The Epstein–Barr virus oncogene product, latent membrane protein 1, induces the downregulation of E-cadherin gene expression via activation of DNA methyltransferases

Tsai, Chun‐Yi; Tsai, Chia-Lung; Tse, Ka-Po; Chang, Hwan‐You; Chang, Yu‐Sun

doi:10.1073/pnas.152059399

Cited by 278 publications

(225 citation statements)

References 39 publications

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“…E Anastasiadou et al activate DNMTs (Tsai et al, 2002). If LMP1 induces miR-29b as shown here, DNMT expression should be adversely affected.…”

Section: Ebv Lmp1 Regulates Tcl1 Through Mir-29bmentioning

confidence: 61%

“…This apparent paradox can be explained by the fact that LMP1 has opposite transforming effects in B cells and epithelial cells. Indeed, it was in the epithelial cell background that LMP1 increased DNMT expression (Tsai et al, 2002) Besides targeting TCL1 and DNMT, miR-29b negatively regulates another oncogene, MCL1 (Mott et al, 2007). LMP1 was shown to increase MCL1 expression (Wang et al, 1996).…”

Section: Ebv Lmp1 Regulates Tcl1 Through Mir-29bmentioning

confidence: 99%

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Epstein–Barr virus encoded LMP1 downregulates TCL1 oncogene through miR-29b

et al. 2009

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Epstein-Barr virus (EBV) encoded latent membrane protein 1 (LMP1) is noted for its transforming potential. Yet, it also acts as a cytostatic and growth-relenting factor in Burkitt's lymphoma (BL) cells. The underlying molecular mechanisms of the growth inhibitory property of LMP1 have remained largely unknown. In this study, we show that LMP1 negatively regulates a major oncogene, TCL1, in diffuse large B-cell lymphoma (DLBCL) and BL cells. MicroRNA (miR) profiling of LMP1 transfectants showed that among others, miR-29b, is upregulated. LMP1 diminished TCL1 by inducing miR29b through C-terminus activation region 1 (CTAR1) and CTAR2. miR-29b locked nucleic acid (LNA) antisense oligonucleotide transfection into LMP1-expressing cells reduced miR-29b expression and consequently reconstituted TCL1, suggesting that LMP1 negatively regulates TCL1 through miR-29b upregulation. The miR-29b increase by LMP1 was due to an increase in the cluster pri-miR-29b1-a transcription, derived from human chromosome 7. Using pharmacological inhibitors, we found that p38 mitogen-activated protein kinase-activating function of LMP1 is important for this effect. The ability of LMP1 to negatively regulate TCL1 through miR-29b might underlie its B-cell lymphoma growth antagonistic property. As LMP1 is also important for B-cell transformation, we suggest that the functional dichotomy of this viral protein may depend on a combination of levels of its expression, lineage and differentiation of the target cells and regulation of miRs, which then directs the outcome of the cellular response.

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“…E Anastasiadou et al activate DNMTs (Tsai et al, 2002). If LMP1 induces miR-29b as shown here, DNMT expression should be adversely affected.…”

Section: Ebv Lmp1 Regulates Tcl1 Through Mir-29bmentioning

confidence: 61%

Section: Ebv Lmp1 Regulates Tcl1 Through Mir-29bmentioning

confidence: 99%

Epstein–Barr virus encoded LMP1 downregulates TCL1 oncogene through miR-29b

et al. 2009

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“…Downregulated expression of target genes results from single transitional changes in these important regulatory sequences. It has been demonstrated that promoter methylation can be induced by viral agents 16,17 or by the recruitment of methyl-transferase enzymatic machinery.…”

Section: Discussionmentioning

confidence: 99%

MEIS 1 expression is downregulated through promoter hypermethylation in AML1-ETO acute myeloid leukemias

et al. 2004

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Retroviral insertional mutagenesis in BXH2 mice commonly induces myeloid leukemias. One of the most frequently involved genes in experimental studies is Meis 1. In contrast to other genes in murine models, Meis 1 has not been affected by recurrent chromosomal translocations or point mutations in human leukemias. We found a constant downregulation of the Meis 1 gene mRNA in AML1-ETO acute myeloid leukemias and in those cases harboring in frame mutations in the bZIP domain of CEBPa. The absence of the Meis 1 mRNA was not caused by inactivating point mutations in the coding sequence. Promoter hypermethylation was present in more than half of the cases (9/14), including samples obtained from the widely employed Kasumi-1 cell line. Double treatment with 5-Aza-2 0 -deoxycytidine and trichostatin A of the Kasumi-1 cell line partially reverses Meis 1 inhibition. HoxA9 levels were also low. In a cell line model (U937 Tet AML1-ETO), AML1-ETO expression was not associated with Meis 1 suppression at 72 h. Nevertheless, Meis 1 repression is dependent on the AML1-ETO transcript levels in treated leukemic patients. Chimeric products that arise from chromosomal translocations may be associated with locus-specific epigenetic inactivation. It remains to be investigated when this methylation process is acquired and which are the basic mechanisms underlying these molecular events in AML1-ETO and CEBPa-mutated AML.

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“…It has been shown that human epithelial cells expressing LMP1 had higher invasive ability, in correlation with reduced E-cadherin expression [55,56]. Our previous data demonstrated that reduction of E-cadherin is the result of LMP1-induced hypermethylation of Ecadherin gene promoter through activation of DNMT1, 3A and 3B [57]. Addition of DNMT inhibitor, 5'-Aza-2'-dC, in LMP1 expressing epithelial cells, restored the expression of the E-cadherin, suggesting that LMP1 regulates the expression of specific cellular gene via epigenetic modification.…”

Section: Epstein-barr Virusmentioning

confidence: 92%

Epigenetic changes in virus-associated human cancers

Leu

Chang

2005

Cell Res

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Epigenetics of human cancer becomes an area of emerging research direction due to a growing understanding of specific epigenetic pathways and rapid development of detection technologies. Aberrant promoter hypermethylation is a prevalent phenonmena in human cancers. Tumor suppressor genes are often hypermethylated due to the increased activity or deregulation of DNMTs. Increasing evidence also reveals that viral genes are one of the key players in regulating DNA methylation. In this review, we will focus on hypermethylation and tumor suppressor gene silencing and the signal pathways that are involved, particularly in cancers closely associated with the hepatitis B virus, simian virus 40 (SV40), and Epstein-Barr virus. In addition, we will discuss current technologies for genome-wide detection of epigenetically regulated targets, which allow for systematic DNA hypermethylation analysis. The study of epigenetic changes should provide a global view of gene profile in cancer, and epigenetic markers could be used for early detection, prognosis, and therapy of cancer.

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The Epstein–Barr virus oncogene product, latent membrane protein 1, induces the downregulation of E-cadherin gene expression via activation of DNA methyltransferases

Cited by 278 publications

References 39 publications

Epstein–Barr virus encoded LMP1 downregulates TCL1 oncogene through miR-29b

Epstein–Barr virus encoded LMP1 downregulates TCL1 oncogene through miR-29b

MEIS 1 expression is downregulated through promoter hypermethylation in AML1-ETO acute myeloid leukemias

Epigenetic changes in virus-associated human cancers

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