Hepatitis viruses exploitation of host DNA methyltransferases functions

Pazienza, Valerio; Panebianco, Concetta; Andriulli, Angelo

doi:10.1007/s10238-015-0372-3

Cited by 10 publications

(7 citation statements)

References 113 publications

(147 reference statements)

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“…We found that HBV suppressed NFAT5 expression by inducing hypermethylation of the AP1-binding site in the NFAT5 promoter. Though HBV doesn’t encode any methylases, however HBV infection can stimulate the overexpression of DNMTs, particularly DNMT1, DNMT3A and DNMT3B [ 25 ]. We speculate the overexpression of DNMTs may result in the hyper-methylation of the AP1-binding site in the NFAT5 promoter.…”

Section: Discussionmentioning

confidence: 99%

Upregulation of DARS2 by HBV promotes hepatocarcinogenesis through the miR-30e-5p/MAPK/NFAT5 pathway

Qin

Guo

et al. 2017

J Exp Clin Cancer Res

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BackgroundInfection with the hepatitis B virus (HBV) is closely associated with the development of hepatocellular carcinoma (HCC). The osmoregulatory transcription factor nuclear factor of activated T-cells 5 (NFAT5) has been shown to play an important role in the development of many types of human cancers. The role of NFAT5 in HBV-associated HCC has never previously been investigated.MethodsWe compared expression profiles of NFAT5, DARS2 and miR-30e-5p in HCC samples, adjacent nontumor tissues and different hepatoma cell lines by quantitative real-time polymerase chain reaction and /or Western blot. Clinical data of HCC patients for up to 80 months were analyzed. The regulatory mechanisms upstream and convergent downstream pathways of NFAT5 in HBV-associated HCC were investigated by ChIP-seq, MSP, luciferase report assay and bioinformation anaylsis.ResultsWe first found that higher levels of NFAT5 expression predict a good prognosis, suggesting that NFAT5 is a potential tumor-suppressing gene, and verified that NFAT5 promotes hepatoma cell apoptosis and inhibits cell growth in vitro. Second, our results showed that HBV could suppress NFAT5 expression by inducing hypermethylation of the AP1-binding site in the NFAT5 promoter in hepatoma cells. In addition, HBV also inhibited NFAT5 through miR-30e-5p targeted MAP4K4, and miR-30e-5p in turn inhibited HBV replication. Finally, we demonstrated that NFAT5 suppressed DARS2 by directly binding to its promoter. DARS2 was identified as an HCC oncogene that promotes HCC cell cycle progression and inhibits HCC cell apoptosis.ConclusionHBV suppresses NFAT5 through the miR-30e-5p/mitogen-activated protein kinase (MAPK) signaling pathway upstream of NFAT5 and inhibits the NFAT5 to enhance HCC tumorigenesis via the downstream target genes of DARS2.Electronic supplementary materialThe online version of this article (10.1186/s13046-017-0618-x) contains supplementary material, which is available to authorized users.

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Section: Discussionmentioning

confidence: 99%

Upregulation of DARS2 by HBV promotes hepatocarcinogenesis through the miR-30e-5p/MAPK/NFAT5 pathway

Qin

Guo

et al. 2017

J Exp Clin Cancer Res

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“…MTases have been found in viruses, for example, LM21 prophage in Sinorizhobium [ 51 ] or the methyltransferase domain in rhinovirus and coronavirus that targets RNA cap [ 52 , 53 ], and ebolavirus that targets adenosine in RNA [ 54 ]. One mechanism exploited by some viruses is to induce the upregulation of mRNA of DNMTs in hepatitis, cirrhosis, and hepatocellular carcinoma, observed in the presence of hepatitis B virus [ 55 , 56 ]; Epstein Barr virus in gastric cancer [ 57 , 58 , 59 ]; herpesvirus LANA, in Kaposi’s sarcoma [ 60 ]; and interestingly in lymphoid cells, infected by human immunodeficiency virus 1 [ 61 ].…”

Section: Dna Methyltransferasesmentioning

confidence: 99%

DNA Methyltransferases: From Evolution to Clinical Applications

Falconi

Torres-Arciga

Matus-Ortega

et al. 2022

IJMS

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DNA methylation is an epigenetic mark that living beings have used in different environments. The MTases family catalyzes DNA methylation. This process is conserved from archaea to eukaryotes, from fertilization to every stage of development, and from the early stages of cancer to metastasis. The family of DNMTs has been classified into DNMT1, DNMT2, and DNMT3. Each DNMT has been duplicated or deleted, having consequences on DNMT structure and cellular function, resulting in a conserved evolutionary reaction of DNA methylation. DNMTs are conserved in the five kingdoms of life: bacteria, protists, fungi, plants, and animals. The importance of DNMTs in whether methylate or not has a historical adaptation that in mammals has been discovered in complex regulatory mechanisms to develop another padlock to genomic insurance stability. The regulatory mechanisms that control DNMTs expression are involved in a diversity of cell phenotypes and are associated with pathologies transcription deregulation. This work focused on DNA methyltransferases, their biology, functions, and new inhibitory mechanisms reported. We also discuss different approaches to inhibit DNMTs, the use of non-coding RNAs and nucleoside chemical compounds in recent studies, and their importance in biological, clinical, and industry research.

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“…The methylation landscape of HCV-positive HCC tissues differs from non-tumor controls and a correlation between HCV infection and aberrant methylation of genes such as CDKN2A (cyclin-dependent kinase inhibitor 2A), CDH1 (cadherin 1), SOCS1 (suppressor of cytokine signaling 1), RASSF1A (Ras associated domain family member 1), APC (adenomatous polyposis coli protein), GSTP1 (glutathione S-transferase Pi 1), STAT1 (Signal transducer and activator of transcription 1), and PRDM2 (PR/SET domain 2) in HCV-positive HCC has been established. Hampered expression of these genes contributes to cancer by promoting cell proliferation, mobility and invasion, and immune evasion [ 27 , 29 , 81 , 82 , 83 , 84 ]. The core protein seems to be implicated in HCV-induced DNA methylation because DNMT1 and DNMT3B levels were enhanced in HCV core protein expressing HepG2 cells and in Huh-7 cells compared to control cells [ 27 , 28 , 29 , 30 ].…”

Section: Oncoviruses and Host Cell Dna Methylationmentioning

confidence: 99%

“…Comparing the DNA methylation profile of HBV-associated HCC and HBV-negative tumors or healthy adjacent liver tissue, HBV-infected and non-infected cells, and HBx transgenic mouse model and control mice disclosed differentially methylation. Several cellular promoters were hypermethylated in the presence of HBV or HBx, including the promoters of the genes encoding cyclin-dependent protein kinases inhibitors p21 CIP1/WAF1 ( CDKN1A ), p14 ARF ( CDKN2A ) and p14 INK4B ( CDKN2B ), cadherin 1, RASSF1A, the spleen associated tyrosine kinase SYK ( SYK ), GSTP1, the protein phosphatase 1 regulatory subunit 13B ( PP1R13B ), the tumor promotor p53 binding protein 2 ( TP53BP2 ), and insulin like growth factor binding protein 3 ( IGFBP3 ) [ 52 , 53 , 82 , 84 , 133 , 134 , 135 , 136 , 137 , 138 ]. These proteins are involved in cell cycle control, apoptosis, migration and invasion, indicating that HBV-induced silencing of these genes play a role in HCC.…”

Section: Oncoviruses and Host Cell Dna Methylationmentioning

confidence: 99%

Role of Virus-Induced Host Cell Epigenetic Changes in Cancer

Pietropaolo¹,

Prezioso

Moens

2021

IJMS

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The tumor viruses human T-lymphotropic virus 1 (HTLV-1), hepatitis C virus (HCV), Merkel cell polyomavirus (MCPyV), high-risk human papillomaviruses (HR-HPVs), Epstein-Barr virus (EBV), Kaposi’s sarcoma-associated herpes virus (KSHV) and hepatitis B virus (HBV) account for approximately 15% of all human cancers. Although the oncoproteins of these tumor viruses display no sequence similarity to one another, they use the same mechanisms to convey cancer hallmarks on the infected cell. Perturbed gene expression is one of the underlying mechanisms to induce cancer hallmarks. Epigenetic processes, including DNA methylation, histone modification and chromatin remodeling, microRNA, long noncoding RNA, and circular RNA affect gene expression without introducing changes in the DNA sequence. Increasing evidence demonstrates that oncoviruses cause epigenetic modifications, which play a pivotal role in carcinogenesis. In this review, recent advances in the role of host cell epigenetic changes in virus-induced cancers are summarized.

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Hepatitis viruses exploitation of host DNA methyltransferases functions

Cited by 10 publications

References 113 publications

Upregulation of DARS2 by HBV promotes hepatocarcinogenesis through the miR-30e-5p/MAPK/NFAT5 pathway

Upregulation of DARS2 by HBV promotes hepatocarcinogenesis through the miR-30e-5p/MAPK/NFAT5 pathway

DNA Methyltransferases: From Evolution to Clinical Applications

Role of Virus-Induced Host Cell Epigenetic Changes in Cancer

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