Viral hit and run-oncogenesis: Genetic and epigenetic scenarios

Niller, Hans Helmut; Wolf, Hans; Minárovits, János

doi:10.1016/j.canlet.2010.08.007

Cited by 104 publications

(97 citation statements)

References 233 publications

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“…The expression of BART miRNAs was highest in clinical stage III samples, with levels in stage IV samples somewhat lower. These findings support the "hit-and-run" viral oncogenesis hypothesis [51,52]. Determination of how EBV-encoded miRNAs control the expression of host genes and the elucidation of molecular mechanisms for EBV miRNAs in NPC carcinogenesis requires comprehensive identification of all host target genes for these miRNAs.…”

Section: Discussionsupporting

confidence: 69%

Regulation network and expression profiles of Epstein-Barr virus-encoded microRNAs and their potential target host genes in nasopharyngeal carcinomas

Zeng

Huang

et al. 2014

Sci. China Life Sci.

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Epstein-Barr virus (EBV) is associated with nasopharyngeal carcinoma (NPC) tumorigenesis. However, the mechanism(s) connecting EBV infection and NPC remain unclear. Recently, a new class of EBV microRNAs (miRNAs) has been described. To determine how EBV miRNAs control the expression of host genes, and to understand their potential role in NPC tumorigenesis, we profiled the expression of 44 mature EBV miRNAs and potential host genes in NPC and non-tumor nasopharyngeal epithelial tissues. We found that 40 EBV miRNAs from the BART transcript were highly expressed in NPC. Analysis of potential BART miRNA target genes revealed that 3140 genes and several important pathways might be involved in the carcinogenesis of NPC. A total of 105 genes with potential EBV miRNA binding sites were significantly downregulated, suggesting that EBV miRNAs may regulate these genes and contribute to NPC carcinogenesis. An EBV miRNA and host gene regulation network was generated to provide useful clues for validating of EBV miRNA functions in NPC tumorigenesis.

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Section: Discussionsupporting

confidence: 69%

Regulation network and expression profiles of Epstein-Barr virus-encoded microRNAs and their potential target host genes in nasopharyngeal carcinomas

Zeng

Huang

et al. 2014

Sci. China Life Sci.

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“…While additional factors could play a role (120), these data provide a priori evidence that mechanisms such as Daxx/ATRX-dependent transcriptional control and adaptation of early viral gene expression are important contributors to species restrictions, at least in the case of some herpesviruses (121). In line with this, viruses undergo the full productive replication cycle in permissive cells, inevitably leading to efficient progeny production, whereas infection of nonpermissive host cells results in an abortive process or can lead to immortalization and/or partial transformation (122).…”

Section: Daxx Impairment By Virion Proteins: Overcoming the Species Bmentioning

confidence: 73%

Virion Factors That Target Daxx To Overcome Intrinsic Immunity

Schreiner

Wodrich

2013

J Virol

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bPML nuclear bodies and their associated functions are part of an intrinsic cellular mechanism aimed at maintaining transcriptional control over viral gene expression and preventing replication of invading viruses. To overcome these barriers, many viruses express early nonstructural, multifunctional proteins to support the viral replication cycle or modulate host immune responses. Virion proteins constituting the invading particle are traditionally investigated for their role in transport during entry or egress and in the assembly of new virions. The additional functions of virion proteins have largely been ignored, in contrast to those of their nonstructural counterparts. A number of recent reports suggest that several virion proteins may also play vital roles in gene activation processes, in particular by counteracting intrinsic immune mechanisms mediated by the PML nuclear body-associated cellular factors Daxx, ATRX, and Sp100. These virion proteins share several features with their more potent nonstructural counterparts, and they may serve to bridge the gap in the early phase of an infection until immediate early viral gene expression is established. In this review, we discuss how virion proteins are an integral part of gene regulation among several viral families and to what extent structural proteins of incoming virions may contribute to species barrier, latency, and oncogenesis.W hen viral genetic information is transferred from cell to cell, it must be compacted and transcriptionally inactivated for storage in the viral capsid during transport. This process needs to be actively reversed upon infection against cellular transcriptional repression through intrinsic antiviral mechanisms. An important factor in the cellular control of viral gene expression is death domain-associated protein (Daxx). Daxx was initially described as a modulator of apoptotic signaling (1), but recent reports suggest that Daxx plays an active role in gene regulation by repressing or modulating transcription through chromatin remodeling (2, 3). Daxx mainly cooperates with alpha-thalassemia retardation syndrome x-linked (ATRX), a putative member of the SNF2 family of ATP-dependent chromatin-remodeling proteins. In this repressive complex, ATRX acts as the core ATPase subunit, while Daxx is the targeting factor, leading to histone deacetylase (HDAC) recruitment (4-6).Daxx is found associated with the promyelocytic leukemia protein nuclear body (PML-NB) or chromatin. Association with PML-NB alleviates gene repression and activates apoptosis, while chromatin-bound Daxx represses transcription (7-9). It has been long established that PML-NBs are nuclear structures with antiviral activity, accumulating an expanding number of transient or constitutive cellular factors involved in transcriptional control, chromatin remodeling, genome integrity, apoptosis, and tumor suppression (10). Moreover, several PML-NB constituents can be induced by type I and II interferon (IFN), resulting in increased antiviral activity by attenuating viral gene exp...

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“…EBV manipulation of the host epigenetic machinery has effects on the host epigenome as well, which is apparent in EBV-associated malignancies and provides a framework for viral "hit-andrun" oncogenesis (14). EBV-positive nasopharyngeal and gastric carcinomas exhibit a high frequency of CpG island (CGI) hypermethylation (CpG island methylator phenotype [CIMP]) at various tumor suppressor genes (9,(15)(16)(17)(18)(19)(20)(21).…”

mentioning

confidence: 99%

Genome-Wide DNA Methylation as an Epigenetic Consequence of Epstein-Barr Virus Infection of Immortalized Keratinocytes

Birdwell

Queen

Kilgore

et al. 2014

J Virol

114

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The oral cavity is a persistent reservoir for Epstein-Barr virus (EBV) with lifelong infection of resident epithelial and B cells. Infection of these cell types results in distinct EBV gene expression patterns regulated by epigenetic modifications involving DNA methylation and chromatin structure. Regulation of EBV gene expression relies on viral manipulation of the host epigenetic machinery that may result in long-lasting host epigenetic reprogramming. To identify epigenetic events following EBV infection, a transient infection model was established to map epigenetic changes in telomerase-immortalized oral keratinocytes. EBV-infected oral keratinocytes exhibited a predominantly latent viral gene expression program with some lytic or abortive replication. Calcium and methylcelluloseinduced differentiation was delayed in EBV-positive clones and in clones that lost EBV compared to uninfected controls, indicating a functional consequence of EBV epigenetic modifications. Analysis of global cellular DNA methylation identified over 13,000 differentially methylated CpG residues in cells exposed to EBV compared to uninfected controls, with CpG island hypermethylation observed at several cellular genes. Although the vast majority of the DNA methylation changes were silent, 65 cellular genes that acquired CpG methylation showed altered transcript levels. Genes with increased transcript levels frequently acquired DNA methylation within the gene body while those with decreased transcript levels acquired DNA methylation near the transcription start site. Treatment with the DNA methyltransferase inhibitor, decitabine, restored expression of some hypermethylated genes in EBV-infected and EBV-negative transiently infected clones. Overall, these observations suggested that EBV infection of keratinocytes leaves a lasting epigenetic imprint that can enhance the tumorigenic phenotype of infected cells. IMPORTANCEHere, we show that EBV infection of oral keratinocytes led to CpG island hypermethylation as an epigenetic scar of prior EBV infection that was retained after loss of the virus. Such EBV-induced epigenetic modification recapitulated the hypermethylated CpG island methylator phenotype (CIMP) observed in EBV-associated carcinomas. These epigenetic alterations not only impacted gene expression but also resulted in delayed calcium and methylcellulose-induced keratinocyte differentiation. Importantly, these epigenetic changes occurred in cells that were not as genetically unstable as carcinoma cells, indicating that EBV infection induced an epigenetic mutator phenotype. The impact of this work is that we have provided a mechanistic framework for how a tumor virus using the epigenetic machinery can act in a "hit-and-run" fashion, with retention of epigenetic alterations after loss of the virus. Unlike genetic alterations, these virally induced epigenetic changes can be reversed pharmacologically, providing therapeutic interventions to EBV-associated malignancies. E pstein-Barr virus (EBV) is a prevalent gammaherpesvirus i...

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Viral hit and run-oncogenesis: Genetic and epigenetic scenarios

Cited by 104 publications

References 233 publications

Regulation network and expression profiles of Epstein-Barr virus-encoded microRNAs and their potential target host genes in nasopharyngeal carcinomas

Regulation network and expression profiles of Epstein-Barr virus-encoded microRNAs and their potential target host genes in nasopharyngeal carcinomas

Virion Factors That Target Daxx To Overcome Intrinsic Immunity

Genome-Wide DNA Methylation as an Epigenetic Consequence of Epstein-Barr Virus Infection of Immortalized Keratinocytes

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