Delta-like 3 is silenced by HBx via histone acetylation in HBV-associated HCCs

Hepatocellular carcinoma (HCC) is a common malignant tumor with poor prognosis. We previously showed that expression of Delta-like 3 (DLL3), a member of the family of Delta/Serrate/Lag2 ligands for the Notch receptor, is silenced by aberrant DNA methylation and that overexpression of DLL3 in an HCC...

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Bibliographic Details
Published in:Scientific reports 2018-03, Vol.8 (1), p.4842-11, Article 4842
Main Authors: Hamamoto, Hiroki, Maemura, Kentaro, Matsuo, Kentaro, Taniguchi, Kohei, Tanaka, Yoshihisa, Futaki, Sugiko, Takeshita, Atsushi, Asai, Akira, Hayashi, Michihiro, Hirose, Yoshinobu, Kondo, Yoichi, Uchiyama, Kazuhisa
Format: Article
Language:English
Subjects:
631/67/1504/1610/4029
631/67/1858
Acetylation
Apoptosis
Chromatin
DNA methylation
Genomes
HBX protein
Hepatitis
Hepatitis B
Hepatocellular carcinoma
Histone deacetylase
Humanities and Social Sciences
Infections
Liver cancer
multidisciplinary
Notch protein
Science
Science (multidisciplinary)
siRNA
Viral infections
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Summary:Hepatocellular carcinoma (HCC) is a common malignant tumor with poor prognosis. We previously showed that expression of Delta-like 3 (DLL3), a member of the family of Delta/Serrate/Lag2 ligands for the Notch receptor, is silenced by aberrant DNA methylation and that overexpression of DLL3 in an HCC cell line induces cellular apoptosis. However, how DLL3 expression is regulated during hepatocarcinogenesis is still unclear. Here, we show that silencing of DLL3 during hepatocarcinogenesis is closely related to viral infection, especially hepatitis B virus (HBV) infection (p = 0.005). HepG2.2.15 cells, which are stably transformed with the HBV genome, showed lower DLL3 expression than the parent cell line, HepG2 cells. Treatment with Hepatitis B virus X protein (HBx) small interfering RNA upregulated DLL3 expression in HepG2.2.15 cells, and overexpression of HBx in HepG2 cells downregulated DLL3 expression. Treatment of cells with a histone deacetylase inhibitor induced DLL3 expression in HepG2.2.15 cells. These data suggest that DLL3 expression is silenced during hepatocarcinogenesis in association with HBV infection via an epigenetic mechanism.
ISSN:2045-2322
2045-2322
DOI:10.1038/s41598-018-23318-1