Epstein–Barr virus latent membrane protein 1 suppresses the growth-inhibitory effect of retinoic acid by inhibiting retinoic acid receptor-β2 expression via DNA methylation

Seo, So Young; Kim, Eun‐Ok; Jang, Kyung Lib

doi:10.1016/j.canlet.2008.04.043

Cited by 59 publications

(34 citation statements)

References 36 publications

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“…1c). Instead, our data support the model that DNMT1 and DNMT3a form a complex to induce DNA methylation (Kim et al, 2002;Seo et al, 2008;Tsai et al, 2002). Further studies are required to understand the roles and action mechanisms of DNMT enzymes in the presence of HBx.…”

Section: Hbx Downregulates Rar-b 2 Expression Via Dna Methylationsupporting

confidence: 88%

Hepatitis B virus X protein overcomes the growth-inhibitory potential of retinoic acid by downregulating retinoic acid receptor- 2 expression via DNA methylation

Jung

Park

Jang

2009

Journal of General Virology

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Aberrant promoter methylation of retinoic acid receptor-b 2 (RAR-b 2 ) is frequently detected in hepatitis B virus (HBV)-positive hepatocellular carcinoma (HCC); however, the mechanism of methylation and its biological significance are unknown. This study showed that HBx, the principal oncogene product of HBV, induced promoter hypermethylation of RAR-b 2 via upregulation of DNA methyltransferases 1 and 3a, resulting in downregulation of its expression in human HCC cells. In addition, HBx abolished the potential of retinoic acid (RA) to downregulate levels of G 1 -checkpoint regulators including p16, p21 and p27, resulting in activation of E2F1 in the presence of RA. As a consequence, HBx-expressing cells were less susceptible to RA-induced cell growth inhibition compared with control cells. These effects almost completely disappeared when levels of RAR-b 2 in HBx-expressing cells were restored by treatment with a universal DNA methylation inhibitor, 5-aza-29-deoxycytidine. As RAR-b 2 is a major executor of the anti-tumour potential of RA, its epigenetic downregulation by HBx is likely to be an important step during HBV-mediated tumorigenesis. INTRODUCTIONRetinoids are vitamin A derivatives and analogues that are involved in many important biological processes, including vision, morphogenesis, differentiation, growth, metabolism and cellular homeostasis (De Luca, 1991). In addition, they act as inhibitors of carcinogenesis by blocking the promotion of initiated or transformed cells by three mechanisms: induction of apoptosis, arrest of further growth of abnormal cells and induction of abnormal cells to differentiate back to normal (Hansen et al., 2000). These effects are executed mainly by regulating gene expression primarily through two classes of nuclear receptors, including retinoic acid (RA) receptors (RARs) and retinoid X receptors (RXRs) (Chambon, 1996). As either homodimers or heterodimers, RARs and RXRs modulate the expression of target genes by acting on the RA response element (RARE) located on the promoter regions of target genes.RAR-b contains four isoforms with different affinities to retinoids and different biological functions (Chambon, 1996). In particular, RAR-b 2 has attracted attention as a major executor of the anti-tumour potential of retinoids in a wide variety of cancers (Houle et al., 1993;Xu, 2007). Loss of RAR-b 2 is closely associated with retinoid resistance during tumorigenesis (Gebert et al., 1991;Hoffman et al., 1996;Hu et al., 1991;Xu et al., 1994). In addition, exogenous introduction of RAR-b 2 into cervical, breast and lung cancer cells enhances cell responsiveness to growth inhibition and induction of apoptosis by retinoids (Seewaldt et al., 1995; Si et al., 1996). Therefore, its loss of function is now considered to play a critical role in tumorigenesis. Aberrant promoter methylation of RAR-b 2 , which can lead to transcriptional downregulation of its expression, is frequently detected in human malignant tumours including hepatocellular carcinoma (HCC) (Lee et al., 2003;Yang et...

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Section: Hbx Downregulates Rar-b 2 Expression Via Dna Methylationsupporting

confidence: 88%

Hepatitis B virus X protein overcomes the growth-inhibitory potential of retinoic acid by downregulating retinoic acid receptor- 2 expression via DNA methylation

Jung

Park

Jang

2009

Journal of General Virology

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“…We cannot rule out stimulation of DNMT activity by extra-transcriptional factors, as is the case for Epstein-Barr virus latent membrane protein 1 induced DNMT1 activity 29 and enhanced expression of other members of the DNMT family (DNMT3A, DNMT3B) as mechanism for the observed DNMT activity increase.…”

Section: Discussionmentioning

confidence: 92%

“…[24][25][26][27] Human papillomavirus E7 and adenovirus E1A proteins have also been shown to directly associate with DNMT1 and stimulate DNMT1 activity. 28 Induction of latent membrane protein 1 of Epstein-Barr virus has been shown to directly activate DNMT1 expression in cultured cancer cells 29 as does Hepatitis B viral infection of a human hepatocellular carcinoma cell line. 30 In addition to genetic alterations, epigenetic silencing by methylation of the promoter region is well documented for many growth-suppressor genes, such as cyclin-dependent kinase inhibitor 2A (CDKN2A (P16INK4A)), mutL homolog 1 (MLH1), O6-methylguanine-DNA-methyltransferase (MGMT) and deathassociated protein kinase 1 (DAPK1) resulting in 'suppressing the suppressors' .…”

mentioning

confidence: 99%

Uropathogenic E. coli infection provokes epigenetic downregulation of CDKN2A (p16INK4A) in uroepithelial cells

Tölg

Sabha

Cortese

et al. 2011

Laboratory Investigation

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Host cell and bacterial factors determine severity and duration of infections. To allow for bacteria pathogenicity and persistence, bacteria have developed mechanisms that modify expression of host genes involved in cell cycle progression, apoptosis, differentiation and the immune response. Recently, Helicobacter pylori infection of the stomach has been correlated with epigenetic changes in the host genome. To identify epigenetic changes during Escherichia coli induced urinary tract infection (UTI), we developed an in vitro model of persistent infection of human uroepithelial cells with uropathogenic E. coli (UPEC), resulting in intracellular bacteria colonies. Cells inoculated with FimH-negative E. coli (N-UPEC) that are not internalized and non-inoculated cells were used as controls. UPEC infection significantly induced de novo methyltransferase (DNMT) activity (12.5-fold P ¼ 0.002 UPEC vs non-inoculated and 250-fold P ¼ 0.001 UPEC vs N-UPEC inoculated cells) and Dnmt1 RNA expression (6-fold P ¼ 0.04 UPEC vs non-inoculated cells) compared with controls. DNMT1 protein levels were significantly increased in three uroepithelial cell lines (5637, J82, HT-1197) in response to UPEC infection as demonstrated by confocal analysis. Real-time PCR analysis of candidate genes previously associated with bacteria infection and/or innate immunity, revealed UPEC-induced downregulation of the tumor suppressor gene CDKN2A (3.3-fold P ¼ 0.007 UPEC vs non-inoculated and 3.3-fold P ¼ 0.001 UPEC vs N-UPEC) and the DNA repair gene MGMT (9-fold P ¼ 0.03 UPEC vs non-inoculated). Expression of CDH1, MLH1, DAPK1 and TLR4 was not affected. Pyrosequencing of CDKN2A and MGMT CpG islands revealed increased methylation in CDKN2A exon 1 (3.8-fold P ¼ 0.04 UPEC vs N-UPEC and UPEC vs non-inoculated). Methylation of MGMT was not affected. UPEC-induced methylation of CDKN2A exon 1 may increase bladder cancer and presage UTI risk, and be useful as a biological marker for UTI susceptibility or recurrence.

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“…This implies that tumor-specific methylation changes may be used as biomarkers in methylation-specific diagnostic PCR assays from the blood for the early detection of occult tumors [63][64][65]. Furthermore, hypermethylation at specific tumor suppressor loci may serve as a predictor for the success of chemotherapy [66,67]. Epigenetic markers other than methylation, such as expression of repressive PcG proteins and the increased presence of the repressive histone mark H3K27me3 were indicators for a poor prognosis both for NPC, gastric carcinoma and B cell lymphomas [68][69][70][71].…”

Section: Discussionmentioning

confidence: 99%

Up-Regulation of Lamin A/C Expression in Epstein-Barr Virus Immortalized B Cells and Burkitt Lymphoma Cell Lines of Activated B Cell Phenotype

Bánáti¹,

Koroknai²,

Szenthe³

et al. 2017

J Microb Biochem Technol

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Epstein–Barr virus latent membrane protein 1 suppresses the growth-inhibitory effect of retinoic acid by inhibiting retinoic acid receptor-β2 expression via DNA methylation

Cited by 59 publications

References 36 publications

Hepatitis B virus X protein overcomes the growth-inhibitory potential of retinoic acid by downregulating retinoic acid receptor- 2 expression via DNA methylation

Hepatitis B virus X protein overcomes the growth-inhibitory potential of retinoic acid by downregulating retinoic acid receptor- 2 expression via DNA methylation

Uropathogenic E. coli infection provokes epigenetic downregulation of CDKN2A (p16INK4A) in uroepithelial cells

Up-Regulation of Lamin A/C Expression in Epstein-Barr Virus Immortalized B Cells and Burkitt Lymphoma Cell Lines of Activated B Cell Phenotype

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