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Series GSE60446 Query DataSets for GSE60446
Status Public on Mar 24, 2015
Title DNA Methyltransferase Inhibitor Zebularine Induces Human Cholangiocarcinoma Cell Death through Alteration of DNA Methylation Status
Organism Homo sapiens
Experiment type Methylation profiling by genome tiling array
Summary 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, DNAdependent” 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.
Overall design DNA methylation profiles of cholangiocarcinoma-derived cell lines, TFK1 and HuCCT1, treated with or without zebularine were obtained in triplicate using Infinium HumanMethylation450 BeadChips (Illumina).
Contributor(s) Nakabayashi K, Nakamura K
Citation(s) 25799509
Submission date Aug 15, 2014
Last update date Mar 22, 2019
Contact name Kazuhiko Nakabayashi
Organization name National Research Institute for Child Health and Development
Department Department of Maternal-Fetal Biology
Street address 2-10-1 Okura
City Setagaya
State/province Tokyo
ZIP/Postal code 157-8535
Country Japan
Platforms (1)
GPL13534 Illumina HumanMethylation450 BeadChip (HumanMethylation450_15017482)
Samples (12)
GSM1480238 TFK1_control-1
GSM1480239 TFK1_control-2
GSM1480240 TFK1_control-3
BioProject PRJNA258282

Download family Format
SOFT formatted family file(s) SOFTHelp
MINiML formatted family file(s) MINiMLHelp
Series Matrix File(s) TXTHelp

Supplementary file Size Download File type/resource
GSE60446_RAW.tar 183.1 Mb (http)(custom) TAR
GSE60446_methylated_unmethylated_signals.txt.gz 25.8 Mb (ftp)(http) TXT
Processed data included within Sample table

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