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

Wu, Jian; Li, Hongzhe; Shi, Minmin; Zhu, Youwei; Ma, Yang; Zhong, Yiming; Xiong, Cheng; Chen, Hao; Peng, Chenghong

doi:10.1186/s13046-019-1334-5

Cited by 60 publications

(45 citation statements)

References 41 publications

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“…TET1, as DNA demethylase, is thought to be related to tumor metastasis [ 280 ]. TET1, as DNA demethylase, is thought to be associated with tumor metastasis, and hypoxia increases the expression of TET1 in a HIF-1α-dependent manner [ 281 , 282 ]. Because the binding of HIF-1α to HRE of target genes depends on the methylation level of CpG, TET1 can regulate the HIF-1α target genes by regulating the methylation state of HRE [ 278 ].…”

Section: Role Of Hif-α In Metastasis Through Epigenetic Regulationmentioning

confidence: 99%

Epigenetic crosstalk between hypoxia and tumor driven by HIF regulation

Mao

Wang

et al. 2020

J Exp Clin Cancer Res

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Hypoxia is the major influence factor in physiological and pathological courses which are mainly mediated by hypoxia-inducible factors (HIFs) in response to low oxygen tensions within solid tumors. Under normoxia, HIF signaling pathway is inhibited due to HIF-α subunits degradation. However, in hypoxic conditions, HIF-α is activated and stabilized, and HIF target genes are successively activated, resulting in a series of tumour-specific activities. The activation of HIFs, including HIF-1α, HIF-2α and HIF-3α, subsequently induce downstream target genes which leads to series of responses, the resulting abnormal processes or metabolites in turn affect HIFs stability. Given its functions in tumors progression, HIFs have been regarded as therapeutic targets for improved treatment efficacy. Epigenetics refers to alterations in gene expression that are stable between cell divisions, and sometimes between generations, but do not involve changes in the underlying DNA sequence of the organism. And with the development of research, epigenetic regulation has been found to play an important role in the development of tumors, which providing accumulating basic or clinical evidences for tumor treatments. Here, given how little has been reported about the overall association between hypoxic tumors and epigenetics, we made a more systematic review from epigenetic perspective in hope of helping others better understand hypoxia or HIF pathway, and providing more established and potential therapeutic strategies in tumors to facilitate epigenetic studies of tumors.

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Section: Role Of Hif-α In Metastasis Through Epigenetic Regulationmentioning

confidence: 99%

Epigenetic crosstalk between hypoxia and tumor driven by HIF regulation

Mao

Wang

et al. 2020

J Exp Clin Cancer Res

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“…Other novel (potential) biomarkers in cervical cancer that undergo hydroxymethylation include ACTG1, SALL3, DNAJA3, SERPINB6, CDC14B, and CALN1 (Wang et al, 2019). Wu et al (2019) have demonstrated the downregulation of TET1 and 5-hmC in pancreatic tissues and cell lines. Pancreatic cancer patients with high TET1 levels exhibit longer overall survival than patients with low levels of TET1.…”

Section: Aberrant Dna Hydroxymethylation In Cervical and Other Cancersmentioning

confidence: 99%

“…Therefore, TET1 can suppress pancreatic tumor development by inhibiting proliferation and metastasis. This is achieved via Wnt signaling where TET1 binds and demethylates the promoter of the secreted frizzled-related protein 2 (SFRP2) to activate SFRP2 transcription (Wu et al, 2019). Interestingly, TET1 can suppress colon cancer, wherein TET1 binds to the promoter of DKK and inhibits Wnt signaling to maintain the hypomethylated state (Neri et al, 2015).…”

Section: Aberrant Dna Hydroxymethylation In Cervical and Other Cancersmentioning

confidence: 99%

DNA Methylation and Hydroxymethylation in Cervical Cancer: Diagnosis, Prognosis and Treatment

Zhu

Tian

et al. 2020

Front. Genet.

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Recent discoveries have led to the development of novel ideas and techniques that have helped elucidate the correlation between epigenetics and tumor biology. Nowadays, the field of tumor genetics has evolved to include a new type of regulation by epigenetics. An increasing number of studies have demonstrated the importance of DNA methylation and hydroxymethylation in specific genes in the progression of cervical cancer. Determining the methylation and hydroxymethylation profiles of these genes will help in the early prevention and diagnosis, monitoring recurrence, prognosis, and treatment of patients with cervical cancer. In this review, we focus on the significance of aberrant DNA methylation and hydroxymethylation in cervical cancer and the use of these epigenetic signatures in clinical settings.

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“…10 As regard to Wnt/β-catenin, it also belongs to a classical signaling pathway in the pathological process of tumor, which is over-expressed in tumor cells and has some certain effects on their proliferation and apoptosis. 11 PRRX1 was supposed to be a potential target site for miR-330-3p through online biological prediction software (http://www.targetscan.org/vert_72/). Based on previous research, we speculated that miR-330-3p could affect the biological function of GC cells by targeting Wnt/β-catenin signaling pathway mediated by PRRX1, and thus the following research was conducted.…”

Section: Introductionmentioning

confidence: 99%

<p>Effects of miR-330-3p on Invasion, Migration and EMT of Gastric Cancer Cells by Targeting PRRX1-Mediated Wnt/β-Catenin Signaling Pathway</p>

Ma¹,

Ma²,

Yang³

et al. 2020

OTT

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Background: miRNA, as a biological marker, had more and more attention in recent years due to the important role it plays in cancer. Currently, there are extensive studies on miRNAs, among which miR-330-3p is reported to be implicated in the pathophysiological processes of various cancers. However, little progress has been made in the mechanism of miR-330-3p in gastric cancer. Objective: To explore the expression and relevant mechanism of miR-330-3p and PRRX1 in gastric cancer (GC). Methods: Forty-five GC patients (study group), from whom paired GC and paracancerous tissues were collected, and another 45 healthy subjects (control group) who underwent physical examination during the same period were enrolled. In addition, GC cells and human gastric mucosa cells were purchased, and miR-330-3p-mimics, miR-330-3pinhibitor, miR-NC, si-PRRX1, and sh-PRRX1 were transfected into MKN45, SGC7901 cell. QRT-PCR was employed to assess the miR-330-3p and PRRX1 expressions in the samples, and the cell expressions of PRRX1, GSK-3β, p-GSK-3β, β-catenin, p-β-catenin, cyclin D1, N-cadherin, E-cadherin and vimentin were evaluated by Western blot (WB). MTT, Transwell and wound-healing experiments were adopted to detect cell proliferation, invasion and migration. Results: MiR-330-3p was under-expressed, while PRRX1 was highly expressed in the serum of patients, both of which had an area under the curve (AUC) of more than 0.9. MiR-330-3p and PRRX1 were associated with tumor diameter, TNM staging, lymph node metastasis and differentiation of GC patients. Overexpression of miR-330-3p and inhibition of PRRX1 expression could suppress epithelial-mesenchymal transition (EMT), proliferation, invasion and apoptosis of cells. What is more, WB assay showed that overexpressed miR-330-3p and inhibited PRRX1 could inhibit the expression levels of p-GSK-3β, β-catenin, cyclin D1, N-cadherin and vimentin proteins, while elevating GSK-3β, p-β-catenin and E-cadherin protein expressions. Dual-luciferase reporter assay confirmed that there was a targeting relation between miR-330-3p and PRRX1. Furthermore, rescue experiments revealed that the cell proliferation, invasion, migration did not differ significantly between co-transfected miR-330-3p-mimics+sh-PRRX1, miR-330-3p-inhibitor+si-PRRX1 groups of MKN45 and SGC7901 and the miR-NC group (without transfected sequences). Conclusion: Overexpressed miR-330-3p can promote cell EMT, proliferation, invasion and apoptosis through inhibiting PRRX1-mediated Wnt/β-catenin signaling pathway, which is expected to be a potential therapeutic target for GC.

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

Cited by 60 publications

References 41 publications

Epigenetic crosstalk between hypoxia and tumor driven by HIF regulation

Epigenetic crosstalk between hypoxia and tumor driven by HIF regulation

DNA Methylation and Hydroxymethylation in Cervical Cancer: Diagnosis, Prognosis and Treatment

<p>Effects of miR-330-3p on Invasion, Migration and EMT of Gastric Cancer Cells by Targeting PRRX1-Mediated Wnt/β-Catenin Signaling Pathway</p>

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