Epigallocatechin-3-gallate up-regulates tumor suppressor gene expression via a reactive oxygen species-dependent down-regulation of UHRF1.

Abstract

Ubiquitin-like containing PHD and Ring finger 1 (UHRF1) contributes to silencing of tumor suppressor genes by recruiting DNA methyltransferase 1 (DNMT1) to their hemi-methylated promoters. Conversely, demethylation of these promoters has been ascribed to the natural anti-cancer drug, epigallocatechin-3-gallate (EGCG). The aim of the present study was to investigate whether the UHRF1/DNMT1 pair is an important target of EGCG action. Here, we show that EGCG down-regulates UHRF1 and DNMT1 expression in Jurkat cells, with subsequent up-regulation of p73 and p16(INK4A) genes. The down-regulation of UHRF1 is dependent upon the generation of reactive oxygen species by EGCG. Up-regulation of p16(INK4A) is strongly correlated with decreased promoter binding by UHRF1. UHRF1 over-expression counteracted EGCG-induced G1-arrested cells, apoptosis, and up-regulation of p16(INK4A) and p73. Mutants of the Set and Ring Associated (SRA) domain of UHRF1 were unable to down-regulate p16(INK4A) and p73, either in the presence or absence of EGCG. Our results show that down-regulation of UHRF1 is upstream to many cellular events, including G1 cell arrest, up-regulation of tumor suppressor genes and apoptosis.

• Authors: Mayada Achour, Marc Mousli, Mahmoud Alhosin, Abdulkhaleg Ibrahim, Jean Peluso, Christian D Muller, Valérie B Schini-Kerth, Ali Hamiche, Sirano Dhe-Paganon, Christian Bronner
• Journal: Biochemical and biophysical research communications (Biochem Biophys Res Commun) Vol. 430 Issue 1 Pg. 208-12 (Jan 04 2013) ISSN: 1090-2104 [Electronic] United States
• PMID: 23201574 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2012 Elsevier Inc. All rights reserved.

Chemical References

• CCAAT-Enhancer-Binding Proteins
• Cyclin-Dependent Kinase Inhibitor p16
• DNA-Binding Proteins
• Nuclear Proteins
• Reactive Oxygen Species
• TP73 protein, human
• Tumor Protein p73
• Tumor Suppressor Proteins
• Vascular Endothelial Growth Factor A
• Catechin
• epigallocatechin gallate
• DNA (Cytosine-5-)-Methyltransferase 1
• DNA (Cytosine-5-)-Methyltransferases
• DNMT1 protein, human
• UHRF1 protein, human
• Ubiquitin-Protein Ligases

Topics

• Apoptosis (drug effects)
• CCAAT-Enhancer-Binding Proteins (antagonists & inhibitors, metabolism)
• Catechin (analogs & derivatives, pharmacology)
• Cell Cycle (drug effects)
• Cyclin-Dependent Kinase Inhibitor p16 (genetics)
• DNA (Cytosine-5-)-Methyltransferase 1
• DNA (Cytosine-5-)-Methyltransferases (antagonists & inhibitors, metabolism)
• DNA-Binding Proteins (genetics)
• Down-Regulation
• Gene Expression Regulation, Neoplastic (drug effects)
• Genes, Tumor Suppressor (drug effects)
• Humans
• Jurkat Cells
• Nuclear Proteins (genetics)
• Promoter Regions, Genetic
• Reactive Oxygen Species (metabolism)
• Tumor Protein p73
• Tumor Suppressor Proteins (genetics)
• Ubiquitin-Protein Ligases
• Vascular Endothelial Growth Factor A (metabolism)