Epigallocatechin-3-gallate up-regulates tumor suppressor gene expression via a reactive oxygen species-dependent down-regulation of UHRF1 |
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| 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 |
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| Institution: | 1. UMR CNRS 7213, Laboratoire de Biophotonique et Pharmacologie, Université de Strasbourg, Faculté de Pharmacie, 74 route du Rhin, 67401 Illkirch Cedex, France;2. UMR CNRS 7200, Laboratoire d’Innovation Thérapeutique, Université de Strasbourg, Faculté de Pharmacie, 74 route du Rhin, 67401 Illkirch Cedex, France;3. Institut de Génétique et de Biologie Moléculaire et Cellulaire, The Centre National de la Recherche Scientifique, The Institut National de la Santé et de la Recherche Médicale, Université de Strasbourg, Parc d’innovation, 1 rue Laurent Fries, 67404 Illkirch Cedex, France;4. Structural Genomics Consortium & Department of Physiology, University of Toronto, 101 College Street, Toronto, Ontario, Canada M5G 1L7;1. Department of Cell Biology, Anhui Medical University, Hefei, Anhui Province 230032, China;2. State Key Laboratory of Proteomics, Beijing Proteome Research Center, Beijing Institute of Radiation Medicine, Beijing 100850, China;3. Department of Molecular Microbiology and Immunology, University of Southern California, Los Angeles, CA 90033, USA;4. Department of Pathology, School of Basic Medical Sciences, Peking University, Beijing 100191, China;1. Division of Liver Diseases, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA;2. Department of Developmental and Regenerative Biology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA;3. Graduate School of Biological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA;4. Liver Cancer Program/Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA;5. Department of Pathology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA;6. Department of Genetics and Genomics, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA;7. HCC Translational Research Laboratory, IDIBAPS, CIBEREHD, Hospital Clinic, University of Barcelona, Catalonia 08036, Spain;8. Institute of Liver Studies, Division of Transplantation Immunology and Mucosal Biology, King’s College London, London SE5 9RS, UK;9. Rodent Histopathology Core Dana Farber/Harvard Cancer Center, Harvard Medical School, Boston, MA 02115, USA;10. Division of Gastroenterology, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02115, USA;11. Institució Catalana de Recerca i Estudis Avançats Lluís Companys, Barcelona 08010, Spain;1. Department of Urology, Shanghai General Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai 200080, China;2. Department of Pathology, Shanghai General Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai 200080, China;3. Department of Urology, Inner Mongolia Autonomous Region Peoples Hospital, Hohhot 010017, Inner Mongolia, China;1. State Key Laboratory of Cell Biology, CAS Center for Excellence in Molecular Cell Science, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China;2. CAS Key Laboratory of Innate Immunity and Chronic Disease, CAS Center for Excellence in Molecular Cell Science, School of Life Sciences and Medical Center, University of Science and Technology of China, Hefei 230027, China;3. School of Life Science and Technology, ShanghaiTech University, Shanghai 200031, China |
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| 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 p16INK4A genes. The down-regulation of UHRF1 is dependent upon the generation of reactive oxygen species by EGCG. Up-regulation of p16INK4A is strongly correlated with decreased promoter binding by UHRF1. UHRF1 over-expression counteracted EGCG-induced G1-arrested cells, apoptosis, and up-regulation of p16INK4A and p73. Mutants of the Set and Ring Associated (SRA) domain of UHRF1 were unable to down-regulate p16INK4A 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. |
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