Expression of delta-like 3 is downregulated by aberrant DNA methylation and histone modification in hepatocellular carcinoma
| Autor: | Masa-Aki Shibata, Kentaro Maemura, Yoshinori Otsuki, Michihiro Hayashi, Hiroki Hamamoto, Sugiko Futaki, Kazuhisa Uchiyama, Kohei Taniguchi, Yoichi Kondo, Yutaka Mizuno, Yoshihisa Tanaka, Azumi Hirata |
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| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Cancer Research Carcinoma Hepatocellular medicine.drug_class Bisulfite sequencing Down-Regulation Decitabine Epigenesis Genetic Histones 03 medical and health sciences Histone H3 0302 clinical medicine Cell Line Tumor Histone methylation medicine Humans Epigenetics Promoter Regions Genetic biology Chemistry Liver Neoplasms Histone deacetylase inhibitor Intracellular Signaling Peptides and Proteins Membrane Proteins Acetylation General Medicine Methylation DNA Methylation Molecular biology Gene Expression Regulation Neoplastic 030104 developmental biology Histone Oncology 030220 oncology & carcinogenesis DNA methylation Azacitidine biology.protein |
| Zdroj: | Oncology Reports. |
| ISSN: | 1791-2431 1021-335X |
| DOI: | 10.3892/or.2018.6293 |
| Popis: | Delta-like 3 (DLL3) is a member of the Delta/Serrate/Lag-2 family of ligands for the Notch receptor and plays a role in Notch signaling. We have previously revealed that the expression of DLL3 is silenced by aberrant DNA methylation and that overexpression of DLL3 in the HuH2 hepatocellular carcinoma (HCC) cell line induced apoptosis. In the present study, we first confirmed the methylation of DLL3 in HuH2 cells and analyzed the methylation status of the DLL3 promoter region by bisulfite sequencing. Furthermore, we investigated whether other epigenetic modifications, such as histone acetylation and histone methylation, affected the expression of DLL3. Treatment with the DNA methylation inhibitor, 5-azadeoxycytidine (5-Aza-dC) slightly reactivated DLL3 mRNA expression and bisulfite sequencing revealed that CpG sites in the DLL3 promoter region of the HuH2 cells were densely-methylated. In addition, a significant increase in the expression of DLL3 was observed when the cells were treated with 5-Aza-dC in combination with the histone deacetylase inhibitor trichostatin A. However, an inhibitor of the dimethylation of histone H3 lysine 9 (H3K9me2) or the trimethylation of histone H3 lysine 27 (H3K27me3), modifications that are associated with gene silencing, had no effect on DLL3 reactivation. In combination with the findings from our previous study, these results indicated that DLL3 expression was silenced in HCC cells by DNA methylation and was more readily affected by histone acetylation than histone methylation (H3K9me2 or H3K27me3). |
| Databáze: | OpenAIRE |
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