Expression of delta-like 3 is downregulated by aberrant DNA methylation and histone modification in hepatocellular carcinoma

  • Authors:
    • Yutaka Mizuno
    • Kentaro Maemura
    • Yoshihisa Tanaka
    • Azumi Hirata
    • Sugiko Futaki
    • Hiroki Hamamoto
    • Kohei Taniguchi
    • Michihiro Hayashi
    • Kazuhisa Uchiyama
    • Masa-Aki Shibata
    • Yoshinori Otsuki
    • Yoichi Kondo
  • View Affiliations

  • Published online on: March 5, 2018     https://doi.org/10.3892/or.2018.6293
  • Pages: 2209-2216
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Abstract

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).
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May-2018
Volume 39 Issue 5

Print ISSN: 1021-335X
Online ISSN:1791-2431

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Spandidos Publications style
Mizuno Y, Maemura K, Tanaka Y, Hirata A, Futaki S, Hamamoto H, Taniguchi K, Hayashi M, Uchiyama K, Shibata M, Shibata M, et al: Expression of delta-like 3 is downregulated by aberrant DNA methylation and histone modification in hepatocellular carcinoma. Oncol Rep 39: 2209-2216, 2018
APA
Mizuno, Y., Maemura, K., Tanaka, Y., Hirata, A., Futaki, S., Hamamoto, H. ... Kondo, Y. (2018). Expression of delta-like 3 is downregulated by aberrant DNA methylation and histone modification in hepatocellular carcinoma. Oncology Reports, 39, 2209-2216. https://doi.org/10.3892/or.2018.6293
MLA
Mizuno, Y., Maemura, K., Tanaka, Y., Hirata, A., Futaki, S., Hamamoto, H., Taniguchi, K., Hayashi, M., Uchiyama, K., Shibata, M., Otsuki, Y., Kondo, Y."Expression of delta-like 3 is downregulated by aberrant DNA methylation and histone modification in hepatocellular carcinoma". Oncology Reports 39.5 (2018): 2209-2216.
Chicago
Mizuno, Y., Maemura, K., Tanaka, Y., Hirata, A., Futaki, S., Hamamoto, H., Taniguchi, K., Hayashi, M., Uchiyama, K., Shibata, M., Otsuki, Y., Kondo, Y."Expression of delta-like 3 is downregulated by aberrant DNA methylation and histone modification in hepatocellular carcinoma". Oncology Reports 39, no. 5 (2018): 2209-2216. https://doi.org/10.3892/or.2018.6293