ArticlePloS one2013
DNA methyltransferase inhibitor zebularine inhibits human hepatic carcinoma cells proliferation and induces apoptosis.
Article in PloS one, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 26 papers.
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Who cites it
26 citing papers in PubMed, 48 citations in OpenAlex.
- Serum ZO-1 and occludin levels in bipolar disorder patients.European archives of psychiatry and clinical neuroscience · 2026Article
- Recent advances on gene-related DNA methylation in cancer diagnosis, prognosis, and treatment: a clinical perspective.Clinical epigenetics · 2025Review
- Article
- Role and mechanism of DNA methylation and its inhibitors in hepatic fibrosis.Frontiers in genetics · 2023Review
- Effect of Zebularine on Apoptotic Pathways in Hepatocellular Carcinoma Cell Lines.International journal of preventive medicine · 2023Article
- Effect of 5'-Fluoro-2'-Deoxycytidine and Sodium Butyrate on the Gene Expression of the Intrinsic Apoptotic Pathway, p21, p27, and p53 Genes Expression, Cell Viability, and Apoptosis in Human Hepatocellular Carcinoma Cell Lines.Advanced biomedical research · 2023Article
- Whole-genome bisulfite sequencing of abdominal adipose reveals DNA methylation pattern variations in broiler lines divergently selected for fatness.Journal of animal science · 2021Article
- Effect of Zebularine in Comparison to Trichostatin A on the Intrinsic and Extrinsic Apoptotic Pathway, Cell Viability, and Apoptosis in Hepatocellular Carcinoma SK-Hep 1, Human Colorectal Cancer SW620, and Human Pancreatic Cancer PaCa-44 Cell Lines.Iranian journal of pharmaceutical research : IJPR · 2021Article
- Effect of Zebularine in Comparison to and in Combination with Trichostatin A on CIP/KIP Family (p21Cip1/Waf1/Sdi1, p27Kip1, and p57Kip2), DNMTs (DNMT1, DNMT3a, and DNMT3b), Class I HDACs (HDACs 1, 2, 3) and Class II HDACs (HDACs 4, 5, 6) Gene Expression, Cell Growth Inhibition and Apoptosis Induction in Colon Cancer LS 174T Cell Line.Asian Pacific journal of cancer prevention : APJCP · 2020Article
- Investigation of the Effect of Zebularine in Comparison to and in Combination with Trichostatin A on p21Cip1/Waf1/ Sdi1, p27Kip1, p57Kip2, DNA Methyltransferases and Histone Deacetylases in Colon Cancer LS 180 Cell Line.Asian Pacific journal of cancer prevention : APJCP · 2020Article
- Article
- Effect of Zebularine on p16INK4a, p14ARF, p15INK4b, and DNA Methyltransferase 1 Gene Expression, Cell Growth Inhibition, and Apoptosis Induction in Human Hepatocellular Carcinoma PLC/PRF5 and Pancreatic Cancer PA-TU-8902 Cell Lines.Iranian journal of pharmaceutical research : IJPR · 2020Article
- Hepigenetics: A Review of Epigenetic Modulators and Potential Therapies in Hepatocellular Carcinoma.BioMed research international · 2020Review
- The role of enhancer of zeste homolog 2: From viral epigenetics to the carcinogenesis of hepatocellular carcinoma.Journal of cellular physiology · 2018Review
- Epigenetic variability in conversion to psychosis: novel findings from an innovative longitudinal methylomic analysis.Translational psychiatry · 2018Article
- Epigenetic outlier profiles in depression: A genome-wide DNA methylation analysis of monozygotic twins.PloS one · 2018Article
- The DNA methyltransferase inhibitor zebularine exerts antitumor effects and reveals BATF2 as a poor prognostic marker for childhood medulloblastoma.Investigational new drugs · 2017Article
- Zebularine upregulates expression of CYP genes through inhibition of DNMT1 and PKR in HepG2 cells.Scientific reports · 2017Article
- New Insights into the Epigenetics of Hepatocellular Carcinoma.BioMed research international · 2017Review
- Altered intragenic DNA methylation of HOOK2 gene in adipose tissue from individuals with obesity and type 2 diabetes.PloS one · 2017Article
Corrections and comments
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Authors and funding
7 authors at 1 institution in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Hepatocellular carcinoma is one of the most common cancers worldwide. 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 hepatocellular carcinoma cell line HepG2. We demonstrate that zebularine exhibits antitumor activity on HepG2 cells by inhibiting cell proliferation and inducing apoptosis, however, it has little effect on DNA methylation in HepG2 cells. On the other hand, zebularine treatment downregulated CDK2 and the phosphorylation of retinoblastoma protein (Rb), and upregulated p21(WAF/CIP1) and p53. We also found that zebularine treatment upregulated the phosphorylation of p44/42 mitogen-activated protein kinase (MAPK). These results suggest that the p44/42 MAPK pathway plays a role in zebularine-induced cell-cycle arrest by regulating the activity of p21(WAF/CIP1) and Rb. Furthermore, although the proapoptotic protein Bax levels were not affected, the antiapoptotic protein Bcl-2 level was downregulated with zebularine treatment. In addition, the data in the present study indicate that inhibition of the double-stranded RNA-dependent protein kinase (PKR) is involved in inducing apoptosis with zebularine. These results suggest a novel mechanism of zebularine-induced cell growth arrest and apoptosis via a DNA methylation-independent pathway in hepatocellular carcinoma.
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