title: Epigenetic modification of TLR4 promotes activation of NF-κB by regulating methyl-CpG-binding domain protein 2 and Sp1 in gastric cancer.
abstract: Toll-like receptor 4 (TLR4) is important in promoting the immune response in various cancers. Recently, TLR4 is highly expressed in a stage-dependent manner in gastric cancer, but the regulatory mechanism of TLR4 expression has been not elucidated it. Here, we investigated the mechanism underlying regulation of TLR4 expression through promoter methylation and histone modification between transcriptional regulation and silencing of the TLR4 gene in gastric cancer cells. Chromatin immunoprecipitation was carried out to screen for factors related to TLR4 methylation such as MeCP2, HDAC1, and Sp1 on the TLR4 promoter. Moreover, DNA methyltransferase inhibitor 5-aza-deoxycytidine (5-aza-dC) induced demethylation of the TLR4 promoter and increased H3K4 trimethylation and Sp1 binding to reactivate silenced TLR4. In contrast, although the silence of TLR4 activated H3K9 trimethylation and MeCP2 complex, combined treatment with TLR4 agonist and 5-aza-dC upregulated H3K4 trimethylation and activated with transcription factors as Sp1 and NF-κB. This study demonstrates that recruitment of the MeCP2/HDAC1 repressor complex increases the low levels of TLR4 expression through epigenetic modification of DNA and histones on the TLR4 promoter, but Sp1 activates TLR4 high expression by hypomethylation and NF-κB signaling in gastric cancer cells.
authors.affiliation: Genome Structure Research Center, Korea Research Institute of Bioscience and Biotechnology, Yuseong-gu, Daejeon, Republic of Korea.|Department of Biomolecular Science, University of Science and Technology (UST), Yuseong-gu, Daejeon, Republic of Korea.
authors.forename: Tae Woo
authors.initials: TW
authors.lastname: Kim
authors.affiliation: Genome Structure Research Center, Korea Research Institute of Bioscience and Biotechnology, Yuseong-gu, Daejeon, Republic of Korea.|Department of Biomolecular Science, University of Science and Technology (UST), Yuseong-gu, Daejeon, Republic of Korea.
authors.forename: Seon-Jin
authors.initials: SJ
authors.lastname: Lee
authors.affiliation: Genome Structure Research Center, Korea Research Institute of Bioscience and Biotechnology, Yuseong-gu, Daejeon, Republic of Korea.|Department of Biomolecular Science, University of Science and Technology (UST), Yuseong-gu, Daejeon, Republic of Korea.
authors.forename: Byung Moo
authors.initials: BM
authors.lastname: Oh
authors.affiliation: Genome Structure Research Center, Korea Research Institute of Bioscience and Biotechnology, Yuseong-gu, Daejeon, Republic of Korea.|Department of Biomolecular Science, University of Science and Technology (UST), Yuseong-gu, Daejeon, Republic of Korea.
authors.forename: Heesoo
authors.initials: H
authors.lastname: Lee
authors.affiliation: Genome Structure Research Center, Korea Research Institute of Bioscience and Biotechnology, Yuseong-gu, Daejeon, Republic of Korea.
authors.forename: Tae Gi
authors.initials: TG
authors.lastname: Uhm
authors.affiliation: Functional Genomics Research Center, Korea Research Institute of Bioscience and Biotechnology, Yuseong-gu, Daejeon, Republic of Korea.
authors.forename: Jeong-Ki
authors.initials: JK
authors.lastname: Min
authors.affiliation: Immunotherapy Research Center, Korea Research Institute of Bioscience and Biotechnology, Yuseong-gu, Daejeon, Republic of Korea.
authors.forename: Young-Jun
authors.initials: YJ
authors.lastname: Park
authors.affiliation: Immunotherapy Research Center, Korea Research Institute of Bioscience and Biotechnology, Yuseong-gu, Daejeon, Republic of Korea.
authors.forename: Suk Ran
authors.initials: SR
authors.lastname: Yoon
authors.affiliation: World Class Institute, Korea Research Institute of Bioscience and Biotechnology, Ochang, Cheongwon, Republic of Korea.
authors.forename: Bo-Yeon
authors.initials: BY
authors.lastname: Kim
authors.affiliation: Department of Laboratory Medicine, College of Medicine, Dankook University, Cheonan, Chungnam, Republic of Korea.
authors.forename: Jong Wan
authors.initials: JW
authors.lastname: Kim
authors.affiliation: Genome Structure Research Center, Korea Research Institute of Bioscience and Biotechnology, Yuseong-gu, Daejeon, Republic of Korea.
authors.forename: Yong-Kyung
authors.initials: YK
authors.lastname: Choe
authors.affiliation: Genome Structure Research Center, Korea Research Institute of Bioscience and Biotechnology, Yuseong-gu, Daejeon, Republic of Korea.|Department of Biomolecular Science, University of Science and Technology (UST), Yuseong-gu, Daejeon, Republic of Korea.
authors.forename: Hee Gu
authors.initials: HG
authors.lastname: Lee
mesh_terms: D017209:Apoptosis; D049109:Cell Proliferation; D047369:Chromatin Immunoprecipitation; D019175:DNA Methylation; D044127:Epigenesis, Genetic; D015972:Gene Expression Regulation, Neoplastic; D020868:Gene Silencing; D056284:Histone Deacetylase 1 / Q000235:genetics / Q000378:metabolism; D006657:Histones / Q000378:metabolism; D006801:Humans; D007124:Immunoenzyme Techniques; D051783:Methyl-CpG-Binding Protein 2 / Q000235:genetics / Q000378:metabolism*; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism*; D011401:Promoter Regions, Genetic / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D016329:Sp1 Transcription Factor / Q000235:genetics / Q000378:metabolism*; D013274:Stomach Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D046888:Tissue Array Analysis; D051197:Toll-Like Receptor 4 / Q000235:genetics* / Q000378:metabolism; D014407:Tumor Cells, Cultured
chemical_list: D006657:Histones; C497392:MECP2 protein, human; D051783:Methyl-CpG-Binding Protein 2; D016328:NF-kappa B; D012333:RNA, Messenger; D016329:Sp1 Transcription Factor; C108209:SP1 protein, human; C495345:TLR4 protein, human; D051197:Toll-Like Receptor 4; C110550:HDAC1 protein, human; D056284:Histone Deacetylase 1
keywords: Sp1; gastric cancer; methyl-CpG-binding domain protein 2; methylation; toll-like receptor 4