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

Abstract

Because the p300/CBP-mediated hyperacetylation of RelA (p65) is critical for nuclear factor-kappa B (NF-kappa 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 mu mol/L, EGCG abrogates p300-induced p65 acetylation in vitro and in vivo, increases the level of cytosolic I kappa B alpha, and suppresses tumor necrosis factor a (TNF alpha)-induced NF-kappa B activation. We also showed that EGCG prevents TNF alpha-induced p65 translocation to the nucleus, confirming that hyperacetylation is critical for NF-kappa B translocation as well as activity. Furthermore, EGCG treatment inhibited the acetylation of p65 and the expression of NF-kappa 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 historic deacetylases in the NF-kappa B-mediated inflammatory signaling pathway. Importantly, EGCG at 50 mu mol/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]