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Epigallocatechin-3-Gallate, a Histone Acetyltransferase Inhibitor, Inhibits EBV-Induced B Lymphocyte Transformation via Suppression of RelA Acetylation

¹ Department of Biochemistry and Molecular Biology, Center for Chronic Metabolic Disease Research, ² Brain Korea 21 Project for Medical Sciences, and ³ Department of Microbiology, Yonsei University College of Medicine; ⁴ Department of Oral Biology, Yonsei University College of Dentistry, Seoul, Korea; ⁵ Department of Food and Nutrition, The University of Suwon, Suwon, Korea; ⁶ Department of Food and Biotechnology, Korea University, Chungnam, Korea; and ⁷ Department of Food and Nutrition, Chonnam National University, Gwangju, Korea

Requests for reprints: Ho-Geun Yoon, Department of Biochemistry and Molecular Biology, Yonsei University College of Medicine, 134 Sicnchon-dong, Seodaemun-gu, Seoul 120-752, South Korea. Phone: 82-2-2228-1683; Fax: 82-2-312-5041; E-mail: yhgeun{at}yuhs.ac.

Key Words: EGCG • histone acetyltransferase inhibitor • NF-B • Inflammation • EBV

Because the p300/CBP-mediated hyperacetylation of RelA (p65) is critical for nuclear factor-B (NF-B) 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 µmol/L, EGCG abrogates p300-induced p65 acetylation in vitro and in vivo, increases the level of cytosolic IB, and suppresses tumor necrosis factor (TNF)–induced NF-B activation. We also showed that EGCG prevents TNF-induced p65 translocation to the nucleus, confirming that hyperacetylation is critical for NF-B translocation as well as activity. Furthermore, EGCG treatment inhibited the acetylation of p65 and the expression of NF-B 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-B–mediated inflammatory signaling pathway. Importantly, EGCG at 50 µmol/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. [Cancer Res 2009;69(2):583–92]

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