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Oncogenic induction of cellular high CpG methylation by Epstein-Barr virus in malignant epithelial cells.

Li L, Zhang Y, Guo BB, Chan FK, Tao Q - Chin J Cancer (2014)

Bottom Line: Epstein-Barr virus (EBV) is a well-known human herpesvirus associated with virtually all nasopharyngeal carcinoma (NPC) and approximately 10% of gastric cancer (GC) worldwide.However, even deep whole exome sequencing studies showed a relatively low frequency of gene mutations in NPC and EBV-associated GC (EBVaGC), suggesting a predominant role of epigenetic abnormities, especially promoter CpG methylation, in the pathogenesis of NPC and EBVaGC.High frequencies of promoter methylation of tumor suppressor genes (TSGs) have been frequently reported in NPC and EBVaGC, with several EBV-induced methylated TSGs identified.

View Article: PubMed Central - PubMed

Affiliation: Cancer Epigenetics Laboratory, Department of Clinical Oncology, State Key Laboratory of Oncology in South China, Sir YK Pao Center for Cancer and Li Ka Shing Institute of Health Sciences, Hong Kong SAR, China. qtao@cuhk.edu.hk.

ABSTRACT
Epstein-Barr virus (EBV) is a well-known human herpesvirus associated with virtually all nasopharyngeal carcinoma (NPC) and approximately 10% of gastric cancer (GC) worldwide. Increasing evidence shows that acquired genetic and epigenetic alterations lead to the initiation and progression of NPC and GC. However, even deep whole exome sequencing studies showed a relatively low frequency of gene mutations in NPC and EBV-associated GC (EBVaGC), suggesting a predominant role of epigenetic abnormities, especially promoter CpG methylation, in the pathogenesis of NPC and EBVaGC. High frequencies of promoter methylation of tumor suppressor genes (TSGs) have been frequently reported in NPC and EBVaGC, with several EBV-induced methylated TSGs identified. Further characterization of the epigenomes (genome-wide CpG methylation profile--methylome) of NPC and EBVaGC shows that these EBV-associated tumors display a unique high CpG methylation epigenotype with more extensive gene methylation accumulation, indicating that EBV acts as a direct epigenetic driver for these cancers. Mechanistically, oncogenic modulation of cellular CpG methylation machinery, such as DNA methyltransferases (DNMTs), by EBV-encoded viral proteins accounts for the EBV-induced high CpG methylation epigenotype in NPC and EBVaGC. Thus, uncovering the EBV-associated unique epigenotype of NPC and EBVaGC would provide new insight into the molecular pathogenesis of these unique EBV-associated tumors and further help to develop pharmacologic strategies targeting cellular methylation machinery in these malignancies.

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Model of oncogenic modulation of cellular CpG methylation machinery by Epstein-Barr virus (EBV) and EBV-induced high methylation epigenotype in malignant epithelial cells.EBV-encoded proteins regulate multiple components of the cellular methylation machinery through either cellular signaling pathways or transcription complexes, which finally leads to tumor suppressor gene (TSG) methylation and silencing and contributes to nasopharyngeal carcinoma (NPC) and EBV-associated gastric cancer (EBVaGC) pathogenesis. EBNA1, EBV-associated nuclear antigen 1; LMP, latent membrane protein; JNK, c-Jun N-terminal kinase; STAT3, signal transducers and activators of transcription 3; PI3K/AKT, phosphatidylinositol 3-kinase (PI3K)/AKT; DNMT, DNA methyltransferase; HDAC, histone deacetylase; PcG, poly-comb group; ?, unknown mechanism.
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cjc-33-12-604-g001: Model of oncogenic modulation of cellular CpG methylation machinery by Epstein-Barr virus (EBV) and EBV-induced high methylation epigenotype in malignant epithelial cells.EBV-encoded proteins regulate multiple components of the cellular methylation machinery through either cellular signaling pathways or transcription complexes, which finally leads to tumor suppressor gene (TSG) methylation and silencing and contributes to nasopharyngeal carcinoma (NPC) and EBV-associated gastric cancer (EBVaGC) pathogenesis. EBNA1, EBV-associated nuclear antigen 1; LMP, latent membrane protein; JNK, c-Jun N-terminal kinase; STAT3, signal transducers and activators of transcription 3; PI3K/AKT, phosphatidylinositol 3-kinase (PI3K)/AKT; DNMT, DNA methyltransferase; HDAC, histone deacetylase; PcG, poly-comb group; ?, unknown mechanism.

Mentions: Thus, EBV-encoded proteins can regulate multiple components of the cellular CpG methylation machinery, including DNMTs, histone modifiers, chromatin remodelers, and PcG complexes (Figure 1), and they can further regulate aberrant TSG methylation and silencing in EBV-infected tumor cells. It is possible that other EBV proteins and miRNAs have similar functions, which requires further in-depth investigation. NPC and EBVaGC are thus typical tumor models of an EBV-induced aberrant high-methylation epigenotype. This unique biological feature has specific therapeutic implications for the clinical treatment of these tumors, as multiple epigenetic agents, such as DNMT inhibitors and HDAC inhibitors, are currently being developed, with some already being approved by the U.S. Food & Drug Administration (FDA) in clinical trials[54],[55]. It is thus predicted that further epigenetic therapy would greatly improve the modern treatment of these patients with EBV-positive tumor[56],[57].


Oncogenic induction of cellular high CpG methylation by Epstein-Barr virus in malignant epithelial cells.

Li L, Zhang Y, Guo BB, Chan FK, Tao Q - Chin J Cancer (2014)

Model of oncogenic modulation of cellular CpG methylation machinery by Epstein-Barr virus (EBV) and EBV-induced high methylation epigenotype in malignant epithelial cells.EBV-encoded proteins regulate multiple components of the cellular methylation machinery through either cellular signaling pathways or transcription complexes, which finally leads to tumor suppressor gene (TSG) methylation and silencing and contributes to nasopharyngeal carcinoma (NPC) and EBV-associated gastric cancer (EBVaGC) pathogenesis. EBNA1, EBV-associated nuclear antigen 1; LMP, latent membrane protein; JNK, c-Jun N-terminal kinase; STAT3, signal transducers and activators of transcription 3; PI3K/AKT, phosphatidylinositol 3-kinase (PI3K)/AKT; DNMT, DNA methyltransferase; HDAC, histone deacetylase; PcG, poly-comb group; ?, unknown mechanism.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4308656&req=5

cjc-33-12-604-g001: Model of oncogenic modulation of cellular CpG methylation machinery by Epstein-Barr virus (EBV) and EBV-induced high methylation epigenotype in malignant epithelial cells.EBV-encoded proteins regulate multiple components of the cellular methylation machinery through either cellular signaling pathways or transcription complexes, which finally leads to tumor suppressor gene (TSG) methylation and silencing and contributes to nasopharyngeal carcinoma (NPC) and EBV-associated gastric cancer (EBVaGC) pathogenesis. EBNA1, EBV-associated nuclear antigen 1; LMP, latent membrane protein; JNK, c-Jun N-terminal kinase; STAT3, signal transducers and activators of transcription 3; PI3K/AKT, phosphatidylinositol 3-kinase (PI3K)/AKT; DNMT, DNA methyltransferase; HDAC, histone deacetylase; PcG, poly-comb group; ?, unknown mechanism.
Mentions: Thus, EBV-encoded proteins can regulate multiple components of the cellular CpG methylation machinery, including DNMTs, histone modifiers, chromatin remodelers, and PcG complexes (Figure 1), and they can further regulate aberrant TSG methylation and silencing in EBV-infected tumor cells. It is possible that other EBV proteins and miRNAs have similar functions, which requires further in-depth investigation. NPC and EBVaGC are thus typical tumor models of an EBV-induced aberrant high-methylation epigenotype. This unique biological feature has specific therapeutic implications for the clinical treatment of these tumors, as multiple epigenetic agents, such as DNMT inhibitors and HDAC inhibitors, are currently being developed, with some already being approved by the U.S. Food & Drug Administration (FDA) in clinical trials[54],[55]. It is thus predicted that further epigenetic therapy would greatly improve the modern treatment of these patients with EBV-positive tumor[56],[57].

Bottom Line: Epstein-Barr virus (EBV) is a well-known human herpesvirus associated with virtually all nasopharyngeal carcinoma (NPC) and approximately 10% of gastric cancer (GC) worldwide.However, even deep whole exome sequencing studies showed a relatively low frequency of gene mutations in NPC and EBV-associated GC (EBVaGC), suggesting a predominant role of epigenetic abnormities, especially promoter CpG methylation, in the pathogenesis of NPC and EBVaGC.High frequencies of promoter methylation of tumor suppressor genes (TSGs) have been frequently reported in NPC and EBVaGC, with several EBV-induced methylated TSGs identified.

View Article: PubMed Central - PubMed

Affiliation: Cancer Epigenetics Laboratory, Department of Clinical Oncology, State Key Laboratory of Oncology in South China, Sir YK Pao Center for Cancer and Li Ka Shing Institute of Health Sciences, Hong Kong SAR, China. qtao@cuhk.edu.hk.

ABSTRACT
Epstein-Barr virus (EBV) is a well-known human herpesvirus associated with virtually all nasopharyngeal carcinoma (NPC) and approximately 10% of gastric cancer (GC) worldwide. Increasing evidence shows that acquired genetic and epigenetic alterations lead to the initiation and progression of NPC and GC. However, even deep whole exome sequencing studies showed a relatively low frequency of gene mutations in NPC and EBV-associated GC (EBVaGC), suggesting a predominant role of epigenetic abnormities, especially promoter CpG methylation, in the pathogenesis of NPC and EBVaGC. High frequencies of promoter methylation of tumor suppressor genes (TSGs) have been frequently reported in NPC and EBVaGC, with several EBV-induced methylated TSGs identified. Further characterization of the epigenomes (genome-wide CpG methylation profile--methylome) of NPC and EBVaGC shows that these EBV-associated tumors display a unique high CpG methylation epigenotype with more extensive gene methylation accumulation, indicating that EBV acts as a direct epigenetic driver for these cancers. Mechanistically, oncogenic modulation of cellular CpG methylation machinery, such as DNA methyltransferases (DNMTs), by EBV-encoded viral proteins accounts for the EBV-induced high CpG methylation epigenotype in NPC and EBVaGC. Thus, uncovering the EBV-associated unique epigenotype of NPC and EBVaGC would provide new insight into the molecular pathogenesis of these unique EBV-associated tumors and further help to develop pharmacologic strategies targeting cellular methylation machinery in these malignancies.

Show MeSH
Related in: MedlinePlus