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Review
. 2017 Jul 25;18(8):1606.
doi: 10.3390/ijms18081606.

The Role of Epigenetic Regulation in Epstein-Barr Virus-Associated Gastric Cancer

Jun Nishikawa  1 , Hisashi Iizasa  2 , Hironori Yoshiyama  3 , Munetaka Nakamura  4 , Mari Saito  5 , Sho Sasaki  6 , Kanami Shimokuri  7 , Masashi Yanagihara  8 , Kouhei Sakai  9 , Yutaka Suehiro  10 , Takahiro Yamasaki  11 , Isao Sakaida  12
Affiliations
Review

The Role of Epigenetic Regulation in Epstein-Barr Virus-Associated Gastric Cancer

Jun Nishikawa et al. Int J Mol Sci. .

Abstract

The Epstein-Barr virus (EBV) is detected in about 10% of gastric carcinoma cases throughout the world. In EBV-associated gastric carcinoma (EBVaGC), all tumor cells harbor the clonal EBV genome. The expression of latent EBV genes is strictly regulated through the methylation of EBV DNA. The methylation of viral DNA regulates the type of EBV latency, and methylation of the tumor suppressor genes is a key abnormality in EBVaGC. The methylation frequencies of several tumor suppressor genes and cell adhesion molecules are significantly higher in EBVaGC than in control cases. EBV-derived microRNAs repress translation from viral and host mRNAs. EBV regulates the expression of non-coding RNA in gastric carcinoma. With regard to the clinical application of demethylating agents against EBVaGC, we investigated the effects of decitabine against the EBVaGC cell lines. Decitabine inhibited the cell growth of EBVaGC cells. The promoter regions of p73 and Runt-related transcription factor 3(RUNX3) were demethylated, and their expression was upregulated by the treatment. We review the role of epigenetic regulation in the development and maintenance of EBVaGC and discuss the therapeutic application of DNA demethylating agents for EBVaGC.

Keywords: DNA methylation; demethylating agent; epigenetics; epstein-barr virus; gastric cancer; microRNA; non-coding RNA.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Representative case of Epstein-Barr virus (EBV)-associated gastric carcinoma. EBV-encoded small RNA 1 (EBER1) in situ hybridization (×100). Signals of EBER1 were detected in the nucleus of almost all cancer cells.
Figure 2
Figure 2
The mechanism of EBV-induced gastric carcinogenesis. DNA methylation can be induced by EBV infection in epithelial cells. Methylation of both viral and host DNA is one of the major mechanisms involved in the development of EBV-associated gastric carcinoma (EBVaGC). Viral DNA methylation regulates EBV latency type and inhibits the expression of EBV latent genes that are possible targets of cytotoxic T lymphocytes. Methylation of host cell DNA might lead to the progression of EBVaGC. The inactivation of cellular genes through DNA methylation might contribute to cell-cycle dysregulation and anti-apoptotic effects in EBVaGC.
Figure 3
Figure 3
The genomic location of EBV-encoded miRNAs. In latently-infected cells, the EBV genome exists in the nucleus as a circular episome. The starting sites of viral replication are indicated as a green box (origin of plasmid replication; oriP) and blue boxes (origins of lytic replication; oriLyt). The coding regions of the latent membrane protein 1 (LMP1) and EBNA2 are indicated as red arrows. These are transcribed in antisense and sense orientations, respectively. EBNA3s and EBNA1 are indicated as black arrows. With regard to the BHRF miRNAs, BHRF1 ORF is encompassed with one 5′-end and two 3′-end miRNAs (light blue arrows). BART miRNAs are located in the intron region of noncoding RNA BART and are indicated as blue arrows. The white arrows indicate the BHRF and BART exons. (1) Drosha processing: pri-miRNAs are processed by Drosha-DGCR8 complex to become pre-miRNAs. (2) Pre-miRNA transport: pre-miRNAs are then transferred from the nucleus to the cytoplasm by Exportin5-RanGTP8 complex. (3) Dicer processing: pre-miRNAs are digested by Dicer-TRBP complex and miRNAs are generated. (4) RISC loading and translational inhibition: and miRNAs are incorporated into RNA-induced silencing complex (RISC) and specifically inhibit the translation of the targeted mRNA.
Figure 4
Figure 4
The role of long non-coding RNAs (lncRNAs). (A) LncRNA-PRC2 complex suppresses gene transcription. LncRNA binds to polycomb proteins, such as EZH2, EED, and Suz12. These proteins are recognized as PRC2. PRC2-lncRNA complex interacts with K27 of histone H3 and induces the trimethylation of K27 (me3K27). The resulting histone modification represses the transcription of targeted genes; (B) LncRNAs repress miRNA function by absorption of miRNA. The upper panel illustrates the well-known repression of translation by RISC-miRNA complex through its binding to 3′UTR of mRNA. The lower panel illustrates the interaction of lncRNA with miRNA via the targeting sequences. Since lncRNA absorbs miRNA, the association of miRNA with protein coding mRNAs will be decreased to increase the protein expression levels.
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