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1
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Agostini M, Traldi P, Hamdan M. Mass Spectrometry Contribution to Pediatric Cancers Research. Medicina (B Aires) 2023; 59:medicina59030612. [PMID: 36984613 PMCID: PMC10053507 DOI: 10.3390/medicina59030612] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2023] [Revised: 03/15/2023] [Accepted: 03/16/2023] [Indexed: 03/22/2023] Open
Abstract
For over four decades, mass spectrometry-based methods have provided a wealth of information relevant to various challenges in the field of cancers research. These challenges included identification and validation of novel biomarkers for various diseases, in particular for various forms of cancer. These biomarkers serve various objectives including monitoring patient response to the various forms of therapy, differentiating subgroups of the same type of cancer, and providing proteomic data to complement datasets generated by genomic, epigenetic, and transcriptomic methods. The same proteomic data can be used to provide prognostic information and could guide scientists and medics to new and innovative targeted therapies The past decade has seen a rapid emergence of epigenetics as a major contributor to carcinogenesis. This development has given a fresh momentum to MS-based proteomics, which demonstrated to be an unrivalled tool for the analyses of protein post-translational modifications associated with chromatin modifications. In particular, high-resolution mass spectrometry has been recently used for systematic quantification of chromatin modifications. Data generated by this approach are central in the search for new therapies for various forms of cancer and will help in attempts to decipher antitumor drug resistance. To appreciate the contribution of mass spectrometry-based proteomics to biomarkers discovery and to our understanding of mechanisms behind the initiation and progression of various forms of cancer, a number of recent investigations are discussed. These investigations also include results provided by two-dimensional gel electrophoresis combined with mass spectrometry.
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2
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Liu S, Li Y, Hong Y, Wang M, Zhang H, Ma J, Qu K, Huang G, Lu TJ. Mechanotherapy in oncology: Targeting nuclear mechanics and mechanotransduction. Adv Drug Deliv Rev 2023; 194:114722. [PMID: 36738968 DOI: 10.1016/j.addr.2023.114722] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2022] [Revised: 12/23/2022] [Accepted: 01/28/2023] [Indexed: 02/05/2023]
Abstract
Mechanotherapy is proposed as a new option for cancer treatment. Increasing evidence suggests that characteristic differences are present in the nuclear mechanics and mechanotransduction of cancer cells compared with those of normal cells. Recent advances in understanding nuclear mechanics and mechanotransduction provide not only further insights into the process of malignant transformation but also useful references for developing new therapeutic approaches. Herein, we present an overview of the alterations of nuclear mechanics and mechanotransduction in cancer cells and highlight their implications in cancer mechanotherapy.
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Affiliation(s)
- Shaobao Liu
- State Key Laboratory of Mechanics and Control of Mechanical Structures, Nanjing University of Aeronautics and Astronautics, Nanjing 210016, PR China; MIIT Key Laboratory of Multifunctional Lightweight Materials and Structures, Nanjing University of Aeronautics, Nanjing 210016, PR China
| | - Yuan Li
- MOE Key Laboratory of Biomedical Information Engineering, School of Life Science and Technology, Xi'an Jiaotong University, Xi'an 710049, PR China; Bioinspired Engineering and Biomechanics Center (BEBC), Xi'an Jiaotong University, Xi'an 710049, PR China
| | - Yuan Hong
- MOE Key Laboratory of Biomedical Information Engineering, School of Life Science and Technology, Xi'an Jiaotong University, Xi'an 710049, PR China; Bioinspired Engineering and Biomechanics Center (BEBC), Xi'an Jiaotong University, Xi'an 710049, PR China; National Science Foundation Science and Technology Center for Engineering Mechanobiology, Washington University, St. Louis, MO 63130, USA
| | - Ming Wang
- MOE Key Laboratory of Biomedical Information Engineering, School of Life Science and Technology, Xi'an Jiaotong University, Xi'an 710049, PR China; Bioinspired Engineering and Biomechanics Center (BEBC), Xi'an Jiaotong University, Xi'an 710049, PR China
| | - Hao Zhang
- State Key Laboratory of Mechanics and Control of Mechanical Structures, Nanjing University of Aeronautics and Astronautics, Nanjing 210016, PR China; MIIT Key Laboratory of Multifunctional Lightweight Materials and Structures, Nanjing University of Aeronautics, Nanjing 210016, PR China
| | - Jinlu Ma
- Department of Radiation Oncology, the First Affiliated Hospital, Xian Jiaotong University, Xi'an 710061, PR China
| | - Kai Qu
- Department of Hepatobiliary Surgery, the First Affiliated Hospital, Xian Jiaotong University, Xi'an 710061, PR China
| | - Guoyou Huang
- Department of Engineering Mechanics, School of Civil Engineering, Wuhan University, Wuhan 430072, PR China.
| | - Tian Jian Lu
- State Key Laboratory of Mechanics and Control of Mechanical Structures, Nanjing University of Aeronautics and Astronautics, Nanjing 210016, PR China; MIIT Key Laboratory of Multifunctional Lightweight Materials and Structures, Nanjing University of Aeronautics, Nanjing 210016, PR China.
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3
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Adibfar S, Elveny M, Kashikova HS, Mikhailova MV, Farhangnia P, Vakili-Samiani S, Tarokhian H, Jadidi-Niaragh F. The molecular mechanisms and therapeutic potential of EZH2 in breast cancer. Life Sci 2021; 286:120047. [PMID: 34653429 DOI: 10.1016/j.lfs.2021.120047] [Citation(s) in RCA: 26] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2021] [Revised: 09/30/2021] [Accepted: 10/07/2021] [Indexed: 02/08/2023]
Abstract
Due to its high occurrence and mortality rate, breast cancer has been studied from various aspects as one of the cancer field's hot topics in the last decade. Epigenetic alterations are spoused to be highly effective in breast cancer development. Enhancer of zeste homolog 2 (EZH2) is an enzymatic epi-protein that takes part in most vital cell functions by its different action modes. EZH2 is suggested to be dysregulated in specific breast cancer types, particularly in advanced stages. Mounting evidence revealed that EZH2 overexpression or dysfunction affects the pathophysiology of breast cancer. In this review, we discuss biological aspects of the EZH2 molecule with a focus on its newly identified action mechanisms. We also highlight how EZH2 plays an essential role in breast cancer initiation, progression, metastasis, and invasion, which emerged as a worthy target for treating breast cancer in different approaches.
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Affiliation(s)
- Sara Adibfar
- Department of Immunology, School of Medicine, Kermanshah University of Medical Sciences, Kermanshah, Iran; Student Research Committee, School of Medicine, Kermanshah University of Medical Sciences, Kermanshah, Iran
| | - Marischa Elveny
- DS & CI Research Group, Universitas Sumatera Utara, Medan, Indonesia
| | | | | | - Pooya Farhangnia
- Department of Immunology, School of Medicine, Iran University of Medical Sciences, Tehran, Iran; Network of Immunity in Infection, Malignancy, and Autoimmunity (NIIMA), Universal Scientific Education and Research Network (USERN), Tehran, Iran; Immunology Board for Transplantation and Advanced Cellular Therapeutics (ImmunoTACT), Universal Scientific Education and Research Network (USERN), Tehran, Iran
| | - Sajjad Vakili-Samiani
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran; Student Research Committee, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Hanieh Tarokhian
- Department of Immunology, School of Medicine, Kermanshah University of Medical Sciences, Kermanshah, Iran.
| | - Farhad Jadidi-Niaragh
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran; Department of Immunology, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran; Integrated Medicine and Aging Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.
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4
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Ari F, Napieralski R, Akgun O, Magdolen V, Ulukaya E. Epigenetic modulators combination with chemotherapy in breast cancer cells. Cell Biochem Funct 2021; 39:571-583. [PMID: 33608886 DOI: 10.1002/cbf.3626] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2020] [Revised: 02/02/2021] [Accepted: 02/05/2021] [Indexed: 12/15/2022]
Abstract
Despite the concerning adverse effects on tumour development, epigenetic drugs are very promising in cancer treatment. The aim of this study was to compare the differential effects of standard chemotherapy regimens (FEC: 5-fluorouracil plus epirubicine plus cyclophosphamide) in combination with epigenetic modulators (decitabine, valproic acid): (a) on gene methylation levels of selected tumour biomarkers (LINE-1, uPA, PAI-1, DAPK); (b) their expression status (uPA and PAI-1); (c) differentiation status (5meC and H3K27me3). Furthermore, cell survival as well as changes concerning the invasion capacity were monitored in cell culture models of breast cancer (MCF-7, MDA-MB-231). A significant overall decrease of cell survival was observed in the FEC-containing combination therapies for both cell lines. Methylation results showed a general tendency towards increased demethylation of the uPA and PAI-1 gene promoters for the MCF-7 cells, as well as the proapoptotic DAPK gene in the treatment regimens for both cell lines. The uPA and PAI-1 antigen levels were mainly increased in the supernatant of FEC-only treated MDA-MB-231 cells. DAC-only treatment induced an increase of secreted uPA protein in MCF-7 cell culture, while most of the VPA-containing regimens also induced uPA and PAI-1 expression in MCF-7 cell fractions. Epigenetically active substances can also induce a re-differentiation in tumour cells, as shown by 5meC, H3K27me3 applying ICC. SIGNIFICANCE OF THE STUDY: Epigenetic modulators especially in the highly undifferentiated and highly malignant MDA-MB-231 tumour cells significantly reduced tumour malignancy thus; further clinical studies applying specific combination therapies with epigenetic modulators may be warranted.
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Affiliation(s)
- Ferda Ari
- Science and Art Faculty, Department of Biology, Bursa Uludag University, Bursa, Turkey
| | - Rudolf Napieralski
- Department of Obstetrics and Gynecology, Clinical Research Unit, Klinikum rechts der Isar, Technische Universität München, Munich, Germany.,Therawis Diagnostics GmbH, Munich, Germany
| | - Oguzhan Akgun
- Science and Art Faculty, Department of Biology, Bursa Uludag University, Bursa, Turkey
| | - Viktor Magdolen
- Department of Obstetrics and Gynecology, Clinical Research Unit, Klinikum rechts der Isar, Technische Universität München, Munich, Germany
| | - Engin Ulukaya
- Faculty of Medicine, Department of Clinical Biochemistry, Istinye University, Istanbul, Turkey
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Xu J, Wang Q, Leung ELH, Li Y, Fan X, Wu Q, Yao X, Liu L. Compound C620-0696, a new potent inhibitor targeting BPTF, the chromatin-remodeling factor in non-small-cell lung cancer. Front Med 2019; 14:60-67. [PMID: 31104301 DOI: 10.1007/s11684-019-0694-8] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2018] [Accepted: 03/13/2019] [Indexed: 12/12/2022]
Abstract
Bromodomain PHD-finger transcription factor (BPTF) is the largest subunit of the nucleosome remodeling factor and plays an important role in chromatin remodeling for gene activation through its association with histone acetylation or methylation. BPTF is also involved in oncogene transcription in diverse progressions of cancers. Despite clinical trials for inhibitors of bromodomain and extra-terminal family proteins in human cancers, no potent and selective inhibitor targeting the BPTF bromodomain has been discovered. In this study, we identified a potential inhibitor, namely, C620-0696, by computational docking modeling to target bromodomain. Results of biolayer interferometry revealed that compound C620-0696 exhibited high binding affinity to the BPTF bromodomain. Moreover, C620-0696 was cytotoxic in BPTF with a high expression of non-small-cell lung cancer (NSCLC) cells. It suppressed the expression of the BPTF target gene c-MYC, which is known as an oncogenic transcriptional regulator in various cancers. C620-0696 also partially inhibited the migration and colony formation of NSCLC cells owing to apoptosis induction and cell cycle blockage. Thus, our study presents an effective strategy to target a bromodomain factor-mediated tumorigenesis in cancers with small molecules, supporting further exploration of the use of these inhibitors in oncology.
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Affiliation(s)
- Jiahui Xu
- State Key Laboratory of Quality Research in Chinese Medicine, Macau Institute for Applied Research in Medicine and Health, Macau University of Science and Technology, Macau (SAR), 519020, China
| | - Qianqian Wang
- State Key Laboratory of Quality Research in Chinese Medicine, Macau Institute for Applied Research in Medicine and Health, Macau University of Science and Technology, Macau (SAR), 519020, China
| | - Elaine Lai Han Leung
- State Key Laboratory of Quality Research in Chinese Medicine, Macau Institute for Applied Research in Medicine and Health, Macau University of Science and Technology, Macau (SAR), 519020, China
- Respiratory Medicine Department, Taihe Hospital, Hubei University of Medicine, Shiyan, 236600, China
- Department of Thoracic Surgery, Guangzhou Institute of Respiratory Health and State Key Laboratory of Respiratory Disease, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, 510182, China
| | - Ying Li
- State Key Laboratory of Quality Research in Chinese Medicine, Macau Institute for Applied Research in Medicine and Health, Macau University of Science and Technology, Macau (SAR), 519020, China
| | - Xingxing Fan
- State Key Laboratory of Quality Research in Chinese Medicine, Macau Institute for Applied Research in Medicine and Health, Macau University of Science and Technology, Macau (SAR), 519020, China
| | - Qibiao Wu
- State Key Laboratory of Quality Research in Chinese Medicine, Macau Institute for Applied Research in Medicine and Health, Macau University of Science and Technology, Macau (SAR), 519020, China.
| | - Xiaojun Yao
- State Key Laboratory of Quality Research in Chinese Medicine, Macau Institute for Applied Research in Medicine and Health, Macau University of Science and Technology, Macau (SAR), 519020, China.
| | - Liang Liu
- State Key Laboratory of Quality Research in Chinese Medicine, Macau Institute for Applied Research in Medicine and Health, Macau University of Science and Technology, Macau (SAR), 519020, China.
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6
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Fardi M, Solali S, Farshdousti Hagh M. Epigenetic mechanisms as a new approach in cancer treatment: An updated review. Genes Dis 2018; 5:304-311. [PMID: 30591931 PMCID: PMC6303480 DOI: 10.1016/j.gendis.2018.06.003] [Citation(s) in RCA: 140] [Impact Index Per Article: 20.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2018] [Accepted: 06/12/2018] [Indexed: 12/13/2022] Open
Abstract
Epigenetic, along with genetic mechanisms, is essential for natural evolution and maintenance of specific patterns of gene expression in mammalians. Global epigenetic variation is inherited somatically and unlike genetic variation, it is dynamic and reversible. They are somatically associated with known genetic variations. Recent studies indicate the broad role of epigenetic mechanisms in the initiation and development of cancers, that they are including DNA methylation, histone modifications, nucleosomes changes, non-coding RNAs. The reversible nature of epigenetic changes has led to the emergence of novel epigenetic therapeutic approaches, so that several types of these medications have been approved by the FDA so far. In this review, we discuss the concept of epigenetic changes in diseases, especially cancers, the role of these changes in the onset and progression of cancers and the potential of using this knowledge in designing novel therapeutic strategies.
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Affiliation(s)
- Masoumeh Fardi
- Immunology Research Center, Tabriz University of Medical Science, Tabriz, Iran.,Department of Immunology, Division of Hematology and Blood Transfusion Medicine, Tabriz University of Medical Science, Tabriz, Iran
| | - Saeed Solali
- Molecular Medicine Research Center, Tabriz University of Medical Science, Tabriz, Iran.,Hematology and Oncology Research Center, Tabriz University of Medical Science, Tabriz, Iran
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Dockry É, O'Leary S, Gleeson LE, Lyons J, Keane J, Gray SG, Doherty DG. Epigenetic induction of CD1d expression primes lung cancer cells for killing by invariant natural killer T cells. Oncoimmunology 2018; 7:e1428156. [PMID: 29872551 DOI: 10.1080/2162402x.2018.1428156] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2017] [Revised: 01/08/2018] [Accepted: 01/09/2018] [Indexed: 01/22/2023] Open
Abstract
Immunotherapies that target CD1d-restricted invariant NKT (iNKT) cells can prevent tumor growth in murine models but trials in humans have shown limited clinical efficacy. Here, we show that iNKT cells are depleted from blood and bronchial lavage samples from patients with non-small cell lung cancer (NSCLC) suggesting a role for these cells in immunity against NSCLC. We interrogated the Lung Cancer Explorer and Kaplan-Meier Plotter databases of NSCLC patients and found that pulmonary CD1d expression is reduced in patients with NSCLC and that low expression of CD1d mRNA is significantly associated with poor patient survival. We hypothesized that CD1d expression in NSCLC is epigenetically regulated and can be modulated using epigenetic targeting therapies. Treatment of the CD1d-negative NSCLC cell lines, A549 and SK-MES-1, with DNA methyltransferase inhibitors and histone deacetylase inhibitors resulted in a dose-dependent induction of CD1d mRNA and protein expression. Chromatin immunoprecipitation analysis indicated that this induction of CD1d expression directly involved chromatin remodelling. Induction of CD1d expression by A549 and SK-MES-1 cells using therapeutic low doses of DNA methyltransferase inhibitors and histone deacetylase inhibitors made them targets for iNKT cell-mediated cytolytic degranulation. Thus, epigenetic manipulation of CD1d expression may augment the efficacy of iNKT cell-based immunotherapies for NSCLC.
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Affiliation(s)
- Éilis Dockry
- Department of Immunology, Trinity Translational Medicine Institute, Trinity College Dublin, Dublin, Ireland.,Thoracic Oncology Research Group, Trinity Translational Medicine Institute, Trinity College Dublin, Dublin, Ireland
| | - Seónadh O'Leary
- Department of Clinical Medicine, Trinity Translational Medicine Institute, Trinity College Dublin, Dublin, Ireland
| | - Laura E Gleeson
- Department of Clinical Medicine, Trinity Translational Medicine Institute, Trinity College Dublin, Dublin, Ireland.,Department of Respiratory Medicine, St. James' Hospital, Dublin, Ireland
| | - Judith Lyons
- Department of Respiratory Medicine, St. James' Hospital, Dublin, Ireland
| | - Joseph Keane
- Department of Clinical Medicine, Trinity Translational Medicine Institute, Trinity College Dublin, Dublin, Ireland.,Department of Respiratory Medicine, St. James' Hospital, Dublin, Ireland
| | - Steven G Gray
- Thoracic Oncology Research Group, Trinity Translational Medicine Institute, Trinity College Dublin, Dublin, Ireland
| | - Derek G Doherty
- Department of Immunology, Trinity Translational Medicine Institute, Trinity College Dublin, Dublin, Ireland
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8
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Zeidler R, de Freitas Soares BL, Bader A, Giri S. Molecular epigenetic targets for liver diseases: current challenges and future prospects. Drug Discov Today 2017; 22:1620-1636. [PMID: 28754290 DOI: 10.1016/j.drudis.2017.07.008] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2016] [Revised: 06/28/2017] [Accepted: 07/18/2017] [Indexed: 02/06/2023]
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9
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Lafreniere MA, Desrochers GF, Mekbib K, Pezacki JP. An affinity-based probe for methyltransferase enzymes based on sinefungin. CAN J CHEM 2017. [DOI: 10.1139/cjc-2017-0168] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
Epigenetics control numerous cellular processes such as gene transcription, signal transduction, and protein stabilization. An understanding of epigenetic mechanisms can lead to the development of therapeutic agents for various diseases. Herein, we report the design and synthesis of a sinefungin affinity-probe (BpyneSF) that targets methyltranferase enzymes and proteins involved in recognition of methylation. This probe contains a bioorthogonal alkyne residue for conjugation using the copper-catalyzed azide–alkyne cycloaddition and a photoactivatable crosslinker group for covalent attachment of the probe to its proteomic targets. We investigate the efficiency and selectivity of the probe to inhibit and label methyltransferase enzymes, and we demonstrate, through in-gel fluorescence, on-bead digestion, and tandem mass spectrometry, that BpyneSF can label methyltransferase SETD2 and reader proteins in vitro. These results establish the utility of BpyneSF as a tool for affinity-based protein profiling in complex biological environments.
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Affiliation(s)
- Matthew A. Lafreniere
- Department of Chemistry and Biomolecular Sciences, University of Ottawa, 10 Marie Curie Street, Ottawa, ON K1N 6N5, Canada
| | - Geneviève F. Desrochers
- Department of Chemistry and Biomolecular Sciences, University of Ottawa, 10 Marie Curie Street, Ottawa, ON K1N 6N5, Canada
| | - Kedous Mekbib
- Department of Chemistry and Biomolecular Sciences, University of Ottawa, 10 Marie Curie Street, Ottawa, ON K1N 6N5, Canada
| | - John Paul Pezacki
- Department of Chemistry and Biomolecular Sciences, University of Ottawa, 10 Marie Curie Street, Ottawa, ON K1N 6N5, Canada
- Department of Biochemistry, Microbiology and Immunology, University of Ottawa, 451 Smyth Road, Ottawa, ON K1H 8M5, Canada
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10
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Karsli-Ceppioglu S. Epigenetic Mechanisms in Psychiatric Diseases and Epigenetic Therapy. Drug Dev Res 2016; 77:407-413. [PMID: 27594444 DOI: 10.1002/ddr.21340] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022]
Abstract
Preclinical Research Epigenetic mechanisms refer covalent modification of DNA and histone proteins that control transcriptional regulation of gene expression. Epigenetic regulation is involved in the development of the nervous system and plays an important role in the pathophysiology of psychiatric disorders, including depression, bipolar disorder, and schizophrenia. Epigenetic drugs, including histone deacetylation and DNA methylation inhibitors have received increased attention for the management of psychiatric diseases. The purpose of this review is to discuss the potential of epigenetic drugs to treat these disorders and to clarify the mechanisms by which they regulate the dysfunctional genes in the brain. Drug Dev Res 77 : 407-413, 2016. © 2016 Wiley Periodicals, Inc.
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11
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Datta J, Islam M, Dutta S, Roy S, Pan Q, Teknos TN. Suberoylanilide hydroxamic acid inhibits growth of head and neck cancer cell lines by reactivation of tumor suppressor microRNAs. Oral Oncol 2016; 56:32-9. [PMID: 27086484 DOI: 10.1016/j.oraloncology.2016.02.015] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2015] [Revised: 02/17/2016] [Accepted: 02/29/2016] [Indexed: 12/11/2022]
Abstract
BACKGROUND microRNAs negatively regulate gene expression at the post-transcriptional level. Mounting evidence shows that miR expression is deregulated in human cancers including head and neck squamous cell carcinoma (HNSCC). Epigenetically silenced tumor suppressor miRs may be re-expressed upon treatment with histone deacetylases inhibitors. Suberoylanilide Hydroxamic Acid (SAHA) is a histone deacetylase inhibitor that is currently being investigated in clinical trials for HNSCC. We hypothesized that SAHA will re-express a set of tumor suppressor miRs and enhance the efficacy of cisplatin and radiation in HNSCC. RESULTS In this study, miR expression profile was utilized to identify the tumor suppressor miRs that are re-expressed following SAHA treatment in HNSCC. Our data demonstrated that two tumor suppressor miRs, miR-107 and miR-138, were significantly up-regulated in CAL27 and SCC25 cell lines, following SAHA treatment. In addition to this, treatment with SAHA in a dose dependent manner significantly inhibited the cell proliferation, cell migration, and anchorage dependent clonogenic survival in CAL27 and SCC25 cell lines, respectively. Further, the expression of several oncogenes, PKCε, HIF1β, CDK6, and RhoC were down regulated in response to SAHA treatment. Additionally, we demonstrated that the combination treatment with SAHA and a chemotherapeutic drug cisplatin caused a significant reduction of cell growth compared to the single agent treatment. CONCLUSION Our data indicate that SAHA treatment results in reactivation of the silenced tumor suppressor miRs. Furthermore, this study emphasizes the usefulness of this drug as a novel combination therapy for HNSCC patients.
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Affiliation(s)
- Jharna Datta
- Comprehensive Cancer Center, The Ohio State University Wexner Medical Center, Columbus, OH 43210, USA.
| | - Mozaffarul Islam
- Department of Otolaryngology-Head and Neck Surgery, The Ohio State University Wexner Medical Center, Columbus, OH 43210, USA; Arthur G. James Cancer Hospital and Richard J. Solove Research Institute, The Ohio State University Wexner Medical Center, Columbus, OH 43210, USA; Comprehensive Cancer Center, The Ohio State University Wexner Medical Center, Columbus, OH 43210, USA
| | - Samidha Dutta
- Comprehensive Cancer Center, The Ohio State University Wexner Medical Center, Columbus, OH 43210, USA
| | - Sounak Roy
- Comprehensive Cancer Center, The Ohio State University Wexner Medical Center, Columbus, OH 43210, USA
| | - Quintin Pan
- Department of Otolaryngology-Head and Neck Surgery, The Ohio State University Wexner Medical Center, Columbus, OH 43210, USA; Arthur G. James Cancer Hospital and Richard J. Solove Research Institute, The Ohio State University Wexner Medical Center, Columbus, OH 43210, USA; Comprehensive Cancer Center, The Ohio State University Wexner Medical Center, Columbus, OH 43210, USA
| | - Theodoros N Teknos
- Department of Otolaryngology-Head and Neck Surgery, The Ohio State University Wexner Medical Center, Columbus, OH 43210, USA; Arthur G. James Cancer Hospital and Richard J. Solove Research Institute, The Ohio State University Wexner Medical Center, Columbus, OH 43210, USA; Comprehensive Cancer Center, The Ohio State University Wexner Medical Center, Columbus, OH 43210, USA
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12
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Lechner M, Fenton TR. The Genomics, Epigenomics, and Transcriptomics of HPV-Associated Oropharyngeal Cancer--Understanding the Basis of a Rapidly Evolving Disease. ADVANCES IN GENETICS 2016; 93:1-56. [PMID: 26915269 DOI: 10.1016/bs.adgen.2015.12.001] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Human papillomavirus (HPV) has been shown to represent a major independent risk factor for head and neck squamous cell cancer, in particular for oropharyngeal carcinoma. This type of cancer is rapidly evolving in the Western world, with rising trends particularly in the young, and represents a distinct epidemiological, clinical, and molecular entity. It is the aim of this review to give a detailed description of genomic, epigenomic, transcriptomic, and posttranscriptional changes that underlie the phenotype of this deadly disease. The review will also link these changes and examine what is known about the interactions between the host genome and viral genome, and investigate changes specific for the viral genome. These data are then integrated into an updated model of HPV-induced head and neck carcinogenesis.
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Affiliation(s)
- M Lechner
- Head and Neck Centre, University College London Hospital, London, UK; UCL Cancer Institute, University College London, London, United Kingdom
| | - T R Fenton
- UCL Cancer Institute, University College London, London, United Kingdom
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13
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Hadjimichael C, Chanoumidou K, Papadopoulou N, Arampatzi P, Papamatheakis J, Kretsovali A. Common stemness regulators of embryonic and cancer stem cells. World J Stem Cells 2015; 7:1150-1184. [PMID: 26516408 PMCID: PMC4620423 DOI: 10.4252/wjsc.v7.i9.1150] [Citation(s) in RCA: 136] [Impact Index Per Article: 13.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/03/2015] [Revised: 05/30/2015] [Accepted: 10/08/2015] [Indexed: 02/06/2023] Open
Abstract
Pluripotency of embryonic stem cells (ESCs) and induced pluripotent stem cells is regulated by a well characterized gene transcription circuitry. The circuitry is assembled by ESC specific transcription factors, signal transducing molecules and epigenetic regulators. Growing understanding of stem-like cells, albeit of more complex phenotypes, present in tumors (cancer stem cells), provides a common conceptual and research framework for basic and applied stem cell biology. In this review, we highlight current results on biomarkers, gene signatures, signaling pathways and epigenetic regulators that are common in embryonic and cancer stem cells. We discuss their role in determining the cell phenotype and finally, their potential use to design next generation biological and pharmaceutical approaches for regenerative medicine and cancer therapies.
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14
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Histone deacetylase inhibitors and epigenetic regulation in lymphoid malignancies. Invest New Drugs 2015; 33:1280-91. [PMID: 26423245 DOI: 10.1007/s10637-015-0290-y] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2015] [Accepted: 09/15/2015] [Indexed: 12/13/2022]
Abstract
A vast majority of lymphomas and leukaemias are results of translocations. These translocations produce various genetic and epigenetic changes that lead to oncogenesis. This opens an opportunity to use a relatively new class of anti-cancer agents, inhibitors of histone deacetylases (HDACi) to target lymphoid malignancies. Surprisingly, the rational basis for treatment of lymphomas with HDACi is far from clear, although some positive results have been obtained. Here we analyze the effect of histone deacetylase (HDAC) inhibitors on lymphoid malignancies.
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Karsli-Ceppioglu S, Dagdemir A, Judes G, Ngollo M, Penault-Llorca F, Pajon A, Bignon YJ, Bernard-Gallon D. Epigenetic mechanisms of breast cancer: an update of the current knowledge. Epigenomics 2015; 6:651-64. [PMID: 25531258 DOI: 10.2217/epi.14.59] [Citation(s) in RCA: 76] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
Epigenetic alterations are heritable changes in gene expression that occur without causing any change in DNA sequence. They are important key factors for cancer development and prognosis. Breast cancer is induced by the accumulation of altered gene regulation. Besides genetic mutations, epigenetics mechanisms have an important role in breast cancer tumorigenesis. Investigations related with aberrant epigenetic regulations in breast cancer focus on initiating molecular mechanisms in cancer development, identification of new biomarkers to predict breast cancer aggressiveness and the potential of epigenetic therapy. In this review, we will summarize the recent knowledge about the role of epigenetic alterations related with DNA methylation and histone modification in breast cancer. In addition, altered regulation of breast cancer specific genes and the potential of epigenetic therapy will be discussed according to epigenetic mechanisms.
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Abstract
Soy phytoestrogens are dietary components with considerable effects on reducing the incidence of prostate cancer. Epidemiological studies demonstrated that occurrence of prostate cancer is relatively low in Asia and Southern Europe, a status associated with consuming of soy isoflavones, such as genistein, daidzein, and glycitein. Soy phytoestrogens exert their activity on molecular mechanisms, including cell-cycle control, induction of apoptosis, inhibition of angiogenesis, and metastasis. In addition, they have antioxidant activity and show regulatory effect on the expression of genes involved in DNA damage and repair. Furthermore, the epigenetic regulation of gene expression can be modified by soy phytoestrogens. They show regulatory effects on gene activity by altering DNA methylation and/or histone modification patterns. In this chapter, we discuss the role of soy phytoestrogens on the genetic and epigenetic mechanisms of prostate cancer. We attempt to provide further insight in order to understand the underlying mechanisms of protective effects of soy phytoestrogens in preventing prostate cancer.
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Dastjerdi MN, Babazadeh Z, Salehi M, Hashemibeni B, Kazemi M. Comparison of the anti-cancer effect of Disulfiram and 5-Aza-CdR on pancreatic cancer cell line PANC-1. Adv Biomed Res 2014; 3:156. [PMID: 25221759 PMCID: PMC4162084 DOI: 10.4103/2277-9175.137866] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2013] [Accepted: 02/02/2014] [Indexed: 01/31/2023] Open
Abstract
Background: Pancreatic cancer has poor prognosis by surgical and chemotherapy when it is diagnosed, so other anti-cancerous assistant therapeutic drugs are suggested e.g. epigenetic reversal of tumor-suppressor genes on promoter hypermethylation. 5-Aza-CdR is a nucleoside analog of DNMTi but it has long-term cytotoxicity effects. This study compares the anticancer effect of 5-Aza-CdR and Disulfiram potencies on PANC-1 cell line and up-regulation of p21. Materials and Methods: PANC-1 cell line was cultured in DMEM high glucose and treated by 5-Aza-CdR with 5 and 10 μM concentration for four days and 13 μM DSF (Diulfiram) for 24 hours. MS-PCR and RT-PCR were carried out to detect the methylation pattern and estimate the mRNA expression of RASSF1A and p21 in PANC-1. Result: MS-PCR demonstrated partial unmethylation after treatment with 5-Aza-CdR while there was no unmethylated band after DSF treatment. RT-PCR showed significant differences between re-expression of RASSF1A before and after treatment with 10 μM 5-Aza-CdR (P < 0.01) but not after treatment with 13 μM DSF (P > 0.05). The significant correlation was observed between RASSF1A re-expression and p21 up-regulation before and after treatment with 10 μM 5-Aza-CdR (P < 0.01) but not after treatment with 13 μM DSF (P > 0.05), while p21 up-regulation was significantly higher after DSF treatment (P < 0.01). Conclusion: Our findings indicated that 5-Aza-CdR induces the re-expression of RASSF1A and p21 up-regulation in PANC-1. DSF showed no epigenetic reversion while it affected p21 up-regulation.
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Affiliation(s)
- Mehdi Nikbakht Dastjerdi
- Department of Anatomical Sciences and Molecular Biology, Faculty of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Zahra Babazadeh
- Department of Anatomical Sciences and Molecular Biology, Faculty of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Mansour Salehi
- Department of Anatomical Sciences and Molecular Biology, Faculty of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Batool Hashemibeni
- Department of Anatomical Sciences and Molecular Biology, Faculty of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Mohammad Kazemi
- Department of Anatomical Sciences and Molecular Biology, Faculty of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran
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Regulation of microRNAs by epigenetics and their interplay involved in cancer. JOURNAL OF EXPERIMENTAL & CLINICAL CANCER RESEARCH : CR 2013; 32:96. [PMID: 24261995 PMCID: PMC3874662 DOI: 10.1186/1756-9966-32-96] [Citation(s) in RCA: 99] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/21/2013] [Accepted: 11/14/2013] [Indexed: 12/15/2022]
Abstract
Similar to protein-coding genes, miRNAs are also susceptible to epigenetic modulation. Although numerous miRNAs have been shown to be affected by DNA methylation, the regulatory mechanism of histone modification on miRNA is not adequately understood. EZH2 and HDACs were recently identified as critical histone modifiers of deregulated miRNAs in cancer and can be recruited to a miRNA promoter by transcription factors such as MYC. Because miRNAs can modulate epigenetic architecture and can be regulated by epigenetic alteration, they could reasonably play an important role in mediating the crosstalk between epigenetic regulators. The complicated network between miRNAs and epigenetic machineries underlies the epigenetic–miRNA regulatory pathway, which is important in monitoring gene expression profiles. Regulation of miRNAs by inducing epigenetic changes reveals promising avenues for the design of innovative strategies in the fight against human cancer.
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Ramakrishnan S, Ellis L, Pili R. Histone modifications: implications in renal cell carcinoma. Epigenomics 2013; 5:453-62. [PMID: 23895657 DOI: 10.2217/epi.13.40] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022] Open
Abstract
In 2012, an estimated 64,770 men and women were diagnosed with malignancy of the kidney and renal pelvis, of which 13,570 succumbed to their disease. Common genetic aberrations in renal cell carcinomas (RCCs) include loss of function of the VHL gene in clear-cell RCC, overexpression of the c-MET gene in papillary RCC type I, deficiency in the FH gene in papillary RCC type II and loss of heterozygozity of the BHD gene in chromophobe RCC. Recent studies illustrate epigenetic silencing of VHL, as well as alterations in histone modifications and their governing enzymes. The possibility of reversing these epigenetic marks has resulted in efforts to target these changes by utilizing inhibitors of HDACs, DNA methyltransferases and, recently, histone methyltransferases in preclinical and clinical studies. This article focuses on potential therapeutic interventions, and the implications of histone modifications and related enzyme alterations in RCC.
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Affiliation(s)
- Swathi Ramakrishnan
- Roswell Park Cancer Institute, Department of Cancer Pathology & Prevention, Grace Cancer Drug Center, Buffalo, NY, USA
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Balasubramanian G, Kilambi N, Rathinasamy S, Rajendran P, Narayanan S, Rajagopal S. Quinolone-based HDAC inhibitors. J Enzyme Inhib Med Chem 2013; 29:555-62. [DOI: 10.3109/14756366.2013.827675] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022] Open
Affiliation(s)
| | | | | | - Praveen Rajendran
- Department of Biology, Drug Discovery Research, Orchid Chemicals & Pharmaceuticals Limited, R&D Center Chennai, Tamil NaduIndia
| | - Shridhar Narayanan
- Department of Biology, Drug Discovery Research, Orchid Chemicals & Pharmaceuticals Limited, R&D Center Chennai, Tamil NaduIndia
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Carneiro P, Figueiredo J, Bordeira-Carriço R, Fernandes MS, Carvalho J, Oliveira C, Seruca R. Therapeutic targets associated to E-cadherin dysfunction in gastric cancer. Expert Opin Ther Targets 2013; 17:1187-201. [PMID: 23957294 DOI: 10.1517/14728222.2013.827174] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
INTRODUCTION Epithelial cadherin (E-cadherin) plays a key role in epithelial cell-cell adhesion, contributing to tissue differentiation and homeostasis. Throughout the past decades, research has shed light on the molecular mechanisms underlying E-cadherin's role in tumor progression, namely in invasion and metastization. Emerging evidence established E-cadherin as a tumor suppressor and suggests that targeting E-cadherin or downstream signaling molecules may constitute effective cancer therapeutics. AREAS COVERED This review aims to cover E-cadherin-mediated signaling during cancer development and progression and highlight putative therapeutic targets. EXPERT OPINION Reconstitution of E-cadherin expression or targeting of E-cadherin downstream molecules holds promise in cancer therapies. Considering the high frequency of CDH1 promoter hypermethylation as a second hit in malignant lesions from hereditary diffuse gastric cancer patients, histone deacetylase inhibitors are potential therapeutic agents in combination with conventional chemotherapy, specifically in initial tumor stages. Concerning E-cadherin-mediated signaling, we propose that HER receptors (as epidermal growth factor receptor) and Notch downstream targets are clinically relevant and should be considered in gastric cancer therapeutics and control.
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Affiliation(s)
- Patrícia Carneiro
- IPATIMUP, Institute of Molecular Pathology and Immunology of the University of Porto , Rua Dr. Roberto Frias s/n, 4200-465 Porto , Portugal +00351 225570700 ; +00351 225570799 ;
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Starlard-Davenport A, Kutanzi K, Tryndyak V, Word B, Lyn-Cook B. Restoration of the methylation status of hypermethylated gene promoters by microRNA-29b in human breast cancer: A novel epigenetic therapeutic approach. J Carcinog 2013; 12:15. [PMID: 23961262 PMCID: PMC3746452 DOI: 10.4103/1477-3163.115720] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2012] [Accepted: 12/13/2012] [Indexed: 01/08/2023] Open
Abstract
It is well established that transcriptional silencing of critical tumor-suppressor genes by DNA methylation is a fundamental component in the initiation of breast cancer. However, the involvement of microRNAs (miRNAs) in restoring abnormal DNA methylation patterns in breast cancer is not well understood. Therefore, we investigated whether miRNA-29b, due to its complimentarity to the 3’- untranslated region of DNA methyltransferase 3A (DNMT3A) and DNMT3B, could restore normal DNA methylation patterns in human breast cancers and breast cancer cell lines. We demonstrated that transfection of pre-miRNA-29b into less aggressive MCF-7 cells, but not MDA-MB-231 mesenchymal cells, inhibited cell proliferation, decreased DNMT3A and DNMT3B messenger RNA (mRNA), and decreased promoter methylation status of ADAM23 , CCNA1, CCND2, CDH1, CDKN1C, CDKN2A, HIC1, RASSF1, SLIT2, TNFRSF10D, and TP73 tumor-suppressor genes. Using methylation polymerase chain reaction (PCR) arrays and real-time PCR, we also demonstrated that the methylation status of several critical tumor-suppressor genes increased as stage of breast disease increased, while miRNA-29b mRNA levels were significantly decreased in breast cancers versus normal breast. This increase in methylation status was accompanied by an increase in DNMT1 and DNMT3B mRNA in advanced stage of human breast cancers and in MCF-7, MDA-MB-361, HCC70, Hs-578T, and MDA-MB-231 breast cancer cells as compared to normal breast specimens and MCF-10-2A, a non-tumorigenic breast cell line, respectively. Our findings highlight the potential for a new epigenetic approach in improving breast cancer therapy by targeting DNMT3A and DNMT3B through miRNA-29b in non-invasive epithelial breast cancer cells.
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Wang YG, Wang N, Li GM, Fang WL, Wei J, Ma JL, Wang T, Shi M. Mechanisms of trichostatin A inhibiting AGS proliferation and identification of lysine-acetylated proteins. World J Gastroenterol 2013; 19:3226-3240. [PMID: 23745024 PMCID: PMC3671074 DOI: 10.3748/wjg.v19.i21.3226] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/16/2013] [Revised: 03/21/2013] [Accepted: 04/09/2013] [Indexed: 02/06/2023] Open
Abstract
AIM To explore the effect of lysine acetylation in related proteins on regulation of the proliferation of gastric cancer cells, and determine the lysine-acetylated proteins and the acetylated modified sites in AGS gastric cancer cells. METHODS The CCK-8 experiment and flow cytometry were used to observe the changes in proliferation and cycle of AGS cells treated with trichostatin A (TSA). Real time polymerase chain reaction and Western blotting were used to observe expression changes in p21, p53, Bax, Bcl-2, CDK2, and CyclinD1 in gastric cancer cells exposed to TSA. Cytoplasmic proteins in gastric cancer cells before and after TSA treatment were immunoprecipitated with anti-acetylated lysine antibodies, separated using sodium dodecyl sulfate polyacrylamide gel electrophoresis gel and silver-stained to detect the proteins by mass spectrometry after removal of the gel. The acetylated proteins in AGS cells were enriched with lysine-acetylated antibodies, and a high-resolution mass spectrometer was used to detect the acetylated proteins and modified sites. RESULTS TSA significantly inhibited AGS cell proliferation, and promoted cell apoptosis, leading to AGS cell cycle arrest in G0/G1 and G2/M phases, especially G0/G1 phase. p21, p53 and Bax gene expression levels in AGS cells were increased with TSA treatment duration; Bcl-2, CDK2, and CyclinD1 gene expression levels were decreased with TSA treatment duration. Two unknown protein bands, 72 kDa (before exposure to TSA) and 28 kDa (after exposure to TSA), were identified by silver-staining after immunoprecipitation of AGS cells with the lysine-acetylated monoclonal antibodies. Mass spectrometry showed that the 72 kDa protein band may be PKM2 and the 28 kDa protein band may be ATP5O. The acetylated proteins and modified sites in AGS cells were determined. CONCLUSION TSA can inhibit gastric cancer cell proliferation, which possibly activated signaling pathways in a variety of tumor-associated factors. ATP5O was obviously acetylated in AGS cells following TSA treatment.
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Friso S, Udali S, Guarini P, Pellegrini C, Pattini P, Moruzzi S, Girelli D, Pizzolo F, Martinelli N, Corrocher R, Olivieri O, Choi SW. Global DNA hypomethylation in peripheral blood mononuclear cells as a biomarker of cancer risk. Cancer Epidemiol Biomarkers Prev 2013; 22:348-55. [PMID: 23300023 DOI: 10.1158/1055-9965.epi-12-0859] [Citation(s) in RCA: 54] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022] Open
Abstract
BACKGROUND Global DNA hypomethylation is an early molecular event in carcinogenesis. Whether methylation measured in peripheral blood mononuclear cells (PBMCs) DNA is a clinically reliable biomarker for early detection or cancer risk assessment is to be established. METHODS From an original sample-set of 753 male and female adults (ages 64.8 ± 7.3 years), PBMCs DNA methylation was measured in 68 subjects with history of cancer at time of enrollment and 62 who developed cancer during follow-up. Age- and sex-matched controls for prevalent and incident cancer cases (n = 68 and 58, respectively) were also selected. Global DNA methylation was assessed by liquid chromatography/mass spectrometry (LC/MS). Methylenetetrahydrofolate reductase (MTHFR) 677C>T genotype and plasma folate concentrations were also determined for the known gene-nutrient interaction affecting DNA methylation. RESULTS Cancer subjects had significantly lower PBMCs-DNA methylation than controls [4.39 (95% confidence intervals (CI), 4.25-4.53) vs. 5.13 (95% CI, 5.03-5.21) %mCyt/(mCyt+Cyt); P < 0.0001]. A DNA methylation threshold of 4.74% clearly categorized patients with cancer from controls so that those with DNA methylation less than 4.74% showed an increased prevalence of cancer than those with higher levels (91.5% vs. 19%; P < 0.001). Subjects with cancer at follow-up had, already at enrollment, reduced DNA methylation as compared with controls [4.34 (95% CI, 4.24-4.51) vs. 5.08 (95% CI, 5.05-5.22) %mCyt/(mCyt+Cyt); P < 0.0001]. Moreover, MTHFR677C>T genotype and folate interact for determining DNA methylation, so that MTHFR677TT carriers with low folate had the lowest DNA methylation and concordantly showed a higher prevalence of cancer history (OR, 7.04; 95% CI, 1.52-32.63; P = 0.013). CONCLUSIONS Genomic PBMCs-DNA methylation may be a useful epigenetic biomarker for early detection and cancer risk estimation. IMPACT This study identifies a threshold for PBMCs-DNA methylation to detect cancer-affected from cancer-free subjects and an at-risk condition for cancer based on genomic DNA methylation and MTHFR677C>T-folate status.
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Affiliation(s)
- Simonetta Friso
- Corresponding Author: Simonetta Friso, Department of Medicine, University of Verona School of Medicine, Policlinico G.B. Rossi, P.le L.A. Scuro, 10, 37134 Verona, Italy.
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Cho HS, Toyokawa G, Daigo Y, Hayami S, Masuda K, Ikawa N, Yamane Y, Maejima K, Tsunoda T, Field HI, Kelly JD, Neal DE, Ponder BAJ, Maehara Y, Nakamura Y, Hamamoto R. The JmjC domain-containing histone demethylase KDM3A is a positive regulator of the G1/S transition in cancer cells via transcriptional regulation of the HOXA1 gene. Int J Cancer 2012; 131:E179-89. [PMID: 22020899 DOI: 10.1002/ijc.26501] [Citation(s) in RCA: 75] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2011] [Accepted: 09/28/2011] [Indexed: 11/08/2022]
Abstract
A number of histone demethylases have been identified and biochemically characterized, yet their biological functions largely remain uncharacterized, particularly in the context of human diseases such as cancer. In this study, we describe important roles for the histone demethylase KDM3A, also known as JMJD1A, in human carcinogenesis. Expression levels of KDM3A were significantly elevated in human bladder carcinomas compared with nonneoplastic bladder tissues (p < 0.0001), when assessed by real-time PCR. We confirmed that some other cancers including lung cancer also overexpressed KDM3A, using cDNA microarray analysis. Treatment of cancer cell lines with small interfering RNA targeting KDM3A significantly knocked down its expression and resulted in the suppression of proliferation. Importantly, we found that KDM3A activates transcription of the HOXA1 gene through demethylating histone H3 at lysine 9 di-methylation by binding to its promoter region. Indeed, expression levels of KDM3A and HOXA1 in several types of cancer cell lines and bladder cancer samples were statistically correlated. We observed the down-regulation of HOXA1 as well as CCND1 after treatment with KDM3A siRNA, indicating G(1) arrest of cancer cells. Together, our results suggest that elevated expression of KDM3A plays a critical role in the growth of cancer cells, and further studies may reveal a cancer therapeutic potential in KDM3A inhibition.
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Affiliation(s)
- Hyun-Soo Cho
- Laboratory of Molecular Medicine, Human Genome Center, Institute of Medical Science, The University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, Tokyo, Japan
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Yang XX, Sun JZ, Li FX, Wu YS, Du HY, Zhu W, Li XH, Li M. Aberrant methylation and downregulation of sall3 in human hepatocellular carcinoma. World J Gastroenterol 2012; 18:2719-26. [PMID: 22690083 PMCID: PMC3370011 DOI: 10.3748/wjg.v18.i21.2719] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/09/2011] [Revised: 10/27/2011] [Accepted: 04/28/2012] [Indexed: 02/06/2023] Open
Abstract
AIM: To investigated whether sall3 transcription was regulated by promoter CpG island hypermethylation in hepatocellular carcinoma (HCC).
METHODS: The cell lines Huh7, HepG2, SK-HEP1, SMMC7721, Bel7402, QGY7703 and a cohort of 38 HCC tissue specimens and corresponding nontumorous tissues were subjected to analysis for sall3 promoter CpG island methylation and mRNA transcription. sall3 promoter CpG island methylation levels were determined using the MassARRAY platform and mRNA transcription levels of the gene were detected by quantitative real-time polymerase chain reaction.
RESULTS: The levels of sall3 mRNA were decreased by more than twofold in 33 of 38 tumor tissues compared to adjacent noncancerous tissues. Among these 33 tumor tissues with lower levels of sall3 mRNA, 24 showed higher levels of methylation. Based on these results, we hypothesized that the decrease in sall3 mRNA transcription level was likely due to promoter CpG island hypermethylation. Changes in sall3 mRNA transcription and promoter CpG island methylation were determined in the above six cell lines after treatment with 0, 0.1, 0.5 and 2.5 μmol 5-aza-2-deoxycytidine, a demethylating agent. Promoter CpG island methylation levels decreased in a dose-dependent manner in all six cell lines, while the mRNA transcription level increased dose-dependently in Huh7, HepG2, SK-HEP1 and SMMC7721 cells and irregularly in Bel7402 and QGY7703 cells.
CONCLUSION: These results indicated that promoter CpG island hypermethylation contributes to the downregulation of sall3 mRNA transcription in HCC.
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Yacqub-Usman K, Richardson A, Duong CV, Clayton RN, Farrell WE. The pituitary tumour epigenome: aberrations and prospects for targeted therapy. Nat Rev Endocrinol 2012; 8:486-94. [PMID: 22525730 DOI: 10.1038/nrendo.2012.54] [Citation(s) in RCA: 34] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Abstract
Global and gene-specific changes in the epigenome are hallmarks of most tumour types, including those of pituitary origin. In contrast to genetic mutations, epigenetic changes (aberrant DNA methylation and histone modifications) are potentially reversible. Drugs that specifically target or inhibit DNA methyltransferases (DNMTs) and histone deacetylases (HDACs) can be used to restore the expression of epigenetically silenced genes. These drugs can potentially increase the sensitivity of tumour cells to conventional treatment modalities, such as chemotherapy and radiotherapy. Drug-induced reversal of transcriptional silencing can also be used to restore dopamine-D(2)-receptor-negative, hormone-refractory tumours to their previous receptor-positive, hormone-responsive status. Synergy between HDAC and DNMT inhibitors makes these pharmacological agents more therapeutically effective when administered in combination than when used alone. Studies in pituitary tumour cell lines show that drug-induced re-expression of the epigenetically silenced dopamine D(2) receptor leads to an increase in apoptosis mediated by a receptor agonist. Collectively, the use of drugs to directly or indirectly reverse gene-specific epigenetic changes, in combination with conventional therapeutic interventions, has potential for the clinical management of multiple tumour types-including those of pituitary origin. Furthermore, these drugs can be used to identify epigenetically regulated genes that could be novel, tumour-specific therapeutic targets.
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Affiliation(s)
- Kiren Yacqub-Usman
- Human Disease and Genomics Group, Institute of Science and Technology in Medicine, School of Medicine, Keele University, Stoke-on-Trent, Staffordshire ST4 7QB, UK
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Toyokawa G, Cho HS, Iwai Y, Yoshimatsu M, Takawa M, Hayami S, Maejima K, Shimizu N, Tanaka H, Tsunoda T, Field HI, Kelly JD, Neal DE, Ponder BAJ, Maehara Y, Nakamura Y, Hamamoto R. The histone demethylase JMJD2B plays an essential role in human carcinogenesis through positive regulation of cyclin-dependent kinase 6. Cancer Prev Res (Phila) 2011; 4:2051-61. [PMID: 21930796 DOI: 10.1158/1940-6207.capr-11-0290] [Citation(s) in RCA: 54] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
Histone methyltransferases and demethylases are known to regulate transcription by altering the epigenetic marks on histones, but the pathologic roles of their dysfunction in human diseases, such as cancer, still remain to be elucidated. Herein, we show that the histone demethylase JMJD2B is involved in human carcinogenesis. Quantitative real-time PCR showed notably elevated levels of JMJD2B expression in bladder cancers, compared with corresponding nonneoplastic tissues (P < 0.0001), and elevated protein expression was confirmed by immunohistochemistry. In addition, cDNA microarray analysis revealed transactivation of JMJD2B in lung cancer, and immunohistochemical analysis showed protein overexpression in lung cancer. siRNA-mediated reduction of expression of JMJD2B in bladder and lung cancer cell lines significantly suppressed the proliferation of cancer cells, and suppressing JMJD2B expression lead to a decreased population of cancer cells in S phase, with a concomitant increase of cells in G(1) phase. Furthermore, a clonogenicity assay showed that the demethylase activity of JMJD2B possesses an oncogenic activity. Microarray analysis after knockdown of JMJD2B revealed that JMJD2B could regulate multiple pathways which contribute to carcinogenesis, including the cell-cycle pathway. Of the downstream genes, chromatin immunoprecipitation showed that CDK6 (cyclin-dependent kinase 6), essential in G(1)-S transition, was directly regulated by JMJD2B, via demethylation of histone H3-K9 in its promoter region. Expression levels of JMJD2B and CDK6 were significantly correlated in various types of cell lines. Deregulation of histone demethylation resulting in perturbation of the cell cycle, represents a novel mechanism for human carcinogenesis and JMJD2B is a feasible molecular target for anticancer therapy.
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Affiliation(s)
- Gouji Toyokawa
- Laboratory of Molecular Medicine, Human Genome Center, Institute of Medical Science, The University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, Tokyo 108-8639, Japan
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Ulucan O, Keskin O, Erman B, Gursoy A. A comparative molecular dynamics study of methylation state specificity of JMJD2A. PLoS One 2011; 6:e24664. [PMID: 21931800 PMCID: PMC3172282 DOI: 10.1371/journal.pone.0024664] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2011] [Accepted: 08/16/2011] [Indexed: 11/19/2022] Open
Abstract
Histone modifications have great importance in epigenetic regulation. JMJD2A is a histone demethylase which is selective for di- and trimethyl forms of residues Lys9 and Lys36 of Histone 3 tail (H3K9 and H3K36). We present a molecular dynamics simulations of mono-, di- and trimethylated histone tails in complex with JMJD2A catalytic domain to gain insight into how JMJD2A discriminates between the methylation states of H3K9. The methyl groups are located at specific distances and orientations with respect to Fe(II) in methylammonium binding pocket. For the trimethyllysine the mechanism which provides the effectual orientation of methyl groups is the symmetry, whereas for the dimethyllysine case the determining factors are the interactions between methyllysine head and its environment and subsequently the restriction on angular motion. The occurrence frequency of methyl groups in a certain proximity of Fe(II) comes out as the explanation of the enzyme activity difference on di- and tri-methylated peptides. Energy analysis suggests that recognition is mostly driven by van der Waals and followed by Coulombic interactions in the enzyme-substrate interface. The number (mono, di or tri) and orientations of methyl groups and water molecules significantly affect the extent of van der Waals interaction strengths. Hydrogen bonding analysis suggests that the interaction between JMJD2A and its substrates mainly comes from main chain-side chain interactions. Binding free energy analysis points out Arg8 as an important residue forming an intra-substrate hydrogen bond with tri and dimethylated Lys9 of the H3 chain. Our study provides new insights into how JMJD2A discriminates between its substrates from both a structural and dynamical point of view.
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Affiliation(s)
- Ozlem Ulucan
- Center for Computational Biology and Bioinformatics and College of Engineering, Koc University, Istanbul, Turkey
| | - Ozlem Keskin
- Center for Computational Biology and Bioinformatics and College of Engineering, Koc University, Istanbul, Turkey
| | - Burak Erman
- Center for Computational Biology and Bioinformatics and College of Engineering, Koc University, Istanbul, Turkey
| | - Attila Gursoy
- Center for Computational Biology and Bioinformatics and College of Engineering, Koc University, Istanbul, Turkey
- * E-mail:
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Ari F, Napieralski R, Ulukaya E, Dere E, Colling C, Honert K, Krüger A, Kiechle M, Schmitt M. Modulation of protein expression levels and DNA methylation status of breast cancer metastasis genes by anthracycline-based chemotherapy and the demethylating agent decitabine. Cell Biochem Funct 2011; 29:651-9. [DOI: 10.1002/cbf.1801] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2011] [Revised: 06/07/2011] [Accepted: 08/01/2011] [Indexed: 01/13/2023]
Affiliation(s)
- Ferda Ari
- Department of Biology; Faculty of Science and Art; Uludag University; Bursa; Turkey
| | - Rudolf Napieralski
- Department of Obstetrics and Gynecology; Technische Universitaet Muenchen; Klinikum rechts der Isar; Munich; Germany
| | - Engin Ulukaya
- Department of Medical Biochemistry; Medical School of Uludag University; Bursa; Turkey
| | - Egemen Dere
- Department of Biology; Faculty of Science and Art; Uludag University; Bursa; Turkey
| | - Christoph Colling
- Department of Obstetrics and Gynecology; Technische Universitaet Muenchen; Klinikum rechts der Isar; Munich; Germany
| | - Katja Honert
- Institute for Experimental Oncology and Therapy Research; Technische Universitaet Muenchen; Klinikum rechts der Isar; Munich; Germany
| | - Achim Krüger
- Institute for Experimental Oncology and Therapy Research; Technische Universitaet Muenchen; Klinikum rechts der Isar; Munich; Germany
| | - Marion Kiechle
- Department of Obstetrics and Gynecology; Technische Universitaet Muenchen; Klinikum rechts der Isar; Munich; Germany
| | - Manfred Schmitt
- Department of Obstetrics and Gynecology; Technische Universitaet Muenchen; Klinikum rechts der Isar; Munich; Germany
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31
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Cai FF, Kohler C, Zhang B, Wang MH, Chen WJ, Zhong XY. Epigenetic therapy for breast cancer. Int J Mol Sci 2011; 12:4465-87. [PMID: 21845090 PMCID: PMC3155363 DOI: 10.3390/ijms12074465] [Citation(s) in RCA: 32] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2011] [Revised: 06/30/2011] [Accepted: 07/01/2011] [Indexed: 01/21/2023] Open
Abstract
Both genetic and epigenetic alterations can control the progression of cancer. Genetic alterations are impossible to reverse, while epigenetic alterations are reversible. This advantage suggests that epigenetic modifications should be preferred in therapy applications. DNA methyltransferases and histone deacetylases have become the primary targets for studies in epigenetic therapy. Some DNA methylation inhibitors and histone deacetylation inhibitors are approved by the US Food and Drug Administration as anti-cancer drugs. Therefore, the uses of epigenetic targets are believed to have great potential as a lasting favorable approach in treating breast cancer.
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Affiliation(s)
- Feng-Feng Cai
- Laboratory for Gynecological Oncology, Department of Biomedicine, Women’s Hospital, University of Basel, Hebelstrasse 20, Room 420, Basel, CH 4031, Switzerland; E-Mails: (F.-F.C.); (C.K.); (B.Z.); (W.-J.C.)
| | - Corina Kohler
- Laboratory for Gynecological Oncology, Department of Biomedicine, Women’s Hospital, University of Basel, Hebelstrasse 20, Room 420, Basel, CH 4031, Switzerland; E-Mails: (F.-F.C.); (C.K.); (B.Z.); (W.-J.C.)
| | - Bei Zhang
- Laboratory for Gynecological Oncology, Department of Biomedicine, Women’s Hospital, University of Basel, Hebelstrasse 20, Room 420, Basel, CH 4031, Switzerland; E-Mails: (F.-F.C.); (C.K.); (B.Z.); (W.-J.C.)
| | - Ming-Hong Wang
- Department of General Practice Medicine, Zhongda Hospital of Southeast University, Nanjing 210009, Jiangsu, China; E-Mail:
| | - Wei-Jie Chen
- Laboratory for Gynecological Oncology, Department of Biomedicine, Women’s Hospital, University of Basel, Hebelstrasse 20, Room 420, Basel, CH 4031, Switzerland; E-Mails: (F.-F.C.); (C.K.); (B.Z.); (W.-J.C.)
| | - Xiao-Yan Zhong
- Laboratory for Gynecological Oncology, Department of Biomedicine, Women’s Hospital, University of Basel, Hebelstrasse 20, Room 420, Basel, CH 4031, Switzerland; E-Mails: (F.-F.C.); (C.K.); (B.Z.); (W.-J.C.)
- Author to whom correspondence should be addressed; E-Mail: ; Tel.: +41-612-659-248; Fax: +41-612-659-399
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32
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Morris KV, Vogt PK. Long antisense non-coding RNAs and their role in transcription and oncogenesis. Cell Cycle 2011; 9:2544-7. [PMID: 20581457 DOI: 10.4161/cc.9.13.12145] [Citation(s) in RCA: 47] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/16/2023] Open
Abstract
Long non-coding RNAs are estimated to qualitatively represent ~98% of expressed transcripts in human cells, a large proportion of which is antisense to protein-coding and non-coding transcripts. Here we review evidence from several experimental systems that suggests long antisense non-coding RNAs are involved in the transcriptional regulation of gene expression by altering epigenetic states at both adjacent and distal loci. We also review the initial evidence for a role of endogenous long antisense non-coding RNAs in oncogenic cellular transformation.
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Affiliation(s)
- Kevin V Morris
- Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, CA, USA.
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33
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Sensitive measurement of unmethylated repeat DNA sequences by end-specific PCR. Biotechniques 2011; 49:xiii-xvii. [PMID: 20964632 DOI: 10.2144/000113494] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/23/2022] Open
Abstract
We describe a new method that is well-suited for the determination of the methylation level of repetitive sequences such as human Alu elements. We have applied the method to the analysis of cell and tissue DNAs and expect it to have wide utility in studies of DNA methylation in cancer and other disease states, in monitoring response to epigenetic cancer therapies and in epidemiological studies. Only 1 ng DNA is needed for a duplex, one-tube real-time PCR in which methylation level and the amount of input DNA are concurrently measured. The relative cutting by the methylation-sensitive enzyme BstUI is compared with that of the methylation-insensitive enzyme DraI to give a measure of DNA methylation. The method depends upon the use of 5'-tailed, 3'-blocked oligonucleotides called facilitator oligonucleotides (Foligos). Only cut DNAs with specific matching sequences at their 3' ends can copy the tails of the Foligos and thus become tagged and available for subsequent PCR. Both the tagging and PCR are carried out by the same enzyme, Taq DNA polymerase. Because amplification only occurs if suitable ends have been generated in the target DNA, we have called this method end-specific PCR (ESPCR). ESPCR avoids the bisulfite treatment step that is usually required to measure methylation.
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Zac1 is a histone acetylation-regulated NF-κB suppressor that mediates histone deacetylase inhibitor-induced apoptosis. Cell Death Differ 2011; 18:1825-35. [PMID: 21546906 DOI: 10.1038/cdd.2011.51] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/21/2023] Open
Abstract
Histone deacetylase (HDAC) inhibitors are a class of promising anticancer reagents. They are able to induce apoptosis in embryonic carcinoma (EC) cells. However, the underlying mechanism remains poorly understood. Here we show that increased expression of zinc-finger protein regulator of apoptosis and cell-cycle arrest (Zac1) is implicated in HDAC inhibitor-induced apoptosis in F9 and P19 EC cells. By chromatin immunoprecipitation analysis we identified that increased Zac1 expression is mediated by histone acetylation of the Zac1 promoter region. Knockdown of Zac1 inhibited HDAC inhibitor-induced cell apoptosis. Moreover, HDAC inhibitors repressed nuclear factor-κB (NF-κB) activity, and this effect is abrogated by Zac1 knockdown. Consistently, Zac1 overexpression suppressed cellular NF-κB activity. Further investigation showed that Zac1 inhibits NF-κB activity by interacting with the C-terminus of the p65 subunit, which suppresses the phosphorylation of p65 at Ser468 and Ser536 residues. These results indicate that Zac1 is a histone acetylation-regulated suppressor of NF-κB, which is induced and implicated in HDAC inhibitor-mediated EC cell apoptosis.
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35
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Hatziapostolou M, Iliopoulos D. Epigenetic aberrations during oncogenesis. Cell Mol Life Sci 2011; 68:1681-702. [PMID: 21249513 PMCID: PMC11114845 DOI: 10.1007/s00018-010-0624-z] [Citation(s) in RCA: 125] [Impact Index Per Article: 8.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2010] [Revised: 12/02/2010] [Accepted: 12/28/2010] [Indexed: 12/18/2022]
Abstract
The aberrant epigenetic landscape of a cancer cell is characterized by global genomic hypomethylation, CpG island promoter hypermethylation of tumor suppressor genes, and changes in histone modification patterns, as well as altered expression profiles of chromatin-modifying enzymes. Recent advances in the field of epigenetics have revealed that microRNAs' expression is also under epigenetic regulation and that certain microRNAs control elements of the epigenetic machinery. The reversibility of epigenetic marks catalyzed the development of epigenetic-altering drugs. However, a better understanding of the intertwined relationship between genetics, epigenetics and microRNAs is necessary in order to resolve how gene expression aberrations that contribute to tumorigenesis can be therapeutically corrected.
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Affiliation(s)
- Maria Hatziapostolou
- Department of Cancer Immunology & AIDS, Dana-Farber Cancer Institute, Boston, MA 02115 USA
- Department of Pathology, Harvard Medical School, Boston, MA 02115 USA
| | - Dimitrios Iliopoulos
- Department of Cancer Immunology & AIDS, Dana-Farber Cancer Institute, Boston, MA 02115 USA
- Department of Pathology, Harvard Medical School, Boston, MA 02115 USA
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Abstract
Over the past few years several drugs that target epigenetic modifications have shown clinical benefits, thus seemingly validating epigenetic cancer therapy. More recently, however, it has become clear that these drugs are either characterized by low specificity or that their target enzymes have low substrate specificity. As such, clinical proof-of-concept for epigenetic cancer therapies remains to be established. Human cancers are characterized by widespread changes in their genomic DNA methylation and histone modification patterns. Epigenetic cancer therapy aims to restore normal epigenetic modification patterns through the inhibition of epigenetic modifier enzymes. In this review, we provide an overview about the known functional roles of DNA methyltransferases, histone deacetylases, histone methyltransferases, and demethylases in cancer development. The available data identify several examples that warrant further consideration as drug targets. Future research should be directed toward targeted enzyme inhibition and toward exploring interactions between epigenetic pathways to maximize cancer specificity.
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Affiliation(s)
- Cora Mund
- Global Drug Discovery, Research and Development, Bayer Schering Pharma, Berlin, Germany
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37
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Nguyen T, Kuo C, Nicholl MB, Sim MS, Turner RR, Morton DL, Hoon DSB. Downregulation of microRNA-29c is associated with hypermethylation of tumor-related genes and disease outcome in cutaneous melanoma. Epigenetics 2011; 6:388-94. [PMID: 21081840 PMCID: PMC3063331 DOI: 10.4161/epi.6.3.14056] [Citation(s) in RCA: 146] [Impact Index Per Article: 10.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2010] [Accepted: 10/30/2010] [Indexed: 12/16/2022] Open
Abstract
Hypermethylation of the promoter region of tumor-related genes (TRGs) has been shown to silence gene expression during melanoma progression, whereas microRNA-29(miR-29) has been found to downregulate DNA methyltransferases DNMT3A and DNMT3B which were shown as essential to the methylation of TRGs. We hypothesized that the expression level of miR-29 is associated to TRG methylation status and may have prognostic utility in melanoma. AJCC stage I-IV cutaneous melanoma paraffin-embedded archival tissue (PEAT) specimens (n=149) were assessed. Expression of miR-29 isoforms a, b, and c were analyzed by reverse-transcription quantitative real-time polymerase chain reaction(RT-qPCR). Expression of DNMT3A and DNMT3B was assessed by immunohistochemistry(IHC) on defined clinically annotated tissue microarrays (TMA) of AJCC stage III melanoma lymph node metastases. Promoter region CpG island methylation status of RASSF1A, TFPI-2, RAR-β, SOCS, GATA4 and genomic repeat sequence MINT17 and MINT31 were previously evaluated in melanoma tissues. Only miR-29c isoform expression was correlated to advancing AJCC stages in melanoma. miR-29c expression was significantly downregulated in AJCC stage IV melanoma tumors compared to primary melanomas. Hypermethylation status of TRGs and non-coding MINT loci in different stages of melanoma showed an inverse association with miR-29c expression. Overall, an increase in miR-29c expression inversely correlated to both DNMT3A and DNMT3B protein expression in melanomas. Expression of DNMT3B and miR-29c were significantly (p=0.004 and p=0.002, respectively) associated with overall survival(OS) in AJCC stage III melanoma patients by multivariate analysis. The studies demonstrated that both miR-29c and DNMT3B have significant roles in melanoma progression, and may be useful epigenetic biomarkers for disease outcome.
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Affiliation(s)
- Tung Nguyen
- Department of Molecular Oncology, John Wayne Cancer Institute, Saint John's Health Center, Santa Monica, CA, USA
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Sun S, Chen Z, Yan PS, Huang YW, Huang THM, Lin S. Identifying hypermethylated CpG islands using a quantile regression model. BMC Bioinformatics 2011; 12:54. [PMID: 21324121 PMCID: PMC3051900 DOI: 10.1186/1471-2105-12-54] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2010] [Accepted: 02/15/2011] [Indexed: 12/25/2022] Open
Abstract
BACKGROUND DNA methylation has been shown to play an important role in the silencing of tumor suppressor genes in various tumor types. In order to have a system-wide understanding of the methylation changes that occur in tumors, we have developed a differential methylation hybridization (DMH) protocol that can simultaneously assay the methylation status of all known CpG islands (CGIs) using microarray technologies. A large percentage of signals obtained from microarrays can be attributed to various measurable and unmeasurable confounding factors unrelated to the biological question at hand. In order to correct the bias due to noise, we first implemented a quantile regression model, with a quantile level equal to 75%, to identify hypermethylated CGIs in an earlier work. As a proof of concept, we applied this model to methylation microarray data generated from breast cancer cell lines. However, we were unsure whether 75% was the best quantile level for identifying hypermethylated CGIs. In this paper, we attempt to determine which quantile level should be used to identify hypermethylated CGIs and their associated genes. RESULTS We introduce three statistical measurements to compare the performance of the proposed quantile regression model at different quantile levels (95%, 90%, 85%, 80%, 75%, 70%, 65%, 60%), using known methylated genes and unmethylated housekeeping genes reported in breast cancer cell lines and ovarian cancer patients. Our results show that the quantile levels ranging from 80% to 90% are better at identifying known methylated and unmethylated genes. CONCLUSIONS In this paper, we propose to use a quantile regression model to identify hypermethylated CGIs by incorporating probe effects to account for noise due to unmeasurable factors. Our model can efficiently identify hypermethylated CGIs in both breast and ovarian cancer data.
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Affiliation(s)
- Shuying Sun
- Case Comprehensive Cancer Center, Case Western Reserve University, Cleveland, Ohio, USA.
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39
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Taberlay PC, Jones PA. DNA methylation and cancer. PROGRESS IN DRUG RESEARCH. FORTSCHRITTE DER ARZNEIMITTELFORSCHUNG. PROGRES DES RECHERCHES PHARMACEUTIQUES 2011; 67:1-23. [PMID: 21141722 DOI: 10.1007/978-3-7643-8989-5_1] [Citation(s) in RCA: 51] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Subscribe] [Scholar Register] [Indexed: 12/25/2022]
Abstract
DNA methylation acts in concert with other epigenetic mechanisms to regulate normal gene expression and facilitate chromatin organization within cells. Aberrant DNA methylation patterns are acquired during carcinogenic transformation; such events are often accompanied by alterations in chromatin structure at gene regulatory regions. The expression pattern of any given gene is achieved by interacting epigenetic mechanisms. First, the insertion of nucleosomes at transcriptional start sites prevents the binding of the transcriptional machinery and additional cofactors that initiate gene expression. Second, nucleosomes anchor all of the DNMT3A and DNMT3B methyltransferase proteins in the cell, which suggests a role for histone octamers in the establishment of DNA methylation patterns. During carcinogenesis, epigenetic switching and 5-methylcytosine reprogramming result in the aberrant hypermethylation of CpG islands, reducing epigenetic plasticity of critical developmental and tumor suppressor genes, rendering them unresponsive to normal stimuli. Here, we will discuss the importance of both established and novel molecular concepts that may underlie the role of DNA methylation in cancer.
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Affiliation(s)
- Phillippa C Taberlay
- Department of Urology, Biochemistry and Molecular Biology, USC/Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, California 90033, USA
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40
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Wiklund ED, Kjems J, Clark SJ. Epigenetic architecture and miRNA: reciprocal regulators. Epigenomics 2010; 2:823-40. [DOI: 10.2217/epi.10.51] [Citation(s) in RCA: 32] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022] Open
Abstract
Deregulation of epigenetic and miRNA pathways are emerging as key events in carcinogenesis. miRNA genes can be epigenetically regulated and miRNAs can themselves repress key enzymes that drive epigenetic remodeling. Epigenetic and miRNA functions are thus tightly interconnected and crucial for maintaining correct local and global genomic architecture as well as gene-expression patterns, yet the underlying molecular mechanisms and their widespread effects remain poorly understood. Owing to the tissue specificity, versatility and relative stability of miRNAs, these small ncRNAs are considered especially promising in clinical applications, and their biogenesis and function is subject of active research. In this article, the current status of epigenetic miRNA regulation is summarized and future therapeutic prospects in the field are discussed with a focus on cancer.
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Affiliation(s)
| | - Jørgen Kjems
- Department of Molecular Biology, Aarhus University, 8000 Aarhus C, Denmark
| | - Susan J Clark
- Cancer Research Program, Garvan Institute of Medical Research, 2010 Darlinghurst NSW, Australia
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41
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Kimura H, Hayashi-Takanaka Y, Yamagata K. Visualization of DNA methylation and histone modifications in living cells. Curr Opin Cell Biol 2010; 22:412-8. [DOI: 10.1016/j.ceb.2010.02.004] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2010] [Revised: 02/10/2010] [Accepted: 02/11/2010] [Indexed: 01/13/2023]
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Gieni RS, Hendzel MJ. Polycomb group protein gene silencing, non-coding RNA, stem cells, and cancer. Biochem Cell Biol 2010; 87:711-46. [PMID: 19898523 DOI: 10.1139/o09-057] [Citation(s) in RCA: 62] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
Epigenetic programming is an important facet of biology, controlling gene expression patterns and the choice between developmental pathways. The Polycomb group proteins (PcGs) silence gene expression, allowing cells to both acquire and maintain identity. PcG silencing is important for stemness, X chromosome inactivation (XCI), genomic imprinting, and the abnormally silenced genes in cancers. Stem and cancer cells commonly share gene expression patterns, regulatory mechanisms, and signalling pathways. Many microRNA species have oncogenic or tumor suppressor activity, and disruptions in these networks are common in cancer; however, long non-coding (nc)RNA species are also important. Many of these directly guide PcG deposition and gene silencing at the HOX locus, during XCI, and in examples of genomic imprinting. Since inappropriate HOX expression and loss of genomic imprinting are hallmarks of cancer, disruption of long ncRNA-mediated PcG silencing likely has a role in oncogenesis. Aberrant silencing of coding and non-coding loci is critical for both the genesis and progression of cancers. In addition, PcGs are commonly abnormally overexpressed years prior to cancer pathology, making early PcG targeted therapy an option to reverse tumor formation, someday replacing the blunt instrument of eradication in the cancer therapy arsenal.
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Affiliation(s)
- Randall S Gieni
- Cross Cancer Institute and Department of Oncology, Faculty of Medicine, University of Alberta, Edmonton, AB T6G1Z2, Canada
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43
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44
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LIM HW, IWATANI M, HATTORI N, TANAKA S, YAGI S, SHIOTA K. Resistance to 5-aza-2'-deoxycytidine in Genic Regions Compared to Non-genic Repetitive Sequences. J Reprod Dev 2010; 56:86-93. [DOI: 10.1262/jrd.20247] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
Affiliation(s)
- Hui Wen LIM
- Laboratory of Cellular Biochemistry, Animal Resource Sciences/Veterinary Medical Sciences, The University of Tokyo
| | - Misa IWATANI
- Laboratory of Cellular Biochemistry, Animal Resource Sciences/Veterinary Medical Sciences, The University of Tokyo
| | - Naoko HATTORI
- Laboratory of Cellular Biochemistry, Animal Resource Sciences/Veterinary Medical Sciences, The University of Tokyo
| | - Satoshi TANAKA
- Laboratory of Cellular Biochemistry, Animal Resource Sciences/Veterinary Medical Sciences, The University of Tokyo
| | - Shintaro YAGI
- Laboratory of Cellular Biochemistry, Animal Resource Sciences/Veterinary Medical Sciences, The University of Tokyo
| | - Kunio SHIOTA
- Laboratory of Cellular Biochemistry, Animal Resource Sciences/Veterinary Medical Sciences, The University of Tokyo
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45
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Sun S, Yan PS, Huang THM, Lin S. Identifying differentially methylated genes using mixed effect and generalized least square models. BMC Bioinformatics 2009; 10:404. [PMID: 20003206 PMCID: PMC2800121 DOI: 10.1186/1471-2105-10-404] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2009] [Accepted: 12/09/2009] [Indexed: 11/10/2022] Open
Abstract
Background DNA methylation plays an important role in the process of tumorigenesis. Identifying differentially methylated genes or CpG islands (CGIs) associated with genes between two tumor subtypes is thus an important biological question. The methylation status of all CGIs in the whole genome can be assayed with differential methylation hybridization (DMH) microarrays. However, patient samples or cell lines are heterogeneous, so their methylation pattern may be very different. In addition, neighboring probes at each CGI are correlated. How these factors affect the analysis of DMH data is unknown. Results We propose a new method for identifying differentially methylated (DM) genes by identifying the associated DM CGI(s). At each CGI, we implement four different mixed effect and generalized least square models to identify DM genes between two groups. We compare four models with a simple least square regression model to study the impact of incorporating random effects and correlations. Conclusions We demonstrate that the inclusion (or exclusion) of random effects and the choice of correlation structures can significantly affect the results of the data analysis. We also assess the false discovery rate of different models using CGIs associated with housekeeping genes.
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Affiliation(s)
- Shuying Sun
- Case Comprehensive Cancer Center, Case Western Reserve University, Cleveland, Ohio 44106, USA.
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46
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Quinn AM, Bedford MT, Espejo A, Spannhoff A, Austin CP, Oppermann U, Simeonov A. A homogeneous method for investigation of methylation-dependent protein-protein interactions in epigenetics. Nucleic Acids Res 2009; 38:e11. [PMID: 19897549 PMCID: PMC2811012 DOI: 10.1093/nar/gkp899] [Citation(s) in RCA: 47] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022] Open
Abstract
Methylation of lysine residues on the tails of histone proteins is a major determinant of the transcription state of associated DNA coding regions. The interplay among methylation states and other histone modifications to direct transcriptional outcome is referred to as the histone code. In addition to histone methyltransferases and demethylases which function to modify the methylation state of lysine sidechains, other proteins recognize specific histone methylation marks essentially serving as code readers. While these interactions are highly specific with respect to site and methylation state of particular lysine residues, they are generally weak and therefore difficult to monitor by traditional assay techniques. Herein, we present the design and implementation of a homogeneous, miniaturizable, and sensitive assay for histone methylation-dependent interactions. We use AlphaScreen, a chemiluminescence-based technique, to monitor the interactions of chromodomains (MPP8, HP1β and CHD1), tudor domains (JMJD2A) and plant homeodomains (RAG2) with their cognate trimethyllysine histone partners. The utility of the method was demonstrated by profiling the binding specificities of chromo- and tudor domains toward several histone marks. The simplicity of design and the sensitive and robust nature of this assay should make it applicable to a range of epigenetic studies, including the search for novel inhibitors of methylation-dependent interactions.
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Affiliation(s)
- Amy M Quinn
- NIH Chemical Genomics Center, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892-3370, USA
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47
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Copeland RA, Solomon ME, Richon VM. Protein methyltransferases as a target class for drug discovery. Nat Rev Drug Discov 2009; 8:724-32. [PMID: 19721445 DOI: 10.1038/nrd2974] [Citation(s) in RCA: 384] [Impact Index Per Article: 24.0] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
The protein methyltransferases (PMTs) - which methylate protein lysine and arginine residues and have crucial roles in gene transcription - are emerging as an important group of enzymes that play key parts in normal physiology and human diseases. The collection of human PMTs is a large and diverse group of enzymes that have a common mechanism of catalysis. Here, we review the biological, biochemical and structural data that together present PMTs as a novel, chemically tractable target class for drug discovery.
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Affiliation(s)
- Robert A Copeland
- Epizyme, Inc., 840 Memorial Drive, Cambridge, Massachussets 02139, USA.
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48
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Abstract
Epigenetic mechanisms are essential for normal development and maintenance of tissue-specific gene expression patterns in mammals. Disruption of epigenetic processes can lead to altered gene function and malignant cellular transformation. Global changes in the epigenetic landscape are a hallmark of cancer. The initiation and progression of cancer, traditionally seen as a genetic disease, is now realized to involve epigenetic abnormalities along with genetic alterations. Recent advancements in the rapidly evolving field of cancer epigenetics have shown extensive reprogramming of every component of the epigenetic machinery in cancer including DNA methylation, histone modifications, nucleosome positioning and non-coding RNAs, specifically microRNA expression. The reversible nature of epigenetic aberrations has led to the emergence of the promising field of epigenetic therapy, which is already making progress with the recent FDA approval of three epigenetic drugs for cancer treatment. In this review, we discuss the current understanding of alterations in the epigenetic landscape that occur in cancer compared with normal cells, the roles of these changes in cancer initiation and progression, including the cancer stem cell model, and the potential use of this knowledge in designing more effective treatment strategies.
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Affiliation(s)
- Shikhar Sharma
- Department of Urology, Biochemistry and Molecular Biology, USC/Norris Comprehensive Cancer Center Keck School of Medicine, University of Southern California, Los Angeles, CA 90089-9181, USA
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