title: Epigallocatechin-3-gallate, a histone acetyltransferase inhibitor, inhibits EBV-induced B lymphocyte transformation via suppression of RelA acetylation.
abstract: Because the p300/CBP-mediated hyperacetylation of RelA (p65) is critical for nuclear factor-kappaB (NF-kappaB) activation, the attenuation of p65 acetylation is a potential molecular target for the prevention of chronic inflammation. During our ongoing screening study to identify natural compounds with histone acetyltransferase inhibitor (HATi) activity, we identified epigallocatechin-3-gallate (EGCG) as a novel HATi with global specificity for the majority of HAT enzymes but with no activity toward epigenetic enzymes including HDAC, SIRT1, and HMTase. At a dose of 100 micromol/L, EGCG abrogates p300-induced p65 acetylation in vitro and in vivo, increases the level of cytosolic IkappaBalpha, and suppresses tumor necrosis factor alpha (TNFalpha)-induced NF-kappaB activation. We also showed that EGCG prevents TNFalpha-induced p65 translocation to the nucleus, confirming that hyperacetylation is critical for NF-kappaB translocation as well as activity. Furthermore, EGCG treatment inhibited the acetylation of p65 and the expression of NF-kappaB target genes in response to diverse stimuli. Finally, EGCG reduced the binding of p300 to the promoter region of interleukin-6 gene with an increased recruitment of HDAC3, which highlights the importance of the balance between HATs and histone deacetylases in the NF-kappaB-mediated inflammatory signaling pathway. Importantly, EGCG at 50 micromol/L dose completely blocks EBV infection-induced cytokine expression and subsequently the EBV-induced B lymphocyte transformation. These results show the crucial role of acetylation in the development of inflammatory-related diseases.
authors.affiliation: Department of Biochemistry and Molecular Biology, Center for Chronic Metabolic Disease Research, Brain Korea 21 Project for Medical Sciences, Yonsei University College of Medicine, Seoul, Korea.
authors.forename: Kyung-Chul
authors.initials: KC
authors.lastname: Choi
authors.forename: Myung Gu
authors.initials: MG
authors.lastname: Jung
authors.forename: Yoo-Hyun
authors.initials: YH
authors.lastname: Lee
authors.forename: Joo Chun
authors.initials: JC
authors.lastname: Yoon
authors.forename: Seung Hyun
authors.initials: SH
authors.lastname: Kwon
authors.forename: Hee-Bum
authors.initials: HB
authors.lastname: Kang
authors.forename: Mi-Jeong
authors.initials: MJ
authors.lastname: Kim
authors.forename: Jeong-Heon
authors.initials: JH
authors.lastname: Cha
authors.forename: Young Jun
authors.initials: YJ
authors.lastname: Kim
authors.forename: Woo Jin
authors.initials: WJ
authors.lastname: Jun
authors.forename: Jae Myun
authors.initials: JM
authors.lastname: Lee
authors.forename: Ho-Geun
authors.initials: HG
authors.lastname: Yoon
mesh_terms: D000107:Acetylation / Q000187:drug effects; D000818:Animals; D001402:B-Lymphocytes / Q000276:immunology / Q000378:metabolism / Q000821:virology*; D002392:Catechin / Q000031:analogs & derivatives* / Q000494:pharmacology; D045744:Cell Line, Tumor; D002472:Cell Transformation, Viral / Q000187:drug effects*; D015536:Down-Regulation / Q000187:drug effects; D006367:HeLa Cells; D004854:Herpesvirus 4, Human / Q000502:physiology*; D051548:Histone Acetyltransferases / Q000037:antagonists & inhibitors*; D006801:Humans; D008213:Lymphocyte Activation; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D016328:NF-kappa B / Q000378:metabolism; D051996:Transcription Factor RelA / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors / Q000494:pharmacology
chemical_list: D016328:NF-kappa B; C498143:RELA protein, human; D051996:Transcription Factor RelA; D014409:Tumor Necrosis Factor-alpha; D002392:Catechin; C045651:epigallocatechin gallate; D051548:Histone Acetyltransferases