title: Hypermethylation of the interferon regulatory factor 5 promoter in Epstein-Barr virus-associated gastric carcinoma.
abstract: 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.
authors.affiliation: Research Institute, National Cancer Center, Goyang, Gyeonggi-do, 410-769, Republic of Korea.
authors.forename: Seung Myung
authors.initials: SM
authors.lastname: Dong
authors.forename: Hyun Gyu
authors.initials: HG
authors.lastname: Lee
authors.forename: Sung-Gyu
authors.initials: SG
authors.lastname: Cho
authors.forename: Seung-Hyun
authors.initials: SH
authors.lastname: Kwon
authors.forename: Heejei
authors.initials: H
authors.lastname: Yoon
authors.forename: Hyun-Jin
authors.initials: HJ
authors.lastname: Kwon
authors.forename: Ji Hae
authors.initials: JH
authors.lastname: Lee
authors.forename: Hyemi
authors.initials: H
authors.lastname: Kim
authors.forename: Pil-Gu
authors.initials: PG
authors.lastname: Park
authors.forename: Hoguen
authors.initials: H
authors.lastname: Kim
authors.forename: S Diane
authors.initials: SD
authors.lastname: Hayward
authors.forename: Jeon Han
authors.initials: JH
authors.lastname: Park
authors.forename: Jae Myun
authors.initials: JM
authors.lastname: Lee
mesh_terms: D001374:Azacitidine / Q000031:analogs & derivatives / Q000494:pharmacology; D002051:Burkitt Lymphoma / Q000235:genetics*; D045744:Cell Line, Tumor; D018899:CpG Islands; D019175:DNA Methylation; D000077209:Decitabine; D044127:Epigenesis, Genetic; D004854:Herpesvirus 4, Human / Q000302:isolation & purification / Q000502:physiology*; D006801:Humans; D050835:Interferon Regulatory Factors / Q000235:genetics*; D011401:Promoter Regions, Genetic; D017422:Sequence Analysis, DNA; D013274:Stomach Neoplasms / Q000235:genetics*; D017735:Virus Latency
chemical_list: C431713:IRF5 protein, human; D050835:Interferon Regulatory Factors; D000077209:Decitabine; D001374:Azacitidine