Dataset Information

Epstein-Barr Virus BART Long Non-coding RNAs Function as Epigenetic Modulators in Nasopharyngeal Carcinoma.

ABSTRACT: Epstein-Barr virus (EBV) establishes lifelong latent infection in humans and is associated with several lymphoid and epithelial cancers. In nasopharyngeal carcinoma (NPC), EBV expresses few viral proteins but elevated levels of Bam-HI A rightward transcripts (BARTs) RNA, which includes viral microRNAs and long non-coding RNAs (lncRNAs). BART lncRNAs localize within the nucleus of EBV-infected cells and knockdown of BART lncRNAs significantly affects the expression of genes associated with cell adhesion, oxidoreductase activity, inflammation, and immunity. Notably, downregulation of IKAROS family zinc finger 3 (IKZF3/Aiolos), which plays a role in lymphocyte development and cell attachment, occurred in NPC C666-1 cells following BART lncRNA-knockdown. Since Aiolos expression is normally restricted to lymphoid cells and rarely observed in epithelial cells, induction of Aiolos by BART lncRNA was confirmed by expressing the major BART lncRNA isoform, RPMS1, in EBV-positive and -negative cells. BART lncRNA associated with the CBP/p300 complex and RNA polymerase II (Pol II) in the nucleus, suggesting that BART lncRNAs may mediate epigenetic regulation of gene expression through interaction with the chromatin remodeling machinery. This contention is further supported by evidence that BART lncRNA appears to stall Pol II at the promoter region and may regulate IFNB1 and CXCL8 expression by inhibiting transcription by Pol II in NPC. We hypothesize that EBV BART lncRNA expression modulates host gene expression and maintains EBV latency by interfering with histone methylation and acetylation processes. Aberrant expression of affected host genes mediated by BART lncRNA may lead to immune evasion, progression, and metastasis of NPC.

SUBMITTER: Verhoeven RJA

PROVIDER: S-EPMC6817499 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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Epstein-Barr Virus BART Long Non-coding RNAs Function as Epigenetic Modulators in Nasopharyngeal Carcinoma.

Verhoeven Rob J A RJA Tong Shuang S Mok Bobo Wing-Yee BW Liu Jiayan J He Songtao S Zong Jingfeng J Chen Yixin Y Tsao Sai-Wah SW Lung Maria Li ML Chen Honglin H

Frontiers in oncology 20191022

Epstein-Barr virus (EBV) establishes lifelong latent infection in humans and is associated with several lymphoid and epithelial cancers. In nasopharyngeal carcinoma (NPC), EBV expresses few viral proteins but elevated levels of <i>Bam-</i>HI A rightward transcripts (BARTs) RNA, which includes viral microRNAs and long non-coding RNAs (lncRNAs). BART lncRNAs localize within the nucleus of EBV-infected cells and knockdown of BART lncRNAs significantly affects the expression of genes associated with ...[more]

PMID: 31696060

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Project description:UnlabelledEpstein-Barr virus (EBV) expresses few viral proteins in nasopharyngeal carcinoma (NPC) but high levels of BamHI-A rightward transcripts (BARTs), which include long noncoding RNAs (lncRNAs) and BART microRNAs (miRNAs). It is hypothesized that the mechanism for regulation of BARTs may relate to EBV pathogenesis in NPC. We showed that nuclear factor-κB (NF-κB) activates the BART promoters and modulates the expression of BARTs in EBV-infected NPC cells but that introduction of mutations into the putative NF-κB binding sites abolished activation of BART promoters by NF-κB. Binding of p50 subunits to NF-κB sites in the BART promoters was confirmed in electrophoretic mobility shift assays (EMSA) and further demonstrated in vivo using chromatin immunoprecipitation (ChIP) analysis. Expression of BART miRNAs and lncRNAs correlated with NF-κB activity in EBV-infected epithelial cells, while treatment of EBV-harboring NPC C666-1 cells with aspirin (acetylsalicylic acid [ASA]) and the IκB kinase inhibitor PS-1145 inhibited NF-κB activity, resulting in downregulation of BART expression. Expression of EBV LMP1 activates BART promoters, whereas an LMP1 mutant which cannot induce NF-κB activation does not activate BART promoters, further supporting the idea that expression of BARTs is regulated by NF-κB signaling. Expression of LMP1 is tightly regulated in NPC cells, and this study confirmed that miR-BART5-5p downregulates LMP1 expression, suggesting a feedback loop between BART miRNA and LMP1-mediated NF-κB activation in the NPC setting. These findings provide new insights into the mechanism underlying the deregulation of BARTs in NPC and identify a regulatory loop through which BARTs support EBV latency in NPC.ImportanceNasopharyngeal carcinoma (NPC) cells are ubiquitously infected with Epstein-Barr virus (EBV). Notably, EBV expresses very few viral proteins in NPC cells, presumably to avoid triggering an immune response, but high levels of EBV BART miRNAs and lncRNAs which exhibit complex functions associated with EBV pathogenesis. The mechanism for regulation of BARTs is critical for understanding NPC oncogenesis. This study provides multiple lines of evidence to show that expression of BARTs is subject to regulation by NF-κB signaling. EBV LMP1 is a potent activator of NF-κB signaling, and we demonstrate that LMP1 can upregulate expression of BARTs through NF-κB signaling and that BART miRNAs are also able to downregulate LMP1 expression. It appears that aberrant NF-κB signaling and expression of BARTs form an autoregulatory loop for maintaining EBV latency in NPC cells. Further exploration of how targeting NF-κB signaling interrupts EBV latency in NPC cells may reveal new options for NPC treatment.

Project description:Nasopharyngeal carcinoma (NPC) is consistently associated with Epstein-Barr virus (EBV) infection in regions in which it is endemic, including Southern China and Southeast Asia. The high mortality rates of NPC patients with advanced and recurrent disease highlight the urgent need for effective treatments. While recent genomic studies have revealed few druggable targets, the unique interaction between the EBV infection and host cells in NPC strongly implies that targeting EBV may be an efficient approach to cure this virus-associated cancer. Key features of EBV-associated NPC are the persistence of an episomal EBV genome and the requirement for multiple viral latent gene products to enable malignant transformation. Many translational studies have been conducted to exploit these unique features to develop pharmaceutical agents and therapeutic strategies that target EBV latent proteins and induce lytic reactivation in NPC. In particular, inhibitors of the EBV latent protein EBNA1 have been intensively explored, because of this protein's essential roles in maintaining EBV latency and viral genome replication in NPC cells. In addition, recent advances in chemical bioengineering are driving the development of therapeutic agents targeting the critical functional regions of EBNA1. Promising therapeutic effects of the resulting EBNA1-specific inhibitors have been shown in EBV-positive NPC tumors. The efficacy of multiple classes of EBV lytic inducers for NPC cytolytic therapy has also been long investigated. However, the lytic-induction efficiency of these compounds varies among different EBV-positive NPC models in a cell-context-dependent manner. In each tumor, NPC cells can evolve and acquire somatic changes to maintain EBV latency during cancer progression. Unfortunately, the poor understanding of the cellular mechanisms regulating EBV latency-to-lytic switching in NPC cells limits the clinical application of EBV cytolytic treatment. In this review, we discuss the potential approaches for improvement of the above-mentioned EBV-targeting strategies.

Project description:This study assessed the effects of Epstein-Barr virus (EBV) and one form of virally encoded BART long noncoding RNAs (lncRNAs) on cellular expression in epithelial cells grown in vitro and as tumors in vivo determined by high-throughput RNA sequencing of mRNA and small RNAs. Hierarchical clustering based on gene expression distinguished the cell lines from the tumors and distinguished the EBV-positive tumors and the BART tumors from the EBV-negative tumors. EBV and BART expression also induced specific expression changes in cellular microRNAs (miRs) and lncRNAs. Multiple known and predicted targets of the viral miRs, the induced cellular miRs, and lncRNAs were identified in the altered gene set. The changes in expression in vivo indicated that the suppression of growth pathways in vivo reflects increased expression of cellular miRs in all tumors. In the EBV and BART tumors, many of the targets of the induced miRs were not changed and the seed sequences of the nonfunctional miRs were found to have homologous regions within the BART lncRNA. The inhibition of these miR effects on known targets suggests that these induced miRs have reduced function due to sponging by the BART lncRNA. This composite analysis identified the effects of EBV on cellular miRs and lncRNAs with a functional readout through identification of the simultaneous effects on gene expression. Major shifts in gene expression in vivo are likely mediated by effects on cellular noncoding RNAs. Additionally, a predicted property of the BART lncRNA is to functionally inhibit the induced cellular miRs. IMPORTANCE This study identified the total effects of EBV and a viral long noncoding RNA (BART lncRNA) on cellular RNA expression when grown as cells in culture and when grown as tumors in immunodeficient mice. The effects on cellular mRNA expression, lncRNA expression, and cellular and viral miR expression were determined using next-generation sequencing (NGS) and bioinformatics functional analysis. Many cellular growth pathways that are activated during growth in culture are decreased during growth as tumors. This study shows that these changes in expression are accompanied by induction of cellular-growth-inhibitory miRs. However, in the EBV tumors and in tumors expressing the BART lncRNA, many of the known targets of the inhibitory miRs are not affected. Regions of strong homology to the seed sequences of these miRs were identified in the BART lncRNA. These findings suggest that the BART lncRNA functions as a sponge for growth-inhibitory miRs.

Dataset Information

Epstein-Barr Virus BART Long Non-coding RNAs Function as Epigenetic Modulators in Nasopharyngeal Carcinoma.

Publications

Epstein-Barr Virus BART Long Non-coding RNAs Function as Epigenetic Modulators in Nasopharyngeal Carcinoma.

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