Hepatitis C virus Core protein overcomes all-trans retinoic acid-induced cell growth arrest by inhibiting retinoic acid receptor-β2 expression via DNA methylation

Lee, Hyehyeon; Woo, Young-Ju; Kim, Soo Shin; Kim, Sung-Hyun; Park, Bum-Joon; Choi, Dongho; Jang, Kyung Lib

doi:10.1016/j.canlet.2013.02.057

Cited by 15 publications

(9 citation statements)

References 34 publications

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“…Therefore, HCV core protein is considered to be responsible for the DNA methylation-mediated inactivation of tumor suppressor genes in HCV-associated HCC [47]. However, most of these studies were performed using HCV core overexpression systems [38,48], which may not properly reflect natural HCV replication in vivo. The present study took advantage of the HCV replication system to demonstrate that HCV core protein activates DNMT by elevating DNMT1 and 3b levels.…”

Section: Discussionmentioning

confidence: 95%

Hepatitis C virus core protein inhibits E6AP expression via DNA methylation to escape from ubiquitin-dependent proteasomal degradation

et al. 2016

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Section: Discussionmentioning

confidence: 95%

Hepatitis C virus core protein inhibits E6AP expression via DNA methylation to escape from ubiquitin-dependent proteasomal degradation

et al. 2016

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“…Unlike HCV Core, ATRA activates p14 expression via promoter hypomethylation, which leads to destabilization of MDM2 and subsequent stabilization of p53 [ 19 ]. For this effect, ATRA in combination with RAR-β2 downregulates both the protein levels and the enzyme activities of DNMT1, DNMT3a, and DNMT3b [ 20 ], via unknown mechanisms. The present study suggests that ATRA represses DNMT1 expression via inactivation of AP-1.…”

Section: Discussionmentioning

confidence: 99%

“…HCV Core appears to exert its oncogenic activity, at least in part, by suppressing the anti-cancer activities of ATRA. For example, HCV Core overcomes ATRA-induced cell growth arrest by inhibiting retinoic acid receptor-β2 ( RAR-β2 ) expression via DNA methylation in human hepatoma cells [ 20 ]. However, it is unknown whether HCV Core suppresses ATRA-induced apoptosis.…”

Section: Introductionmentioning

confidence: 99%

Hepatitis C virus Core overcomes all-transretinoic acid-induced apoptosis in human hepatoma cells by inhibitingp14expression via DNA methylation

2017

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All-trans retinoic acid (ATRA), the most biologically active metabolite of vitamin A, is known to induce p14 expression via promoter hypomethylation to activate the p14-MDM2-p53 pathway, which leads to activation of the p53-dependent apoptotic pathway and subsequent induction of apoptosis in human hepatoma cells. In the present study, we found that hepatitis C virus (HCV) Core derived from ectopic expression or HCV infection overcomes ATRA-induced apoptosis in p53-positive hepatoma cells. For this effect, HCV Core upregulated both protein levels and enzyme activities of DNA methyltransferase 1 (DNMT1), DNMT3a, and DNMT3b and thereby repressed p14 expression via promoter hypermethylation, resulting in inactivation of the pathway leading to p53 accumulation in the presence of ATRA. As a result, HCV Core prevented ATRA from activating several apoptosis-related molecules, including Bax, p53 upregulated modulator of apoptosis, caspase-9, caspase-3, and poly (ADP-ribose) polymerase. In addition, complementation of p14 in the Core-expressing cells by either ectopic expression or treatment with 5-Aza-2′dC almost completely abolished the potential of HCV Core to suppress ATRA-induced apoptosis. Based on these observations, we conclude that HCV Core executes its oncogenic potential by suppressing the p53-dependent apoptosis induced by ATRA in human hepatoma cells.

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“…One may speculate that expression of certain HCV core proteins may affect the stability of DNMT3B. HCV core induced upregulation of DNMT1 and DNMT3B mediated the hypermethylation and silencing of the RARB2 promoter as well, where transcripts encoding the tumor suppressor protein retinoic acid receptor-β2 are initiated (Lee et al 2013 ). Such a mechanism may block the growthinhibitory effect of all-trans retinoic acid in HCV infected cells.…”

Section: Hepatitis C Virus (Hcv)mentioning

confidence: 98%

Epigenetic Dysregulation in Virus-Associated Neoplasms

Minárovits

Demcsák

Bánáti³

et al. 2015

Advances in Experimental Medicine and Biology

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The oncoproteins of human tumor viruses regularly interact with the cellular epigenetic machinery. Such interactions alter the epigenome of the host cell and reprogram its gene expression pattern. Altered levels or redistribution of (cytosine-5)-DNA methyltransferases and changes in the cellular methylome were observed in Kaposi sarcoma-associated herpesvirus (KSHV), hepatitis B virus (HBV), hepatitis D virus (HDV), hepatitis C virus (HCV), and human papillomavirus (HPV) associated neoplasms and cell lines. Methylation-mediated silencing of cellular promoters was also noted in Merkel cell polyomavirus (MCPyV) positive Merkel cell carcinomas, and, as discussed elsewhere, in EBV-associated malignancies and adenovirus-induced rodent tumors as well. Promoter activation also occurred, either associated with DNA hypomethylation or with the induction of euchromatic histone modifications by viral oncoproteins. It is worthy to notice that HCV infection induced large, hypomethylated blocks of cellular chromatin, although the exact molecular mechanism remains to be elucidated. In hepatoma cells expressing HBx, the oncoprotein encoded by the HBV genome, demethylation of the repetitive satellite 2 sequences was observed, due to downregulation of the de novo DNA methyltransferase DNMT3B. Tax and HBZ, the oncoproteins of human T-cell lymphotropic virus type I (HTLV-I), can both activate and silence distinct cellular promoters by interacting with cellular enzymes involved in histone modification.

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Hepatitis C virus Core protein overcomes all-trans retinoic acid-induced cell growth arrest by inhibiting retinoic acid receptor-β2 expression via DNA methylation

Cited by 15 publications

References 34 publications

Hepatitis C virus core protein inhibits E6AP expression via DNA methylation to escape from ubiquitin-dependent proteasomal degradation

Hepatitis C virus core protein inhibits E6AP expression via DNA methylation to escape from ubiquitin-dependent proteasomal degradation

Hepatitis C virus Core overcomes all-transretinoic acid-induced apoptosis in human hepatoma cells by inhibitingp14expression via DNA methylation

Epigenetic Dysregulation in Virus-Associated Neoplasms

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