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Hypermethylation of the interferon regulatory factor 5 promoter in Epstein-Barr virus-associated gastric carcinoma

 Seung Myung Dong  ;  Hyun Gyu Lee  ;  Sung Gyu Cho  ;  Seung Hyun Kwon  ;  Heejei Yoon  ;  Hyun Jin Kwon  ;  Ji Hae Lee  ;  Hyemi Kim  ;  Pil Gu Park  ;  Hoguen Kim  ;  S. Diane Hayward  ;  Jeon Han Park  ;  Jae Myun Lee 
 JOURNAL OF MICROBIOLOGY, Vol.53(1) : 70-76, 2015 
Journal Title
Issue Date
Azacitidine/analogs & derivatives ; Azacitidine/pharmacology ; Burkitt Lymphoma/genetics* ; Cell Line, Tumor ; CpG Islands ; DNA Methylation* ; Epigenesis, Genetic ; Herpesvirus 4, Human/isolation & purification ; Herpesvirus 4, Human/physiology* ; Humans ; Interferon Regulatory Factors/genetics* ; Promoter Regions, Genetic* ; Sequence Analysis, DNA ; Stomach Neoplasms/genetics* ; Virus Latency
interferon regulatory factor 5 ; Epstein-Barr virus ; gastric carcinoma ; CpG island ; promoter methylation
Interferon regulatory factor-5 (IRF-5), a member of the mammalian IRF transcription factor family, is regulated by p53, type I interferon and virus infection. IRF-5 participates in virus-induced TLR-mediated innate immune responses and may play a role as a tumor suppressor. It was suppressed in various EBV-infected transformed cells, thus it is valuable to identify the suppression mechanism. We focused on a promoter CpG islands methylation, a kind of epigenetic regulation in EBV-associated Burkitt's lymphomas (BLs) and gastric carcinomas. IRF-5 is not detected in most of EBV-infected BL cell lines due to hypermethylation of IRF-5 distal promoter (promoter-A), which was restored by a demethylating agent, 5-aza-2'-deoxycytidine. Hypomethylation of CpG islands in promoter-A was observed only in EBV type III latent infected BL cell lines (LCL and Mutu III). Similarly, during EBV infection to Akata-4E3 cells, IRF-5 was observed at early time periods (2 days to 8 weeks), concomitant unmethylation of promoter-A, but suppressed in later infection periods as observed in latency I BL cell lines. Moreover, hypermethylation in IRF-5 promoter-A region was also observed in EBV-associated gastric carcinoma (EBVaGC) cell lines or primary gastric carcinoma tissues, which show type I latent infection. In summary, IRF-5 is suppressed by hypermethylation of its promoter-A in most of EBV-infected transformed cells, especially BLs and EBVaGC. EBV-induced carcinogenesis takes an advantage of proliferative effects of TLR signaling, while limiting IRF-5 mediated negative effects in the establishment of EBVaGCs.
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1. College of Medicine (의과대학) > Research Institute (부설연구소) > 1. Journal Papers
1. College of Medicine (의과대학) > BioMedical Science Institute (의생명과학부) > 1. Journal Papers
1. College of Medicine (의과대학) > Dept. of Microbiology (미생물학교실) > 1. Journal Papers
1. College of Medicine (의과대학) > Dept. of Pathology (병리학교실) > 1. Journal Papers
Yonsei Authors
Kwon, Seung Hyun(권승현)
Kwon, Hyun Jin(권현진)
Kim, Hogeun(김호근)
Park, Jeon Han(박전한) ORCID logo https://orcid.org/0000-0001-9604-3205
Park, Pil Gu(박필구) ORCID logo https://orcid.org/0000-0002-3024-3439
Lee, Jae Myun(이재면) ORCID logo https://orcid.org/0000-0002-5273-3113
Lee, Hyun Gyu(이현규)
Cho, Sung Gyu(조성규)
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