PMID- 30854739 OWN - NLM STAT- MEDLINE DCOM- 20191107 LR - 20191107 IS - 1098-2744 (Electronic) IS - 0899-1987 (Linking) VI - 58 IP - 7 DP - 2019 Jul TI - Green tea-induced epigenetic reactivation of tissue inhibitor of matrix metalloproteinase-3 suppresses prostate cancer progression through histone-modifying enzymes. PG - 1194-1207 LID - 10.1002/mc.23003 [doi] AB - Green tea polyphenols (GTPs) and their major constituent, epigallocatechin-3-gallate (EGCG), have been reported to demonstrate many interesting biological activities, including anticancer properties. Recent studies on prostate cancer provide strong evidence that epigenetic mechanisms are major players in the regulation of matrix metalloproteinases (MMPs) and their binding partner tissue inhibitor of MMPs (TIMPs) involved in prostate cancer progression. Here we demonstrate that GTP/EGCG mediate epigenetic reactivation of TIMP-3 that plays a key role in suppressing invasiveness and cancer progression. Treatment of human prostate cancer DUPRO and LNCaP cells with 10 microg/mL GTP and 20 microM EGCG induced TIMP-3 mRNA and protein expression. This transcriptional activation of TIMP-3 was associated with the decrease in the expression of both enhancers of zeste homolog 2 (EZH2) and its catalytic product trimethylation of histone H3 at lysine 27 (H3K27me3) repressive marks at the TIMP-3 promoter with an accompanying increase in histone H3K9/18 acetylation. In addition, GTP/EGCG treatment significantly reduced class I histone deacetylase (HDAC) activity/expression and EZH2 and H3K27me3 levels in prostate cancer cells. EGCG/GTP exposure also reduced MMP-2/MMP-9 gelatinolytic activity and abrogated invasion and migration capabilities in these cells. Silencing of EZH2 and class I HDACs strikingly increased the expression of TIMP-3 independent of DNA methylation. Furthermore, clinical trials performed on patients undergoing prostatectomy consuming 800 mg EGCG (Polyphenon E) up to 6 weeks and grade-matched controls demonstrate an increase in plasma TIMP-3 levels. A marked reduction in class I HDACs activity/expression and EZH2 and H3K27me3 levels were noted in GTP-supplemented prostate tissue. Our findings highlight that TIMP-3 induction, as a key epigenetic event modulated by green tea in restoring the MMP:TIMP balance suppresses prostate cancer progression. CI - (c) 2019 Wiley Periodicals, Inc. FAU - Deb, Gauri AU - Deb G AD - Department of Urology, Case Western Reserve University, Cleveland, Ohio. AD - Department of Biotechnology, Indian Institute of Technology, Guwahati, Assam, India. FAU - Shankar, Eswar AU - Shankar E AD - Department of Urology, Case Western Reserve University, Cleveland, Ohio. FAU - Thakur, Vijay S AU - Thakur VS AD - Department of Urology, Case Western Reserve University, Cleveland, Ohio. FAU - Ponsky, Lee E AU - Ponsky LE AD - Department of Urology, Case Western Reserve University, Cleveland, Ohio. AD - Department of Urology, The Urology Institute, University Hospitals Cleveland Medical Center, Cleveland, Ohio. FAU - Bodner, Donald R AU - Bodner DR AD - Department of Urology, Case Western Reserve University, Cleveland, Ohio. AD - Department of Urology, The Urology Institute, University Hospitals Cleveland Medical Center, Cleveland, Ohio. FAU - Fu, Pingfu AU - Fu P AD - Department of Population and Quantitative Health Sciences, Case Western Reserve University, Cleveland, Ohio. AD - Department of Nutrition, Case Western Reserve University, Cleveland, Ohio. FAU - Gupta, Sanjay AU - Gupta S AUID- ORCID: 0000-0002-9492-3249 AD - Department of Urology, Case Western Reserve University, Cleveland, Ohio. AD - Department of Urology, The Urology Institute, University Hospitals Cleveland Medical Center, Cleveland, Ohio. AD - Division of General Medical Sciences, Case Comprehensive Cancer Center, Cleveland, Ohio. AD - Department of Nutrition, Case Western Reserve University, Cleveland, Ohio. AD - Department of Urology, Louis Stokes Cleveland Veterans Affairs Medical Center, Cleveland, Ohio. LA - eng GR - R21 CA193080/CA/NCI NIH HHS/United States GR - R03 CA186179/CA/NCI NIH HHS/United States GR - R01 CA115491/CA/NCI NIH HHS/United States GR - R21 CA193080/CA/NCI NIH HHS/United States GR - R03 CA186179/CA/NCI NIH HHS/United States GR - I01 BX002494/BX/BLRD VA/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't PT - Research Support, U.S. Gov't, Non-P.H.S. DEP - 20190310 PL - United States TA - Mol Carcinog JT - Molecular carcinogenesis JID - 8811105 RN - 0 (Antineoplastic Agents) RN - 0 (Histones) RN - 0 (Plant Preparations) RN - 0 (Polyphenols) RN - 0 (TIMP3 protein, human) RN - 0 (Tea) RN - 0 (Tissue Inhibitor of Metalloproteinase-3) RN - 0 (histone H3 trimethyl Lys4) RN - 8R1V1STN48 (Catechin) RN - BQM438CTEL (epigallocatechin gallate) RN - EC 2.1.1.43 (EZH2 protein, human) RN - EC 2.1.1.43 (Enhancer of Zeste Homolog 2 Protein) RN - EC 3.4.24.35 (MMP9 protein, human) RN - EC 3.4.24.35 (Matrix Metalloproteinase 9) RN - EC 3.5.1.98 (HDAC1 protein, human) RN - EC 3.5.1.98 (Histone Deacetylase 1) RN - T432289GYZ (polyphenon E) SB - IM MH - Acetylation/drug effects MH - Antineoplastic Agents/*therapeutic use MH - Catechin/*analogs & derivatives/therapeutic use MH - Cell Line, Tumor MH - Cell Movement/drug effects MH - DNA Methylation/drug effects MH - Enhancer of Zeste Homolog 2 Protein/biosynthesis MH - Histone Code/drug effects/physiology MH - Histone Deacetylase 1/metabolism MH - Histones/biosynthesis MH - Humans MH - Male MH - Matrix Metalloproteinase 9/metabolism MH - Neoplasm Invasiveness/pathology MH - Plant Preparations/therapeutic use MH - Polyphenols/therapeutic use MH - Promoter Regions, Genetic/drug effects MH - Prostatic Neoplasms/*drug therapy/pathology MH - Tea/*chemistry MH - Tissue Inhibitor of Metalloproteinase-3/blood/genetics/*metabolism MH - Transcriptional Activation/drug effects OTO - NOTNLM OT - enhancer of zeste homolog 2 (EZH2) OT - green tea polyphenols (GTPs) OT - histone deacetylases (HDAC) OT - prostate cancer OT - tissue inhibitors of matrix metalloproteinase-3 (TIMP-3) EDAT- 2019/03/12 06:00 MHDA- 2019/11/08 06:00 CRDT- 2019/03/12 06:00 PHST- 2018/11/15 00:00 [received] PHST- 2019/02/11 00:00 [revised] PHST- 2019/02/24 00:00 [accepted] PHST- 2019/03/12 06:00 [pubmed] PHST- 2019/11/08 06:00 [medline] PHST- 2019/03/12 06:00 [entrez] AID - 10.1002/mc.23003 [doi] PST - ppublish SO - Mol Carcinog. 2019 Jul;58(7):1194-1207. doi: 10.1002/mc.23003. Epub 2019 Mar 10.