Evidence map›Paper›PMID 25799509›Full record

ArticlePloS one2015

DNA methyltransferase inhibitor zebularine induces human cholangiocarcinoma cell death through alteration of DNA methylation status.

Kazuaki Nakamura, Kazuhiko Nakabayashi, Kyaw Htet Aung, Kazuko Aizawa, Naoko Hori, Junji Yamauchi, Kenichiro Hata, Akito Tanoue

Open access · goldAbstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in PloS one, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 19 papers.

0numbers the graph read from it
0cells of the map it votes in
19citing papers in PubMed
3.0field-weighted citation impact, top 8% of its field
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

19 citing papers in PubMed, 71 citations in OpenAlex.

  1. Review
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  9. Zebularine elevates STING expression and enhances cGAMP cancer immunotherapy in mice.Molecular therapy : the journal of the American Society of Gene Therapy · 2021
    Article
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  14. The role of tumour microenvironment: a new vision for cholangiocarcinoma.Journal of cellular and molecular medicine · 2019
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4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

8 authors at 1 institution in 1 country.

Kazuaki NakamuraDepartment of Pharmacology, National Research Institute for Child Health and Development, Tokyo, Japan.
Kazuhiko NakabayashiDepartment of Maternal-Fetal Biology, National Research Institute for Child Health and Development, Tokyo, Japan.
Kyaw Htet AungDepartment of Pharmacology, National Research Institute for Child Health and Development, Tokyo, Japan.
Kazuko AizawaDepartment of Pharmacology, National Research Institute for Child Health and Development, Tokyo, Japan.
Naoko HoriDepartment of Pharmacology, National Research Institute for Child Health and Development, Tokyo, Japan.
Junji YamauchiDepartment of Pharmacology, National Research Institute for Child Health and Development, Tokyo, Japan.
Kenichiro HataDepartment of Maternal-Fetal Biology, National Research Institute for Child Health and Development, Tokyo, Japan.
Akito TanoueDepartment of Pharmacology, National Research Institute for Child Health and Development, Tokyo, Japan.
National Center For Child Health and Development · JP

Funding

No grant is acknowledged in the PubMed record.

6 · The paper itself

Abstract

Cholangiocarcinoma (CCA) is a cancer arising from the neoplastic transformation of cholangiocytes. During tumorigenesis, tumor suppressor and cancer-related genes are commonly silenced by aberrant DNA methylation in their promoter regions. Zebularine (1-(β-D-ribofuranosyl)-1,2-dihydropyrimidin-2-one) acts as an inhibitor of DNA methylation and exhibits chemical stability and minimal cytotoxicity both in vitro and in vivo. In this study, we explore the effect and possible mechanism of action of zebularine on CCA cells. We demonstrate that zebularine exerts an antitumor effect on CCA cells. Zebularine treatment decreased the concentrations of DNA methyltransferase (DNMT) proteins, and DNMT1 knockdown led to apoptotic cell death in the CCA cell lines TFK-1 and HuCCT1. DNA methylation analysis demonstrated that zebularine induced DNA demethylation, and the GO Biological Process terms "hemophilic cell adhesion", "regulation of transcription, DNA-dependent" and "Wnt signaling pathway" were found to be significantly enriched in association with demethylated genes. Furthermore, we observed that zebularine treatment decreased β-catenin protein levels in TFK-1 and HuCCT1 cells. These results suggest that zebularine alters DNA methylation status, and that some aspect of DNA demethylation by zebularine induces suppression of the Wnt signaling pathway, which leads to apoptotic cell death in CCA. We previously reported a novel mechanism of zebularine-induced cell growth arrest and apoptosis in hepatocellular carcinoma via a DNA methylation-independent pathway. Together, our present and previous studies indicate that zebularine could function as both a DNMT inhibitor and a non-DNMT inhibitor reagent, and that, while the optimal usage of zebularine may depend on cancer type, zebularine may be useful for chemotherapy against cancer.

Indexed as

Antineoplastic AgentsApoptosisbeta CateninBile Duct NeoplasmsCell Line, TumorCell ProliferationCell SurvivalCholangiocarcinomaCpG IslandsCytidineDNA (Cytosine-5-)-Methyltransferase 1DNA (Cytosine-5-)-MethyltransferasesDNA DamageDNA MethylationDose-Response Relationship, DrugEnzyme InhibitorsAntineoplastic Agentsbeta CateninCytidineDNA (Cytosine-5-)-Methyltransferase 1DNA (Cytosine-5-)-MethyltransferasesDNMT1 protein, humanEnzyme Inhibitorspyrimidin-2-one beta-ribofuranoside

Identifiers

PMID25799509
PMCPMC4370694
OpenAlexW2079724584

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Registered trials

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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.