title: (-)-Epigallocatechin-3-gallate reverses the expression of various tumor-suppressor genes by inhibiting DNA methyltransferases and histone deacetylases in human cervical cancer cells.
abstract: There has been increasing evidence that numerous bioactive dietary agents can hamper the process of carcinogenesis by targeting epigenetic alterations including DNA methylation. This therapeutic approach is considered as a significant goal for cancer therapy due to the reversible nature of epigenetic-mediated gene silencing and warrants further attention. One such dietary agent, green tea catechin, (-)-epigallocatechin-3-gallate (EGCG) has been shown to modulate many cancer-related pathways. Thus, the present study was designed to investigate the role of EGCG as an epigenetic modifier in HeLa cells. DNA methyltransferase (DNMT) and histone deacetylase (HDAC) inhibition assays were conducted, and the transcription levels of DNMT3B and HDAC1 were assessed by enzymatic activity assay and RT-PCR, respectively. Furthermore, we studied the binding interaction of EGCG with DNMT3B and HDAC1 by molecular modeling as well as promoter DNA methylation and expression of retinoic acid receptor-β (RARβ), cadherin 1 (CDH1) and death-associated protein kinase-1 (DAPK1) in EGCG-treated HeLa cells by RT-PCR and MS-PCR. In the present study, time-dependent EGCG-treated HeLa cells were found to have a significant reduction in the enzymatic activity of DNMT and HDAC. However, the expression of DNMT3B was significantly decreased in a time-dependent manner whereas there was no significant change in HDAC1 expression. Molecular modeling data also supported the EGCG-mediated DNMT3B and HDAC1 activity inhibition. Furthermore, time-dependent exposure to EGCG resulted in reactivation of known tumor-suppressor genes (TSGs) in HeLa cells due to marked changes in the methylation of the promoter regions of these genes. Overall, the present study suggests that EGCG may have a significant impact on the development of novel epigenetic-based therapy.
authors: Department of Natural Science and Public Health, College of Sustainability Sciences and Humanities, Zayed University, Dubai, United Arab Emirates.
authors: Munawwar Ali
authors: MA
authors: Khan
authors: School of Life Sciences, Manipal University, Dubai, United Arab Emirates.
authors: Arif
authors: A
authors: Hussain
authors: School of Life Sciences, Manipal University, Dubai, United Arab Emirates.
authors: Madhumitha Kedhari
authors: MK
authors: Sundaram
authors: Department of Natural Science and Public Health, College of Sustainability Sciences and Humanities, Zayed University, Dubai, United Arab Emirates.
authors: Usama
authors: U
authors: Alalami
authors: School of Life Sciences, Manipal University, Dubai, United Arab Emirates.
authors: Dian
authors: D
authors: Gunasekera
authors: School of Life Sciences, Manipal University, Dubai, United Arab Emirates.
authors: Laveena
authors: L
authors: Ramesh
authors: School of Life Sciences, Manipal University, Dubai, United Arab Emirates.
authors: Amina
authors: A
authors: Hamza
authors: School of Life Sciences, Manipal University, Dubai, United Arab Emirates.
authors: Uzma
authors: U
authors: Quraishi
mesh_terms: D016588:Anticarcinogenic Agents / Q000494:pharmacology*; D002392:Catechin / Q000031:analogs & derivatives* / Q000494:pharmacology; D042002:Chromatin Assembly and Disassembly / Q000187:drug effects; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology; D019175:DNA Methylation / Q000187:drug effects; D004790:Enzyme Induction / Q000187:drug effects; D044127:Epigenesis, Genetic / Q000187:drug effects*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D016147:Genes, Tumor Suppressor / Q000187:drug effects*; D006367:HeLa Cells; D056284:Histone Deacetylase 1 / Q000096:biosynthesis / Q000235:genetics; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology*; D006655:Histone Deacetylases / Q000502:physiology; D006801:Humans; D008958:Models, Molecular; D062105:Molecular Docking Simulation; D009363:Neoplasm Proteins / Q000096:biosynthesis / Q000235:genetics; D011487:Protein Conformation; D012333:RNA, Messenger / Q000096:biosynthesis; D012334:RNA, Neoplasm / Q000096:biosynthesis; D025521:Tumor Suppressor Proteins / Q000096:biosynthesis / Q000235:genetics; D002583:Uterine Cervical Neoplasms / Q000235:genetics* / Q000473:pathology; D000097584:DNA Methyltransferase 3B
chemical_list: D016588:Anticarcinogenic Agents; D002392:Catechin; D004248:DNA (Cytosine-5-)-Methyltransferases; D056284:Histone Deacetylase 1; D056572:Histone Deacetylase Inhibitors; D006655:Histone Deacetylases; D009363:Neoplasm Proteins; D012333:RNA, Messenger; D012334:RNA, Neoplasm; D025521:Tumor Suppressor Proteins; D000097584:DNA Methyltransferase 3B; C045651:epigallocatechin gallate; C110550:HDAC1 protein, human