title: Gallic acid suppresses lipopolysaccharide-induced nuclear factor-kappaB signaling by preventing RelA acetylation in A549 lung cancer cells.
abstract: Although multiple studies have revealed that gallic acid plays an important role in the inhibition of malignant transformation, cancer development, and inflammation, the molecular mechanism of gallic acid in inflammatory diseases is still unclear. In this study, we identified gallic acid from Rosa rugosa as a histone acetyltransferase (HAT) inhibitor with global specificity for the majority of HAT enzymes, but with no activity toward epigenetic enzymes including sirtuin (silent mating type information regulation 2 homologue) 1 (S. cerevisiae), histone deacetylase, and histone methyltransferase. Enzyme kinetic studies indicated that gallic acid uncompetitively inhibits p300/CBP-dependent HAT activities. We found that gallic acid inhibits p300-induced p65 acetylation, both in vitro and in vivo, increases the level of cytosolic IkappaBalpha, prevents lipopolysaccharide (LPS)-induced p65 translocation to the nucleus, and suppresses LPS-induced nuclear factor-kappaB activation in A549 lung cancer cells. We have also shown that gallic acid treatment inhibits the acetylation of p65 and the LPS-induced serum levels of interleukin-6 in vivo. Importantly, gallic acid generally inhibited inflammatory responses caused by other stimuli, including LPS, IFN-gamma, and interleukin-1beta, and further downregulated the expression of nuclear factor-kappaB-regulated antiapoptotic genes. These results show the crucial role of acetylation in the development of inflammatory diseases.
authors.affiliation: Department of Biochemistry and Molecular Biology, Yonsei University College of Medicine, 134 Sicnchon-dong, Seodaemun-gu, Seoul 120-752, South Korea.
authors.forename: Kyung-Chul
authors.initials: KC
authors.lastname: Choi
authors.forename: Yoo-Hyun
authors.initials: YH
authors.lastname: Lee
authors.forename: Myung Gu
authors.initials: MG
authors.lastname: Jung
authors.forename: Seung Hyun
authors.initials: SH
authors.lastname: Kwon
authors.forename: Mi-Jeong
authors.initials: MJ
authors.lastname: Kim
authors.forename: Woo Jin
authors.initials: WJ
authors.lastname: Jun
authors.forename: Jeongmin
authors.initials: J
authors.lastname: Lee
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; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects / Q000235:genetics; D050881:E1A-Associated p300 Protein / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005707:Gallic Acid / Q000494:pharmacology*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D051548:Histone Acetyltransferases / Q000037:antagonists & inhibitors; D006801:Humans; D007249:Inflammation / Q000473:pathology; D008070:Lipopolysaccharides / Q000494:pharmacology*; D008175:Lung Neoplasms / Q000201:enzymology / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D027824:Rosaceae / Q000737:chemistry; D015398:Signal Transduction / Q000187:drug effects*; D051996:Transcription Factor RelA / Q000378:metabolism*
chemical_list: D004791:Enzyme Inhibitors; D008070:Lipopolysaccharides; D051996:Transcription Factor RelA; D005707:Gallic Acid; D050881:E1A-Associated p300 Protein; C494360:EP300 protein, human; D051548:Histone Acetyltransferases