this study, we investigated the role of TET1 in the progression of pancreatic tumor and its mechanism of tumor suppression.

Methods

Quantitative real-time PCR (qRT-PCR), immunohistochemical (IHC) staining and dot blot were performed to detect the TET1 and 5-hmC expression in pancreatic tumor tissues and its adjacent non-tumor tissues. The clinical parameters significance of pancreatic tumor tissues was determined statistically. TET1 over-expression and knock-out cell lines were built and confirmed in vitro. Cell proliferation assay, wound-healing assays, transwell migration assay and nude mice model of orthotopic pancreatic cancer implantation were performed to assess the function of TET1 in pancreatic tumor. Western blot, qRT-PCR, immunofluorescence (IF), bisulfate sequencing (BSP), Chromatin immunoprecipitation (ChIP) were used to uncover the mechanism.

Results

TET1 levels and 5-hmC content were downregulated in pancreatic tumor tissues and cell lines, and pancreatic tumor patients with low TET1 levels had a shorter overall survival than patients with high levels of TET1. TET1 suppressed pancreatic tumor proliferation and metastasis in vivo and in vitro. TET1 bound to the secreted frizzled-related protein 2 (SFRP2) promoter and catalyzed demethylation to activate transcription of SFRP2, inhibiting both the canonical and non-canonical Wnt signaling pathways, and ultimately obstructing epithelial-mesenchymal transition (EMT) in pancreatic tumors.

Conclusion

We found TET1 plays as a suppressor in pancreatic tumor progression via obstructing Wnt signaling pathways.

SUBMITTER: Wu J

PROVIDER: S-EPMC6688318 | biostudies-literature | 2019 Aug

REPOSITORIES: biostudies-literature

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Publications

TET1-mediated DNA hydroxymethylation activates inhibitors of the Wnt/β-catenin signaling pathway to suppress EMT in pancreatic tumor cells.

Wu Jian J Li Hongzhe H Shi Minmin M Zhu Youwei Y Ma Yang Y Zhong Yiming Y Xiong Cheng C Chen Hao H Peng Chenghong C

Journal of experimental & clinical cancer research : CR 20190809 1

<h4>Background</h4>Ten-eleven translocation 1 (TET1) is a dioxygenase that converts 5-methylcytosine (5-mC) to 5-hydroxymethylcytosine (5-hmC) to induce DNA demethylation. TET1 has been reported to be absent in cancers, and to influence various oncogenes and anti-oncogenes. However the function of TET1 in pancreatic tumor remains poorly understood. In this study, we investigated the role of TET1 in the progression of pancreatic tumor and its mechanism of tumor suppression.<h4>Methods</h4>Quantit ...[more]

PMID: 31399111

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Project description:BackgroundThe Wnt/β-catenin signaling pathway plays an important role in the development of second heart field (SHF Isl1+) that gives rise to the anterior heart field (AHF) cardiac progenitor cells (CPCs) for the formation of the right ventricle, outflow tract (OFT), and a portion of the inflow tract (IFT). During early cardiogenesis, these AHF CPCs reside within the pharyngeal mesoderm (PM) that provides a microenvironment for them to receive signals that direct their cell fates. Here, N-cadherin, which is weakly expressed by CPCs, plays a significant role by promoting the adhesion of CPCs within the AHF, regulating β-catenin levels in the cytoplasm to maintain high Wnt signaling and cardioproliferation while also preventing the premature differentiation of CPCs. On the contrary, strong expression of N-cadherin observed throughout matured myocardium is associated with downregulation of Wnt signaling due to β-catenin sequestration at the cell membrane, inhibiting cardioproliferation. As such, upregulation of Wnt signaling pathway to enhance cardiac tissue proliferation in mature cardiomyocytes can be explored as an interesting avenue for regenerative treatment to patients who have suffered from myocardial infarction.MethodsTo investigate if Wnt signaling is able to enhance cellular proliferation of matured cardiomyocytes, we treated cardiomyocytes isolated from adult mouse heart and both murine and human ES cell-derived matured cardiomyocytes with N-cadherin antibody or CHIR99021 GSK inhibitor in an attempt to increase levels of cytoplasmic β-catenin. Immunostaining, western blot, and quantitative PCR for cell proliferation markers, cell cycling markers, and Wnt signaling pathway markers were used to quantitate re-activation of cardioproliferation and Wnt signaling.ResultsN-cadherin antibody treatment releases sequestered β-catenin at N-cadherin-based adherens junction, resulting in an increased pool of cytoplasmic β-catenin, similar in effect to CHIR99021 GSK inhibitor treatment. Both treatments therefore upregulate Wnt signaling successfully and result in significant increases in matured cardiomyocyte proliferation.ConclusionAlthough both N-cadherin antibody and CHIR99021 treatment resulted in increased Wnt signaling and cardioproliferation, CHIR99021 was found to be the more effective treatment method for human ES cell-derived cardiomyocytes. Therefore, we propose that CHIR99021 could be a potential therapeutic option for myocardial infarction patients in need of regeneration of cardiac tissue.

Dataset Information

TET1-mediated DNA hydroxymethylation activates inhibitors of the Wnt/β-catenin signaling pathway to suppress EMT in pancreatic tumor cells.

Background

Methods

Results

Conclusion

Publications

TET1-mediated DNA hydroxymethylation activates inhibitors of the Wnt/β-catenin signaling pathway to suppress EMT in pancreatic tumor cells.

Similar Datasets

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