Abstract
BackgroundTen-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.MethodsQuantitative 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.ResultsTET1 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.ConclusionWe found TET1 plays as a suppressor in pancreatic tumor progression via obstructing Wnt signaling pathways.
Highlights
Ten-eleven translocation 1 (TET1) is a dioxygenase that converts 5-methylcytosine (5-mC) to 5hydroxymethylcytosine (5-hmC) to induce DNA demethylation
We found that TET1 mRNA but not TET2 or TET3 was significantly reduced in tumor tissues compared with non-tumor tissues (P = 0.02, P = 0.55, and P = 0.21 respectively) (Fig. 1a–c)
MRNA expression of JAG1 and Notch 1 (NOTCH1) in the NOTCH pathway were upregulated in the TET1 overexpressing group, the NOTCH pathway is considered to be an activator of epithelial-mesenchymal transition (EMT) [29], and cross-talk between the NOTCH and Wnt/β-catenin pathways did not support the phenotype in our study; we focused on the Wnt/β-catenin pathway
Summary
Ten-eleven translocation 1 (TET1) is a dioxygenase that converts 5-methylcytosine (5-mC) to 5hydroxymethylcytosine (5-hmC) to induce DNA demethylation. The members of the teneleven translocation family (TET1, TET2, and TET3) of dioxygenases play a key role in DNA demethylation by catalyzing the hydroxylation of 5-methylcytosine (5-mC) to 5-hydroxymethylcytosine (5-hmC) [1,2,3] and regulating the methylation levels of 5-cytosine (5-C) in coordination with DNA methyltransferases (DNMTs) [4]. Abnormal expression or gene mutations of members of the TET family have been reported in various kinds of cancers in humans. It was reported that aberrant expression of TET1 was more frequent in solid tumors [6,7,8], TET2 was frequently mutated in hematopoietic tumors [9], while TET3 remains less discussed [10]
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