title: Green tea polyphenols increase p53 transcriptional activity and acetylation by suppressing class I histone deacetylases.
abstract: Acetylation of the tumor suppressor gene p53 at the carboxy-terminal lysine (Lys) residues enhances its transcriptional activity associated with cell cycle arrest and apoptosis. Histone deacetylases (HDACs), a family of evolutionarily conserved enzymes, counterbalance the acetylation of lysine residues on histone and non-histone proteins. In this study, we demonstrate that green tea polyphenols (GTPs) and their major constituent, (-) epigallocatechin-3-gallate (EGCG), activate p53 through acetylation at the Lys373 and Lys382 residues by inhibiting class I HDACs in LNCaP human prostate cancer cells. Treatment of cells with GTPs (2.5-10 µg/ml) and EGCG (5-20 µM) resulted in dose- and time-dependent inhibition of class I HDACs (HDAC1, 2, 3 and 8), albeit at varying levels. Discontinuation of treatment with GTP/EGCG resulted in the loss of p53 acetylation at both the sites in these cells. GTP/EGCG treatment also resulted in increased expression of p21/waf1 and Bax at the protein and message levels in these cells. The increased GTP/EGCG-mediated p53 acetylation enhanced its binding on the promoters of p21/waf1 and Bax, which was associated with increased accumulation of cells in the G0/G1 phase of the cell cycle and induction of apoptosis. Our findings indicate that GTP/EGCG causes acetylation of p53 by inhibiting class I HDACs, a function that is likely to be part of the mechanisms that control the physiological activity of p53.
authors.affiliation: Department of Urology and Nutrition, Case Western Reserve University,                     Cleveland, OH 44106, USA.
authors.forename: Vijay S
authors.initials: VS
authors.lastname: Thakur
authors.forename: Karishma
authors.initials: K
authors.lastname: Gupta
authors.forename: Sanjay
authors.initials: S
authors.lastname: Gupta
mesh_terms: D000107:Acetylation; D017209:Apoptosis; D028241:Camellia sinensis / Q000737:chemistry*; D002392:Catechin / Q000031:analogs & derivatives* / Q000494:pharmacology; D045744:Cell Line, Tumor; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000235:genetics / Q000378:metabolism; D059585:G1 Phase Cell Cycle Checkpoints / Q000187:drug effects; D015870:Gene Expression / Q000187:drug effects; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology*; D006655:Histone Deacetylases / Q000235:genetics / Q000378:metabolism; D006801:Humans; D008297:Male; D010936:Plant Extracts / Q000494:pharmacology*; D059808:Polyphenols / Q000494:pharmacology*; D011401:Promoter Regions, Genetic; D011471:Prostatic Neoplasms; D011485:Protein Binding; D011499:Protein Processing, Post-Translational; D055550:Protein Stability; D015533:Transcriptional Activation / Q000187:drug effects*; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D051028:bcl-2-Associated X Protein / Q000235:genetics / Q000378:metabolism
chemical_list: C494826:BAX protein, human; C493956:CDKN1A protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; D056572:Histone Deacetylase Inhibitors; D010936:Plant Extracts; D059808:Polyphenols; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D051028:bcl-2-Associated X Protein; D002392:Catechin; C045651:epigallocatechin gallate; D006655:Histone Deacetylases