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

Hamamoto, Hiroki; Maemura, Kentaro; Matsuo, Kentaro; Taniguchi, Kohei; Tanaka, Yoshihisa; Futaki, Sugiko; Takeshita, Atsushi; Asai, Akira; Hayashi, Michihiro; Hirose, Yoshinobu; Kondo, Yoichi; Uchiyama, Kazuhisa

doi:10.1038/s41598-018-23318-1

Cited by 15 publications

(17 citation statements)

References 36 publications

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“…DLL3 is expressed in the cytoplasm of normal hepatocytes, but is silenced in HCC by DNA methylation and histone acetylation induced by the hepatitis B virus (HBV). 45 Histone deacetylase (HDAC) inhibitors such as TSA effectively restore DLL3 expression in HCC cells. The reactivation of DLL3 inhibits HCC cell growth and induces cell apoptosis independently of Notch1, suggesting that DLL3 has a tumor-suppressive role through Notch-independent mechanisms.…”

Section: Delta-like Ligands In Liver Cancermentioning

confidence: 99%

<p>The Role of DLLs in Cancer: A Novel Therapeutic Target</p>

Xiu

Liu

Kuang

2020

OTT

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Delta-like ligands (DLLs) control Notch signaling. DLL1, DLL3 and DLL4 are frequently deregulated in cancer and influence tumor growth, the tumor vasculature and tumor immunity, which play different roles in cancer progression. DLLs have attracted intense research interest as anti-cancer therapeutics. In this review, we discuss the role of DLLs in cancer and summarize the emerging DLL-relevant targeting methods to aid future studies.

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Section: Delta-like Ligands In Liver Cancermentioning

confidence: 99%

<p>The Role of DLLs in Cancer: A Novel Therapeutic Target</p>

Xiu

Liu

Kuang

2020

OTT

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“…In other cancers types, our group proved that DLL3 was suppressed in HCC. 14 In contrast, the expression levels of DLL3 were increased in pancreatic ductal adenocarcinoma. 22 Therefore, the roles of DLL3 seem to depend on the cancer type.…”

Section: Discussionmentioning

confidence: 95%

Delta‐like 3 localizes to neuroendocrine cells and plays a pivotal role in gastrointestinal neuroendocrine malignancy

et al. 2019

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Delta‐like 3 (DLL3) is a member of the Delta/Serrate/Lag2 (DSL) group of Notch receptor ligands. Five DSL ligands are known in mammals, among which DLL3 has a unique structure. In the last few years, DLL3 has attracted attention as a novel molecular targeting gene in neuroendocrine carcinoma of the lung due to its high expression. However, the expression pattern and functions of DLL3 in the gastrointestinal tract and gastrointestinal neuroendocrine carcinoma remain unclear. In this study, we examined the expression and role of DLL3 in the gastrointestinal tract, as well as in gastrointestinal neuroendocrine carcinoma. Immunohistochemical staining of the human normal gastrointestinal tract revealed that DLL3 localized in neuroendocrine cells. DLL3 showed intense staining in chromogranin A‐positive gastric cancer specimens. Real‐time quantitative RT‐PCR and western blotting analyses showed considerable upregulation of DLL3 in gastrointestinal neuroendocrine carcinoma cell lines. Immuno‐electron microscopy demonstrated abundant expression of DLL3 in neurosecretory granules in these cells. Furthermore, gene silencing of DLL3 caused significant growth inhibition through the induction of intrinsic apoptosis. Our findings suggest that DLL3 is expressed in neuroendocrine cells of the gastrointestinal tract and that it has a pivotal role in gastrointestinal neuroendocrine carcinoma cells. Based on these findings, further investigations are required to achieve a breakthrough in developing therapeutic strategies for gastrointestinal neuroendocrine carcinoma.

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“…Regardless of the data provided, the exact mechanism by which HBV proteins altered the early fate of the cells was still unclear. Several studies had shown that DNA demethylation could be a major mechanism in the increase of the expression of CSC markers in normal hepatocytes [29] , also correlated with HBV DNA integration [30] and the axis of HBx-DLL3 (Delta-like 3) of Notch receptor [31] . In the last study, the treatment of HBV-transformed cells with a histone deacetylase inhibitor induced DLL3 expression [31] .…”

Section: Hbvmentioning

confidence: 99%

“…Several studies had shown that DNA demethylation could be a major mechanism in the increase of the expression of CSC markers in normal hepatocytes [29] , also correlated with HBV DNA integration [30] and the axis of HBx-DLL3 (Delta-like 3) of Notch receptor [31] . In the last study, the treatment of HBV-transformed cells with a histone deacetylase inhibitor induced DLL3 expression [31] . In a recent 2018 study, it was shown that in the very early stage of HCC, the global DNA methylation 5hmC and 5fC contents were decreased significantly.…”

Section: Hbvmentioning

confidence: 99%

Oncogenicity of viral hepatitis B and C in the initiation of hepatic cancer stem cells

Sukowati¹,

Reyes²,

Tell³

et al. 2019

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Chronic infection of hepatitis B virus (HBV) or/and hepatitis C virus (HCV) is one of major risk factors in the development of the hepatocellular carcinoma. Recent studies had shown the capacity of viral proteins in inducing the presence of the population of so-called the cancer stem cells (CSC). The integration of HBV S and X gene in the host genome indicates its direct oncogenicity. In addition, the presence HBV and HCV proteins were shown to modulate intracellular molecular pathways and epigenetic modification. This review summarizes current literature regarding direct oncogenic properties of HBV and HCV in the initiation of CSC both in in vitro and in vivo studies.

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

Cited by 15 publications

References 36 publications

<p>The Role of DLLs in Cancer: A Novel Therapeutic Target</p>

<p>The Role of DLLs in Cancer: A Novel Therapeutic Target</p>

Delta‐like 3 localizes to neuroendocrine cells and plays a pivotal role in gastrointestinal neuroendocrine malignancy

Oncogenicity of viral hepatitis B and C in the initiation of hepatic cancer stem cells

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