Clinical implications of DNA methylation in hepatocellular carcinoma

Sceusi, Eric; Loose, David S.; Wray, Curtis J.

doi:10.1111/j.1477-2574.2011.00303.x

Cited by 59 publications

(37 citation statements)

References 61 publications

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“…DNMT3A seems to be the prominent responsible for the methylation of TTP promoter [45]. HCC tumors exhibit specific DNA methylation signatures associated with risk factors, tumor stage and grade of differentiation, survival after cancer therapy [35,46,47]. More interestingly, it has been shown that most CpG sites tend to become progressively hypermethylated from stage T1 through stage T3 [35].…”

Section: Dna Methylation In Hepatocellular Carcinomamentioning

confidence: 99%

Methylation and liver cancer

Raggi

Invernizzi

2013

Clinics and Research in Hepatology and Gastroenterology

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Section: Dna Methylation In Hepatocellular Carcinomamentioning

confidence: 99%

Methylation and liver cancer

Raggi

Invernizzi

2013

Clinics and Research in Hepatology and Gastroenterology

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“…Global hypomethylation and promoter hypermethylation have been found in hepatocarcinogenesis (14–16); therefore, the present study investigated the effects of ginsenoside Rg3 on methylation in the HepG2 human hepatocarcinoma cell line. The results showed that ginsenoside Rg3 inhibited HepG2 cell proliferation in a dose-dependent manner, induced a reduction in global DNA methylation, altered methylated cystosines in the promoter regions of specific genes, upregulated the expression of DNMT1, and downregulated the expression of DNMT3a and DNMT 3b.…”

Section: Introductionmentioning

confidence: 99%

Effects of R type and S type ginsenoside Rg3 on DNA methylation in human hepatocarcinoma cells

Teng

Wang

et al. 2017

Molecular Medicine Reports

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Ginsenoside Rg3, a bioactive constituent isolated from Panax ginseng, exhibits antitumorigenic, antioxidative, antiangiogenic, neuroprotective and other biological activities are associated with the regulation of multiple genes. DNA methylation patterns, particularly those in the promoter region, affect gene expression, and DNA methylation is catalyzed by DNA methylases. However, whether ginsenoside Rg3 affects DNA methylation is unknown. High performance liquid chromatography assay, MspI/HpaII polymerase chain reaction (PCR) and reverse transcription-quantitative PCR were performed to assess DNA methylation. It was demonstrated that 20(S)-ginsenoside Rg3 treatment resulted in increased inhibition of cell growth, compared with treatment with 20(R)-ginsenoside Rg3 in the human HepG2 hepatocarcinoma cell line. It was additionally revealed that treatment with 20(S)-ginsenoside Rg3 reduced global genomic DNA methylation, altered cystosine methylation of the promoter regions of P53, B cell lymphoma 2 and vascular endothelial growth factor, and downregulated the expression of DNA methyltransferase (DNMT) 3a and DNMT3b more than treatment with 20(R)-ginsenoside Rg3 in HepG2 cells. These results revealed that the modulation of DNA methylation may be important in the pharmaceutical activities of ginsenoside Rg3.

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“…A variety of genetic events have been relevant to the development of HCC including genome instability, suppression of tumor suppressors and overexpression of oncogenes [20, 21]. Along with genetic aspects, epigenetic disruptions including changes in DNA methylation, microRNA expression have also been studied in liver cancer, and mutations or abnormal expression of epigenetic regulatory genes have been recognized [22–24]. Despite these efforts, the underlying mechanism responsible for liver carcinogenesis is largely unknown and therapeutic options remain limited.…”

Section: Introductionmentioning

confidence: 99%

Epigenetic reader BRD4 inhibition as a therapeutic strategy to suppress E2F2-cell cycle regulation circuit in liver cancer

et al. 2016

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Deregulation of the epigenome component affects multiple pathways in the cancer phenotype since the epigenome acts at the pinnacle of the hierarchy of gene expression. Pioneering work over the past decades has highlighted that targeting enzymes or proteins involved in the epigenetic regulation is a valuable approach to cancer therapy. Very recent results demonstrated that inhibiting the epigenetic reader BRD4 has notable efficacy in diverse cancer types. We investigated the potential of BRD4 as a therapeutic target in liver malignancy. BRD4 was overexpressed in three different large cohort of hepatocellular carcinoma (HCC) patients as well as in liver cancer cell lines. BRD4 inhibition by JQ1 induced anti-tumorigenic effects including cell cycle arrest, cellular senescence, reduced wound healing capacity and soft agar colony formation in liver cancer cell lines. Notably, BRD4 inhibition caused MYC-independent large-scale gene expression changes in liver cancer cells. Serial gene expression analyses with SK-Hep1 liver cancer cells treated with JQ1 to delineate the key player of BRD4 inhibition identified E2F2 as the first line of downstream direct target of BRD4. Further experiments including chromatin immunoprecipitation (ChIP) assay and loss of function study confirmed E2F2 as key player of BRD4 inhibition. Overexpressed E2F2 is a crucial center of cell cycle regulation and high expression of E2F2 is significantly associated with poor prognosis of HCC patients. Our findings reveal BRD4-E2F2-cell cycle regulation as a novel molecular circuit in liver cancer and provide a therapeutic strategy and innovative insights for liver cancer therapies.

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Clinical implications of DNA methylation in hepatocellular carcinoma

Abstract: Epigenetic changes and profiles may correlate to the biological behaviour of tumours and clinical outcome of HCC patients. The use of DNA methylation profiles as a surrogate biomarker remains an active area of clinical cancer research.

Cited by 59 publications

References 61 publications

Methylation and liver cancer

Methylation and liver cancer

Effects of R type and S type ginsenoside Rg3 on DNA methylation in human hepatocarcinoma cells

Epigenetic reader BRD4 inhibition as a therapeutic strategy to suppress E2F2-cell cycle regulation circuit in liver cancer

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