|
1
|
Younesian S, Mohammadi MH, Younesian O, Momeny M, Ghaffari SH, Bashash D. DNA methylation in human diseases. Heliyon 2024; 10:e32366. [PMID: 38933971 PMCID: PMC11200359 DOI: 10.1016/j.heliyon.2024.e32366] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2023] [Revised: 05/30/2024] [Accepted: 06/03/2024] [Indexed: 06/28/2024] Open
Abstract
Aberrant epigenetic modifications, particularly DNA methylation, play a critical role in the pathogenesis and progression of human diseases. The current review aims to reveal the role of aberrant DNA methylation in the pathogenesis and progression of diseases and to discuss the original data obtained from international research laboratories on this topic. In the review, we mainly summarize the studies exploring the role of aberrant DNA methylation as diagnostic and prognostic biomarkers in a broad range of human diseases, including monogenic epigenetics, autoimmunity, metabolic disorders, hematologic neoplasms, and solid tumors. The last section provides a general overview of the possibility of the DNA methylation machinery from the perspective of pharmaceutic approaches. In conclusion, the study of DNA methylation machinery is a phenomenal intersection that each of its ways can reveal the mysteries of various diseases, introduce new diagnostic and prognostic biomarkers, and propose a new patient-tailored therapeutic approach for diseases.
Collapse
Affiliation(s)
- Samareh Younesian
- Department of Hematology and Blood Banking, School of Allied Medical Sciences, Shahid Beheshti University of Medical Sciences, Tehran, 1971653313 Iran
| | - Mohammad Hossein Mohammadi
- Department of Hematology and Blood Banking, School of Allied Medical Sciences, Shahid Beheshti University of Medical Sciences, Tehran, 1971653313 Iran
| | - Ommolbanin Younesian
- School of Medicine, Tonekabon Branch, Islamic Azad University, Tonekabon, 46841-61167 Iran
| | - Majid Momeny
- The Brown Foundation Institute of Molecular Medicine, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, 77030 TX, USA
| | - Seyed H. Ghaffari
- Hematology, Oncology and Stem Cell Transplantation Research Center, Shariati Hospital, Tehran University of Medical Sciences, Tehran, 1411713135 Iran
| | - Davood Bashash
- Department of Hematology and Blood Banking, School of Allied Medical Sciences, Shahid Beheshti University of Medical Sciences, Tehran, 1971653313 Iran
| |
Collapse
|
|
2
|
Dong Y, Liu X, Jiang B, Wei S, Xiang B, Liao R, Wang Q, He X. A Genome-Wide Investigation of Effects of Aberrant DNA Methylation on the Usage of Alternative Promoters in Hepatocellular Carcinoma. Front Oncol 2022; 11:780266. [PMID: 35111672 PMCID: PMC8803206 DOI: 10.3389/fonc.2021.780266] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2021] [Accepted: 12/15/2021] [Indexed: 11/25/2022] Open
Abstract
BACKGROUND The alternative usage of promoters provides a way to regulate gene expression, has a significant influence on the transcriptome, and contributes to the cellular transformation of cancer. However, the function of alternative promoters (APs) in hepatocellular carcinoma (HCC) has not been systematically studied yet. In addition, the potential mechanism of regulation to the usage of APs remains unclear. DNA methylation, one of the most aberrant epigenetic modifications in cancers, is known to regulate transcriptional activity. Whether DNA methylation regulates the usage of APs needs to be explored. Here, we aim to investigate the effects of DNA methylation on usage of APs in HCC. METHODS Promoter activities were calculated based on RNA-seq data. Functional enrichment analysis was implemented to conduct GO terms. Correlation tests were used to detect the correlation between promoter activity and methylation status. The LASSO regression model was used to generate a diagnostic model. Kaplan-Meier analysis was used to compare the overall survival between high and low methylation groups. RNA-seq and whole-genome bisulfite sequencing (WGBS) in HCC samples were performed to validate the correlation of promoter activity and methylation. RESULTS We identified 855 APs in total, which could be well used to distinguish cancer from normal samples. The correlation of promoter activity and DNA methylation in APs was observed, and the APs with negative correlation were defined as methylation-regulated APs (mrAPs). Six mrAPs were identified to generate a diagnostic model with good performance (AUC = 0.97). Notably, the majority of mrAPs had CpG sites that could be used to predict clinical outcomes by methylation status. Finally, we verified 85.6% of promoter activity variation and 92.3% of methylation changes in our paired RNA-seq and WGBS samples, respectively. The negative correlation between promoter activity and methylation status was further confirmed in our HCC samples. CONCLUSION The aberrant methylation status plays a critical role in the precision usage of APs in HCC, which sheds light on the mechanism of cancer development and provides a new insight into cancer screening and treatment.
Collapse
Affiliation(s)
- Yuting Dong
- Department of Physiology, School of Basic Medical Science, Huazhong University of Science and Technology, Wuhan, China
- Center for Genomics and Proteomics Research, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Hubei Key Laboratory of Drug Target Research and Pharmacodynamic Evaluation, Huazhong University of Science and Technology, Wuhan, China
| | - Xiaozhao Liu
- Department of Physiology, School of Basic Medical Science, Huazhong University of Science and Technology, Wuhan, China
- Center for Genomics and Proteomics Research, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Hubei Key Laboratory of Drug Target Research and Pharmacodynamic Evaluation, Huazhong University of Science and Technology, Wuhan, China
| | - Bijun Jiang
- Department of Physiology, School of Basic Medical Science, Huazhong University of Science and Technology, Wuhan, China
- Center for Genomics and Proteomics Research, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Hubei Key Laboratory of Drug Target Research and Pharmacodynamic Evaluation, Huazhong University of Science and Technology, Wuhan, China
| | - Siting Wei
- Department of Physiology, School of Basic Medical Science, Huazhong University of Science and Technology, Wuhan, China
- Center for Genomics and Proteomics Research, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Hubei Key Laboratory of Drug Target Research and Pharmacodynamic Evaluation, Huazhong University of Science and Technology, Wuhan, China
| | - Bangde Xiang
- Department of Hepatobiliary Surgery, Guangxi Medical University Cancer Hospital, Nanning, China
| | - Ruichu Liao
- Department of Physiology, School of Basic Medical Science, Huazhong University of Science and Technology, Wuhan, China
- Center for Genomics and Proteomics Research, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Hubei Key Laboratory of Drug Target Research and Pharmacodynamic Evaluation, Huazhong University of Science and Technology, Wuhan, China
| | - Qiuyan Wang
- Center for Genomic and Personalized Medicine, Guangxi Medical University, Nanning, China
- Guangxi Key Laboratory for Genomic and Personalized Medicine, Guangxi, Collaborative Innovation Center for Genomic and Personalized Medicine, Nanning, China
| | - Ximiao He
- Department of Physiology, School of Basic Medical Science, Huazhong University of Science and Technology, Wuhan, China
- Center for Genomics and Proteomics Research, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Hubei Key Laboratory of Drug Target Research and Pharmacodynamic Evaluation, Huazhong University of Science and Technology, Wuhan, China
| |
Collapse
|
|
3
|
Nishiyama A, Nakanishi M. Navigating the DNA methylation landscape of cancer. Trends Genet 2021; 37:1012-1027. [PMID: 34120771 DOI: 10.1016/j.tig.2021.05.002] [Citation(s) in RCA: 479] [Impact Index Per Article: 119.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2021] [Revised: 05/06/2021] [Accepted: 05/11/2021] [Indexed: 12/11/2022]
Abstract
DNA methylation is a chemical modification that defines cell type and lineage through the control of gene expression and genome stability. Disruption of DNA methylation control mechanisms causes a variety of diseases, including cancer. Cancer cells are characterized by aberrant DNA methylation (i.e., genome-wide hypomethylation and site-specific hypermethylation), mainly targeting CpG islands in gene expression regulatory elements. In particular, the early findings that a variety of tumor suppressor genes (TSGs) are targets of DNA hypermethylation in cancer led to the proposal of a model in which aberrant DNA methylation promotes cellular oncogenesis through TSGs silencing. However, recent genome-wide analyses have revealed that this classical model needs to be reconsidered. In this review, we will discuss the molecular mechanisms of DNA methylation abnormalities in cancer as well as their therapeutic potential.
Collapse
Affiliation(s)
- Atsuya Nishiyama
- Division of Cancer Cell Biology, Institute of Medical Science, University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, Tokyo 108-8639, Japan.
| | - Makoto Nakanishi
- Division of Cancer Cell Biology, Institute of Medical Science, University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, Tokyo 108-8639, Japan.
| |
Collapse
|
|
4
|
Clapier CR. Sophisticated Conversations between Chromatin and Chromatin Remodelers, and Dissonances in Cancer. Int J Mol Sci 2021; 22:5578. [PMID: 34070411 PMCID: PMC8197500 DOI: 10.3390/ijms22115578] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2021] [Revised: 05/18/2021] [Accepted: 05/18/2021] [Indexed: 01/13/2023] Open
Abstract
The establishment and maintenance of genome packaging into chromatin contribute to define specific cellular identity and function. Dynamic regulation of chromatin organization and nucleosome positioning are critical to all DNA transactions-in particular, the regulation of gene expression-and involve the cooperative action of sequence-specific DNA-binding factors, histone modifying enzymes, and remodelers. Remodelers are molecular machines that generate various chromatin landscapes, adjust nucleosome positioning, and alter DNA accessibility by using ATP binding and hydrolysis to perform DNA translocation, which is highly regulated through sophisticated structural and functional conversations with nucleosomes. In this review, I first present the functional and structural diversity of remodelers, while emphasizing the basic mechanism of DNA translocation, the common regulatory aspects, and the hand-in-hand progressive increase in complexity of the regulatory conversations between remodelers and nucleosomes that accompanies the increase in challenges of remodeling processes. Next, I examine how, through nucleosome positioning, remodelers guide the regulation of gene expression. Finally, I explore various aspects of how alterations/mutations in remodelers introduce dissonance into the conversations between remodelers and nucleosomes, modify chromatin organization, and contribute to oncogenesis.
Collapse
Affiliation(s)
- Cedric R Clapier
- Department of Oncological Sciences & Howard Hughes Medical Institute, Huntsman Cancer Institute, University of Utah School of Medicine, 2000 Circle of Hope, Salt Lake City, UT 84112, USA
| |
Collapse
|
|
5
|
Liu Z, Sun L, Cai Y, Shen S, Zhang T, Wang N, Wu G, Ma W, Li ST, Suo C, Hao Y, Jia WD, Semenza GL, Gao P, Zhang H. Hypoxia-Induced Suppression of Alternative Splicing of MBD2 Promotes Breast Cancer Metastasis via Activation of FZD1. Cancer Res 2021; 81:1265-1278. [PMID: 33402389 DOI: 10.1158/0008-5472.can-20-2876] [Citation(s) in RCA: 38] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2020] [Revised: 11/19/2020] [Accepted: 12/29/2020] [Indexed: 11/16/2022]
Abstract
Metastasis is responsible for the majority of breast cancer-related deaths, however, the mechanisms underlying metastasis in this disease remain largely elusive. Here we report that under hypoxic conditions, alternative splicing of MBD2 is suppressed, favoring the production of MBD2a, which facilitates breast cancer metastasis. Specifically, MBD2a promoted, whereas its lesser known short form MBD2c suppressed metastasis. Activation of HIF1 under hypoxia facilitated MBD2a production via repression of SRSF2-mediated alternative splicing. As a result, elevated MBD2a outcompeted MBD2c for binding to promoter CpG islands to activate expression of FZD1, thereby promoting epithelial-to-mesenchymal transition and metastasis. Strikingly, clinical data reveal significantly correlated expression of MBD2a and MBD2c with the invasiveness of malignancy, indicating opposing roles for MBD2 splicing variants in regulating human breast cancer metastasis. Collectively, our findings establish a novel link between MBD2 switching and tumor metastasis and provide a promising therapeutic strategy and predictive biomarkers for hypoxia-driven breast cancer metastasis. SIGNIFICANCE: This study defines the opposing roles and clinical relevance of MBD2a and MBD2c, two MBD2 alternative splicing products, in hypoxia-driven breast cancer metastasis. GRAPHICAL ABSTRACT: http://cancerres.aacrjournals.org/content/canres/81/5/1265/F1.large.jpg.
Collapse
Affiliation(s)
- Zhaoji Liu
- Department of General Surgery, Anhui Provincial Hospital, The First Affiliated Hospital of USTC, University of Science and Technology of China, Hefei, China
- Hefei National Laboratory for Physical Sciences at Microscale, The CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Life Sciences and Medical Center, University of Science and Technology of China, Hefei, China
| | - Linchong Sun
- Department of General Surgery, Anhui Provincial Hospital, The First Affiliated Hospital of USTC, University of Science and Technology of China, Hefei, China
- Laboratory of Cancer and Stem Cell Metabolism, School of Medicine, Institutes for Life Sciences, South China University of Technology, Guangzhou, China
| | - Yongping Cai
- Department of Pathology, School of Medicine, Anhui Medical University, Hefei, China
| | - Shengqi Shen
- Department of General Surgery, Anhui Provincial Hospital, The First Affiliated Hospital of USTC, University of Science and Technology of China, Hefei, China
- Hefei National Laboratory for Physical Sciences at Microscale, The CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Life Sciences and Medical Center, University of Science and Technology of China, Hefei, China
| | - Tong Zhang
- Department of General Surgery, Anhui Provincial Hospital, The First Affiliated Hospital of USTC, University of Science and Technology of China, Hefei, China
- Hefei National Laboratory for Physical Sciences at Microscale, The CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Life Sciences and Medical Center, University of Science and Technology of China, Hefei, China
| | - Nana Wang
- Department of Pathology, School of Medicine, Anhui Medical University, Hefei, China
| | - Gongwei Wu
- Department of General Surgery, Anhui Provincial Hospital, The First Affiliated Hospital of USTC, University of Science and Technology of China, Hefei, China
| | - Wenhao Ma
- Department of General Surgery, Anhui Provincial Hospital, The First Affiliated Hospital of USTC, University of Science and Technology of China, Hefei, China
| | - Shi-Ting Li
- Department of General Surgery, Anhui Provincial Hospital, The First Affiliated Hospital of USTC, University of Science and Technology of China, Hefei, China
| | - Caixia Suo
- Laboratory of Cancer and Stem Cell Metabolism, School of Medicine, Institutes for Life Sciences, South China University of Technology, Guangzhou, China
| | - Yijie Hao
- Department of General Surgery, Anhui Provincial Hospital, The First Affiliated Hospital of USTC, University of Science and Technology of China, Hefei, China
| | - Wei-Dong Jia
- Department of General Surgery, Anhui Provincial Hospital, The First Affiliated Hospital of USTC, University of Science and Technology of China, Hefei, China
| | - Gregg L Semenza
- School of Medicine, Johns Hopkins University, Baltimore, Maryland
| | - Ping Gao
- Hefei National Laboratory for Physical Sciences at Microscale, The CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Life Sciences and Medical Center, University of Science and Technology of China, Hefei, China.
- Laboratory of Cancer and Stem Cell Metabolism, School of Medicine, Institutes for Life Sciences, South China University of Technology, Guangzhou, China
- Guangzhou Regenerative Medicine and Health Guangdong Laboratory, Guangzhou, China
| | - Huafeng Zhang
- Department of General Surgery, Anhui Provincial Hospital, The First Affiliated Hospital of USTC, University of Science and Technology of China, Hefei, China.
- Hefei National Laboratory for Physical Sciences at Microscale, The CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Life Sciences and Medical Center, University of Science and Technology of China, Hefei, China
| |
Collapse
|
|
6
|
Li L, Li N, Liu N, Huo F, Zheng J. MBD2 Correlates with a Poor Prognosis and Tumor Progression in Renal Cell Carcinoma. Onco Targets Ther 2020; 13:10001-10012. [PMID: 33116585 PMCID: PMC7548338 DOI: 10.2147/ott.s256226] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2020] [Accepted: 08/27/2020] [Indexed: 01/21/2023] Open
Abstract
Purpose DNA methylation plays an important role in regulating gene expression. Methyl-CpG-binding domain (MBD) proteins recognize and bind to methylated DNA, which mediate gene silencing by the interaction with deacetylases and histone methyltransferases. MBD2 has been reported in various human cancers; however, its clinical implication and potential regulatory role in renal cell carcinoma (RCC) have not been elaborated. Materials and Methods In the study, we estimated the expression and prognostic value of MBD2 in RCC cell lines and tissues by Western blotting and immunohistochemistry. The associations of MBD2 expression and pathological characters and survival in RCC patients were performed using χ2 and Kaplan-Meier survival analysis, respectively. Univariate and multivariable Cox regression analyses suggested the independent predictors in RCC prognosis. The functional role of MBD2 in RCC progression was assessed by in vitro cell experiments. In addition, we identified the MBD2-mediated alterations of protein-related proliferation and EMT markers in RCC cells after MBD2 overexpression and knockdown. Results We found that the protein levels of MBD2 were upregulated in RCC cells and tissues. High MBD2 expression was related to TNM stage and predicted poorer survival in RCC. Enforced expression of MBD2 significantly promoted the proliferation, cycle progress, invasion and migration of RCC cells in vitro. However, downregulating MBD2 remarkably weakened the above cell functions. Mechanistically, the promotive effect of MBD2 overexpression may be regulated by its effects onp21, p53 and Cyclin D1 expression and EMT process. Conclusion These results indicated that MBD2confers an oncogenic function in the malignant progression of RCC. MBD2 could be served as a meaningful prognostic biomarker and a latent therapeutic target in RCC patients.
Collapse
Affiliation(s)
- Liantao Li
- Cancer Institute, Xuzhou Medical University, Xuzhou 221000, People's Republic of China.,Center of Clinical Oncology, Affiliated Hospital of Xuzhou Medical University, Xuzhou 221000, People's Republic of China.,Department of Radiation Oncology, Affiliated Hospital of Xuzhou Medical University, Xuzhou 221000, People's Republic of China.,Jiangsu Center for the Collaboration and Innovation of Cancer Biotherapy, Xuzhou 221000, People's Republic of China
| | - Na Li
- Center of Clinical Oncology, Affiliated Hospital of Xuzhou Medical University, Xuzhou 221000, People's Republic of China.,Department of Radiation Oncology, Affiliated Hospital of Xuzhou Medical University, Xuzhou 221000, People's Republic of China
| | - Nianli Liu
- Cancer Institute, Xuzhou Medical University, Xuzhou 221000, People's Republic of China.,Jiangsu Center for the Collaboration and Innovation of Cancer Biotherapy, Xuzhou 221000, People's Republic of China
| | - Fuchun Huo
- Department of Pathology, Xuzhou Medical University, Xuzhou 221000, People's Republic of China
| | - Junnian Zheng
- Cancer Institute, Xuzhou Medical University, Xuzhou 221000, People's Republic of China.,Center of Clinical Oncology, Affiliated Hospital of Xuzhou Medical University, Xuzhou 221000, People's Republic of China
| |
Collapse
|
|
7
|
Gong W, Ni M, Chen Z, Zheng Z. Expression and clinical significance of methyl-CpG binding domain protein 2 in high-grade serous ovarian cancer. Oncol Lett 2020; 20:2749-2756. [PMID: 32782591 PMCID: PMC7400232 DOI: 10.3892/ol.2020.11836] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2020] [Accepted: 06/08/2020] [Indexed: 12/12/2022] Open
Abstract
Platinum resistance is an important cause of clinical recurrence and mortality of patients with high-grade serous ovarian cancer (HGSOC). Methyl-CpG binding domain protein 2 (MBD2) serves an important role in tumor progression; however, its role in HGSOC remains unclear. The aim of the present study was to investigate the expression of MBD2 in HGSOC and its role in drug resistance and prognosis of HGSOC. MBD2 expression was analyzed by immunohistochemical staining and western blotting. The associations between MBD2 expression and clinical pathological features, platinum resistance and patient prognosis were analyzed using a χ2 test, Kaplan-Meier analysis and Cox regression analysis. Positive MBD2 expression was detected in 73 (63.5%) of the HGSOC tissue samples, whereas it was undetectable in all 16 normal tissue samples (100%) analyzed, indicating a significantly higher expression level in tumor tissues compared with normal tissues (P<0.001). Additionally, MBD2 expression was significantly higher in platinum-resistant cases compared with that in platinum-sensitive cases (P<0.05). In addition, high expression of MBD2 was negatively associated with relapse-free survival (P<0.05). In conclusion, MBD2 was demonstrated to be a potential drug target and a biomarker for poor prognosis in HGSOC.
Collapse
Affiliation(s)
- Wangang Gong
- College of Life Sciences, Zhejiang Chinese Medical University, Hangzhou, Zhejiang 310053, P.R. China.,Institute of Cancer and Basic Medicine, Chinese Academy of Sciences, Zhejiang Cancer Hospital, Hangzhou, Zhejiang 310022, P.R. China.,Zhejiang Cancer Research Institute, Cancer Hospital of The University of Chinese Academy of Sciences, Hangzhou, Zhejiang 310022, P.R. China.,Zhejiang Cancer Research Institute, Zhejiang Cancer Hospital, Hangzhou, Zhejiang 310022, P.R. China
| | - Maowei Ni
- Institute of Cancer and Basic Medicine, Chinese Academy of Sciences, Zhejiang Cancer Hospital, Hangzhou, Zhejiang 310022, P.R. China.,Zhejiang Cancer Research Institute, Cancer Hospital of The University of Chinese Academy of Sciences, Hangzhou, Zhejiang 310022, P.R. China.,Zhejiang Cancer Research Institute, Zhejiang Cancer Hospital, Hangzhou, Zhejiang 310022, P.R. China
| | - Zhongbo Chen
- Institute of Cancer and Basic Medicine, Chinese Academy of Sciences, Zhejiang Cancer Hospital, Hangzhou, Zhejiang 310022, P.R. China.,Zhejiang Cancer Research Institute, Cancer Hospital of The University of Chinese Academy of Sciences, Hangzhou, Zhejiang 310022, P.R. China.,Zhejiang Cancer Research Institute, Zhejiang Cancer Hospital, Hangzhou, Zhejiang 310022, P.R. China
| | - Zhiguo Zheng
- Institute of Cancer and Basic Medicine, Chinese Academy of Sciences, Zhejiang Cancer Hospital, Hangzhou, Zhejiang 310022, P.R. China.,Zhejiang Cancer Research Institute, Cancer Hospital of The University of Chinese Academy of Sciences, Hangzhou, Zhejiang 310022, P.R. China.,Zhejiang Cancer Research Institute, Zhejiang Cancer Hospital, Hangzhou, Zhejiang 310022, P.R. China
| |
Collapse
|
|
8
|
Brumbaugh J, Di Stefano B, Hochedlinger K. Reprogramming: identifying the mechanisms that safeguard cell identity. Development 2019; 146:146/23/dev182170. [PMID: 31792064 DOI: 10.1242/dev.182170] [Citation(s) in RCA: 37] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
Development and homeostasis rely upon concerted regulatory pathways to establish the specialized cell types needed for tissue function. Once a cell type is specified, the processes that restrict and maintain cell fate are equally important in ensuring tissue integrity. Over the past decade, several approaches to experimentally reprogram cell fate have emerged. Importantly, efforts to improve and understand these approaches have uncovered novel molecular determinants that reinforce lineage commitment and help resist cell fate changes. In this Review, we summarize recent studies that have provided insights into the various chromatin factors, post-transcriptional processes and features of genomic organization that safeguard cell identity in the context of reprogramming to pluripotency. We also highlight how these factors function in other experimental, physiological and pathological cell fate transitions, including direct lineage conversion, pluripotency-to-totipotency reversion and cancer.
Collapse
Affiliation(s)
- Justin Brumbaugh
- Department of Molecular, Cellular, and Developmental Biology, University of Colorado Boulder, Boulder, CO 80309, USA
| | - Bruno Di Stefano
- Department of Molecular Biology, Massachusetts General Hospital, 185 Cambridge Street, Boston, MA 02114, USA.,Center for Regenerative Medicine, Massachusetts General Hospital, 185 Cambridge Street, Boston, MA 02114, USA.,Cancer Center, Massachusetts General Hospital, 185 Cambridge Street, Boston, MA 02114, USA.,Department of Genetics, Harvard Medical School, Boston, 77 Avenue Louis Pasteur, Boston, MA 02115, USA.,Harvard Stem Cell Institute, 1350 Massachusetts Avenue, Cambridge, MA 02138, USA
| | - Konrad Hochedlinger
- Department of Molecular Biology, Massachusetts General Hospital, 185 Cambridge Street, Boston, MA 02114, USA .,Center for Regenerative Medicine, Massachusetts General Hospital, 185 Cambridge Street, Boston, MA 02114, USA.,Cancer Center, Massachusetts General Hospital, 185 Cambridge Street, Boston, MA 02114, USA.,Department of Genetics, Harvard Medical School, Boston, 77 Avenue Louis Pasteur, Boston, MA 02115, USA.,Harvard Stem Cell Institute, 1350 Massachusetts Avenue, Cambridge, MA 02138, USA
| |
Collapse
|
|
9
|
Mahmood N, Rabbani SA. DNA Methylation Readers and Cancer: Mechanistic and Therapeutic Applications. Front Oncol 2019; 9:489. [PMID: 31245293 PMCID: PMC6579900 DOI: 10.3389/fonc.2019.00489] [Citation(s) in RCA: 84] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2019] [Accepted: 05/23/2019] [Indexed: 12/14/2022] Open
Abstract
DNA methylation is a major epigenetic process that regulates chromatin structure which causes transcriptional activation or repression of genes in a context-dependent manner. In general, DNA methylation takes place when methyl groups are added to the appropriate bases on the genome by the action of "writer" molecules known as DNA methyltransferases. How these methylation marks are read and interpreted into different functionalities represents one of the main mechanisms through which the genes are switched "ON" or "OFF" and typically involves different types of "reader" proteins that can recognize and bind to the methylated regions. A tightly balanced regulation exists between the "writers" and "readers" in order to mediate normal cellular functions. However, alterations in normal methylation pattern is a typical hallmark of cancer which alters the way methylation marks are written, read and interpreted in different disease states. This unique characteristic of DNA methylation "readers" has identified them as attractive therapeutic targets. In this review, we describe the current state of knowledge on the different classes of DNA methylation "readers" identified thus far along with their normal biological functions, describe how they are dysregulated in cancer, and discuss the various anti-cancer therapies that are currently being developed and evaluated for targeting these proteins.
Collapse
Affiliation(s)
- Niaz Mahmood
- Department of Medicine, McGill University Health Centre, Montréal, QC, Canada
| | - Shafaat A Rabbani
- Department of Medicine, McGill University Health Centre, Montréal, QC, Canada
| |
Collapse
|
|
10
|
Ginder GD, Williams DC. Readers of DNA methylation, the MBD family as potential therapeutic targets. Pharmacol Ther 2017; 184:98-111. [PMID: 29128342 DOI: 10.1016/j.pharmthera.2017.11.002] [Citation(s) in RCA: 45] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
DNA methylation represents a fundamental epigenetic modification that regulates chromatin architecture and gene transcription. Many diseases, including cancer, show aberrant methylation patterns that contribute to the disease phenotype. DNA methylation inhibitors have been used to block methylation dependent gene silencing to treat hematopoietic neoplasms and to restore expression of developmentally silenced genes. However, these inhibitors disrupt methylation globally and show significant off-target toxicities. As an alternative approach, we have been studying readers of DNA methylation, the 5-methylcytosine binding domain family of proteins, as potential therapeutic targets to restore expression of aberrantly and developmentally methylated and silenced genes. In this review, we discuss the role of DNA methylation in gene regulation and cancer development, the structure and function of the 5-methylcytosine binding domain family of proteins, and the possibility of targeting the complexes these proteins form to treat human disease.
Collapse
Affiliation(s)
- Gordon D Ginder
- Department of Human and Molecular Genetics, Virginia Commonwealth University, Richmond, VA 23298, United States; Department of Internal Medicine, Virginia Commonwealth University, Richmond, VA 23298, United States; Massey Cancer Center, Virginia Commonwealth University, Richmond, VA 23298, United States.
| | - David C Williams
- Department of Pathology and Laboratory Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, United States; Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, United States.
| |
Collapse
|
|
11
|
Biogenesis of Pro-senescent Microparticles by Endothelial Colony Forming Cells from Premature Neonates is driven by SIRT1-Dependent Epigenetic Regulation of MKK6. Sci Rep 2017; 7:8277. [PMID: 28811647 PMCID: PMC5557933 DOI: 10.1038/s41598-017-08883-1] [Citation(s) in RCA: 28] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2017] [Accepted: 07/19/2017] [Indexed: 12/18/2022] Open
Abstract
Senescent cells may exert detrimental effect on microenvironment through the secretion of soluble factors and the release of extracellular vesicles, such as microparticles, key actors in ageing and cardiovascular diseases. We previously reported that sirtuin-1 (SIRT1) deficiency drives accelerated senescence and dysfunction of endothelial colony-forming cells (ECFC) in PT neonates. Because preterm birth (PT) increases the risk for cardiovascular diseases during neonatal period as well as at adulthood, we hypothesized that SIRT1 deficiency could control the biogenesis of microparticles as part of a senescence–associated secretory phenotype (SASP) of PT-ECFC and investigated the related molecular mechanisms. Compared to control ECFC, PT-ECFC displayed a SASP associated with increased release of endothelial microparticles (EMP), mediating a paracrine induction of senescence in naïve endothelial cells. SIRT1 level inversely correlated with EMP release and drives PT-ECFC vesiculation. Global transcriptomic analysis revealed changes in stress response pathways, specifically the MAPK pathway. We delineate a new epigenetic mechanism by which SIRT1 deficiency regulates MKK6/p38MAPK/Hsp27 pathway to promote EMP biogenesis in senescent ECFC. These findings deepen our understanding of the role of ECFC senescence in the disruption of endothelial homeostasis and provide potential new targets towards the control of cardiovascular risk in individuals born preterm.
Collapse
|
|
12
|
Gigek CO, Chen ES, Smith MAC. Methyl-CpG-Binding Protein (MBD) Family: Epigenomic Read-Outs Functions and Roles in Tumorigenesis and Psychiatric Diseases. J Cell Biochem 2016. [PMID: 26205787 DOI: 10.1002/jcb.25281] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Epigenetics is the study of the heritable changes on gene expression that are responsible for the regulation of development and that have an impact on several diseases. However, it is of equal importance to understand how epigenetic machinery works. DNA methylation is the most studied epigenetic mark and is generally associated with the regulation of gene expression through the repression of promoter activity and by affecting genome stability. Therefore, the ability of the cell to interpret correct methylation marks and/or the correct interpretation of methylation plays a role in many diseases. The major family of proteins that bind methylated DNA is the methyl-CpG binding domain proteins, or the MBDs. Here, we discuss the structure that makes these proteins a family, the main functions and interactions of all protein family members and their role in human disease such as psychiatric disorders and cancer.
Collapse
Affiliation(s)
- Carolina Oliveira Gigek
- Disciplina de Genética, Departamento de Morfologia e Genética, Universidade Federal de São Paulo (UNIFESP), Rua Botucatu, 740, Edifício Leitão da Cunha, 1, ° andar, CEP 04023-900, São Paulo, SP, Brazil.,Disciplina de Gastroenterologia Cirúrgica, Departamento de Cirurgia, Universidade Federal de São Paulo (UNIFESP), R. Napoleão de Barros, 715, 2º andar, CEP:04024-002, São Paulo, Brazil
| | - Elizabeth Suchi Chen
- Disciplina de Genética, Departamento de Morfologia e Genética, Universidade Federal de São Paulo (UNIFESP), Rua Botucatu, 740, Edifício Leitão da Cunha, 1, ° andar, CEP 04023-900, São Paulo, SP, Brazil
| | - Marilia Arruda Cardoso Smith
- Disciplina de Genética, Departamento de Morfologia e Genética, Universidade Federal de São Paulo (UNIFESP), Rua Botucatu, 740, Edifício Leitão da Cunha, 1, ° andar, CEP 04023-900, São Paulo, SP, Brazil
| |
Collapse
|
|
13
|
Methyl-CpG-binding protein MBD2 plays a key role in maintenance and spread of DNA methylation at CpG islands and shores in cancer. Oncogene 2016; 36:1328-1338. [PMID: 27593931 DOI: 10.1038/onc.2016.297] [Citation(s) in RCA: 47] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2016] [Revised: 07/04/2016] [Accepted: 07/17/2016] [Indexed: 02/07/2023]
Abstract
Cancer is characterised by DNA hypermethylation and gene silencing of CpG island-associated promoters, including tumour-suppressor genes. The methyl-CpG-binding domain (MBD) family of proteins bind to methylated DNA and can aid in the mediation of gene silencing through interaction with histone deacetylases and histone methyltransferases. However, the mechanisms responsible for eliciting CpG island hypermethylation in cancer, and the potential role that MBD proteins play in modulation of the methylome remain unclear. Our previous work demonstrated that MBD2 preferentially binds to the hypermethylated GSTP1 promoter CpG island in prostate cancer cells. Here, we use functional genetic approaches to investigate if MBD2 plays an active role in reshaping the DNA methylation landscape at this locus and genome-wide. First, we show that loss of MBD2 results in inhibition of both maintenance and spread of de novo methylation of a transfected construct containing the GSTP1 promoter CpG island in prostate cancer cells and Mbd2-/- mouse fibroblasts. De novo methylation was rescued by transient expression of Mbd2 in Mbd2-/- cells. Second, we show that MBD2 depletion triggers significant hypomethylation genome-wide in prostate cancer cells with concomitant loss of MBD2 binding at promoter and enhancer regulatory regions. Finally, CpG islands and shores that become hypomethylated after MBD2 depletion in LNCaP cancer cells show significant hypermethylation in clinical prostate cancer samples, highlighting a potential active role of MBD2 in promoting cancer-specific hypermethylation. Importantly, co-immunoprecipiation of MBD2 shows that MBD2 associates with DNA methyltransferase enzymes 1 and 3A. Together our results demonstrate that MBD2 has a critical role in 'rewriting' the cancer methylome at specific regulatory regions.
Collapse
|
|
14
|
Wood KH, Zhou Z. Emerging Molecular and Biological Functions of MBD2, a Reader of DNA Methylation. Front Genet 2016; 7:93. [PMID: 27303433 PMCID: PMC4880565 DOI: 10.3389/fgene.2016.00093] [Citation(s) in RCA: 52] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2016] [Accepted: 05/10/2016] [Indexed: 01/25/2023] Open
Abstract
DNA methylation is an epigenetic mark that is essential for many biological processes and is linked to diseases such as cancer. Methylation is usually associated with transcriptional silencing, but new research has challenged this model. Both transcriptional activation and repression have recently been found to be associated with DNA methylation in a context-specific manner. How DNA methylation patterns are interpreted into different functional output remains poorly understood. One mechanism involves the protein ‘readers’ of methylation, which includes the methyl-CpG binding domain (MBD) family of proteins. This review examines the molecular and biological functions of MBD2, which binds to CpG methylation and is an integral part of the nucleosome remodeling and histone deacetylation (NuRD) complex. MBD2 has been linked to immune system function and tumorigenesis, yet little is known about its functions in vivo. Recent studies have found the MBD2 protein is ubiquitously expressed, with relatively high levels in the lung, liver, and colon. Mbd2 null mice surprisingly show relatively mild phenotypes compared to mice with loss of function of other MBD proteins. This evidence has previously been interpreted as functional redundancy between the MBD proteins. Here, we examine and contextualize research that suggests MBD2 has unique properties and functions among the MBD proteins. These functions translate to recently described roles in the development and differentiation of multiple cell lineages, including pluripotent stem cells and various cell types of the immune system, as well as in tumorigenesis. We also consider possible models for the dynamic interactions between MBD2 and NuRD in different tissues in vivo. The functions of MBD2 may have direct therapeutic implications for several areas of human disease, including autoimmune conditions and cancer, in addition to providing insights into the actions of NuRD and chromatin regulation.
Collapse
Affiliation(s)
- Kathleen H Wood
- Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia PA, USA
| | - Zhaolan Zhou
- Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia PA, USA
| |
Collapse
|
|
15
|
Kazanets A, Shorstova T, Hilmi K, Marques M, Witcher M. Epigenetic silencing of tumor suppressor genes: Paradigms, puzzles, and potential. BIOCHIMICA ET BIOPHYSICA ACTA 2016; 1865:275-88. [PMID: 27085853 DOI: 10.1016/j.bbcan.2016.04.001] [Citation(s) in RCA: 96] [Impact Index Per Article: 10.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/05/2016] [Accepted: 04/08/2016] [Indexed: 12/20/2022]
Abstract
Cancer constitutes a set of diseases with heterogeneous molecular pathologies. However, there are a number of universal aberrations common to all cancers, one of these being the epigenetic silencing of tumor suppressor genes (TSGs). The silencing of TSGs is thought to be an early, driving event in the oncogenic process. With this in consideration, great efforts have been made to develop small molecules aimed at the restoration of TSGs in order to limit tumor cell proliferation and survival. However, the molecular forces that drive the broad epigenetic reprogramming and transcriptional repression of these genes remain ill-defined. Undoubtedly, understanding the molecular underpinnings of transcriptionally silenced TSGs will aid us in our ability to reactivate these key anti-cancer targets. Here, we describe what we consider to be the five most logical molecular mechanisms that may account for this widely observed phenomenon: 1) ablation of transcription factor binding, 2) overexpression of DNA methyltransferases, 3) disruption of CTCF binding, 4) elevation of EZH2 activity, 5) aberrant expression of long non-coding RNAs. The strengths and weaknesses of each proposed mechanism is highlighted, followed by an overview of clinical efforts to target these processes.
Collapse
Affiliation(s)
- Anna Kazanets
- The Lady Davis Institute of the Jewish General Hospital, Department of Oncology, McGill University, Montreal, Canada.
| | - Tatiana Shorstova
- The Lady Davis Institute of the Jewish General Hospital, Department of Oncology, McGill University, Montreal, Canada.
| | - Khalid Hilmi
- The Lady Davis Institute of the Jewish General Hospital, Department of Oncology, McGill University, Montreal, Canada.
| | - Maud Marques
- The Lady Davis Institute of the Jewish General Hospital, Department of Oncology, McGill University, Montreal, Canada.
| | - Michael Witcher
- The Lady Davis Institute of the Jewish General Hospital, Department of Oncology, McGill University, Montreal, Canada.
| |
Collapse
|
|
16
|
Du Q, Luu PL, Stirzaker C, Clark SJ. Methyl-CpG-binding domain proteins: readers of the epigenome. Epigenomics 2015; 7:1051-73. [DOI: 10.2217/epi.15.39] [Citation(s) in RCA: 332] [Impact Index Per Article: 33.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
How DNA methylation is interpreted and influences genome regulation remains largely unknown. Proteins of the methyl-CpG-binding domain (MBD) family are primary candidates for the readout of DNA methylation as they recruit chromatin remodelers, histone deacetylases and methylases to methylated DNA associated with gene repression. MBD protein binding requires both functional MBD domains and methyl-CpGs; however, some MBD proteins also bind unmethylated DNA and active regulatory regions via alternative regulatory domains or interaction with the nucleosome remodeling deacetylase (NuRD/Mi-2) complex members. Mutations within MBD domains occur in many diseases, including neurological disorders and cancers, leading to loss of MBD binding specificity to methylated sites and gene deregulation. Here, we summarize the current state of knowledge about MBD proteins and their role as readers of the epigenome.
Collapse
Affiliation(s)
- Qian Du
- Epigenetics Research Laboratory, Genomics & Epigenetics Division, Garvan Institute of Medical Research, Darlinghurst, NSW 2010, Australia
| | - Phuc-Loi Luu
- Epigenetics Research Laboratory, Genomics & Epigenetics Division, Garvan Institute of Medical Research, Darlinghurst, NSW 2010, Australia
| | - Clare Stirzaker
- Epigenetics Research Laboratory, Genomics & Epigenetics Division, Garvan Institute of Medical Research, Darlinghurst, NSW 2010, Australia
- St Vincent's Clinical School, University of NSW, Darlinghurst, NSW 2010, Australia
| | - Susan J Clark
- Epigenetics Research Laboratory, Genomics & Epigenetics Division, Garvan Institute of Medical Research, Darlinghurst, NSW 2010, Australia
- St Vincent's Clinical School, University of NSW, Darlinghurst, NSW 2010, Australia
| |
Collapse
|
|
17
|
Devailly G, Grandin M, Perriaud L, Mathot P, Delcros JG, Bidet Y, Morel AP, Bignon JY, Puisieux A, Mehlen P, Dante R. Dynamics of MBD2 deposition across methylated DNA regions during malignant transformation of human mammary epithelial cells. Nucleic Acids Res 2015; 43:5838-54. [PMID: 26007656 PMCID: PMC4499136 DOI: 10.1093/nar/gkv508] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2014] [Accepted: 05/05/2015] [Indexed: 12/26/2022] Open
Abstract
DNA methylation is thought to induce transcriptional silencing through the combination of two mechanisms: the repulsion of transcriptional activators unable to bind their target sites when methylated, and the recruitment of transcriptional repressors with specific affinity for methylated DNA. The Methyl CpG Binding Domain proteins MeCP2, MBD1 and MBD2 belong to the latter category. Here, we present MBD2 ChIPseq data obtained from the endogenous MBD2 in an isogenic cellular model of oncogenic transformation of human mammary cells. In immortalized (HMEC-hTERT) or transformed (HMLER) cells, MBD2 was found in a large proportion of methylated regions and associated with transcriptional silencing. A redistribution of MBD2 on methylated DNA occurred during oncogenic transformation, frequently independently of local DNA methylation changes. Genes downregulated during HMEC-hTERT transformation preferentially gained MBD2 on their promoter. Furthermore, depletion of MBD2 induced an upregulation of MBD2-bound genes methylated at their promoter regions, in HMLER cells. Among the 3,160 genes downregulated in transformed cells, 380 genes were methylated at their promoter regions in both cell lines, specifically associated by MBD2 in HMLER cells, and upregulated upon MBD2 depletion in HMLER. The transcriptional MBD2-dependent downregulation occurring during oncogenic transformation was also observed in two additional models of mammary cell transformation. Thus, the dynamics of MBD2 deposition across methylated DNA regions was associated with the oncogenic transformation of human mammary cells.
Collapse
Affiliation(s)
- Guillaume Devailly
- Dependence Receptors, Cancer and Development Laboratory - Equipe labellisée 'La Ligue', LabEx DEVweCAN, Centre de Recherche en Cancérologie de Lyon (CRCL), INSERM U1052-CNRS UMR5286, Université de Lyon, Centre Léon Bérard, 69008 Lyon, France
| | - Mélodie Grandin
- Dependence Receptors, Cancer and Development Laboratory - Equipe labellisée 'La Ligue', LabEx DEVweCAN, Centre de Recherche en Cancérologie de Lyon (CRCL), INSERM U1052-CNRS UMR5286, Université de Lyon, Centre Léon Bérard, 69008 Lyon, France
| | - Laury Perriaud
- Institut Curie and INSERM U612, Centre Universitaire, 91405, Orsay, France
| | - Pauline Mathot
- Dependence Receptors, Cancer and Development Laboratory - Equipe labellisée 'La Ligue', LabEx DEVweCAN, Centre de Recherche en Cancérologie de Lyon (CRCL), INSERM U1052-CNRS UMR5286, Université de Lyon, Centre Léon Bérard, 69008 Lyon, France
| | - Jean-Guy Delcros
- Dependence Receptors, Cancer and Development Laboratory - Equipe labellisée 'La Ligue', LabEx DEVweCAN, Centre de Recherche en Cancérologie de Lyon (CRCL), INSERM U1052-CNRS UMR5286, Université de Lyon, Centre Léon Bérard, 69008 Lyon, France
| | - Yannick Bidet
- Laboratoire d'Oncologie Moléculaire, Centre Jean Perrin, 63011 Clermont-Ferrand, France
| | - Anne-Pierre Morel
- EMT and cancer cell plasticity Laboratory - Equipe labellisée 'La Ligue', LabEx DEVweCAN, CRCL, INSERM U1052-CNRS UMR5286, Université de Lyon, Centre Léon Bérard, 69008 Lyon, France
| | - Jean-Yves Bignon
- Laboratoire d'Oncologie Moléculaire, Centre Jean Perrin, 63011 Clermont-Ferrand, France
| | - Alain Puisieux
- EMT and cancer cell plasticity Laboratory - Equipe labellisée 'La Ligue', LabEx DEVweCAN, CRCL, INSERM U1052-CNRS UMR5286, Université de Lyon, Centre Léon Bérard, 69008 Lyon, France
| | - Patrick Mehlen
- Dependence Receptors, Cancer and Development Laboratory - Equipe labellisée 'La Ligue', LabEx DEVweCAN, Centre de Recherche en Cancérologie de Lyon (CRCL), INSERM U1052-CNRS UMR5286, Université de Lyon, Centre Léon Bérard, 69008 Lyon, France
| | - Robert Dante
- Dependence Receptors, Cancer and Development Laboratory - Equipe labellisée 'La Ligue', LabEx DEVweCAN, Centre de Recherche en Cancérologie de Lyon (CRCL), INSERM U1052-CNRS UMR5286, Université de Lyon, Centre Léon Bérard, 69008 Lyon, France
| |
Collapse
|
|
18
|
Mayes K, Qiu Z, Alhazmi A, Landry JW. ATP-dependent chromatin remodeling complexes as novel targets for cancer therapy. Adv Cancer Res 2015; 121:183-233. [PMID: 24889532 DOI: 10.1016/b978-0-12-800249-0.00005-6] [Citation(s) in RCA: 40] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
The progression to advanced stage cancer requires changes in many characteristics of a cell. These changes are usually initiated through spontaneous mutation. As a result of these mutations, gene expression is almost invariably altered allowing the cell to acquire tumor-promoting characteristics. These abnormal gene expression patterns are in part enabled by the posttranslational modification and remodeling of nucleosomes in chromatin. These chromatin modifications are established by a functionally diverse family of enzymes including histone and DNA-modifying complexes, histone deposition pathways, and chromatin remodeling complexes. Because the modifications these enzymes deposit are essential for maintaining tumor-promoting gene expression, they have recently attracted much interest as novel therapeutic targets. One class of enzyme that has not generated much interest is the chromatin remodeling complexes. In this review, we will present evidence from the literature that these enzymes have both causal and enabling roles in the transition to advanced stage cancers; as such, they should be seriously considered as high-value therapeutic targets. Previously published strategies for discovering small molecule regulators to these complexes are described. We close with thoughts on future research, the field should perform to further develop this potentially novel class of therapeutic target.
Collapse
Affiliation(s)
- Kimberly Mayes
- Department of Human and Molecular Genetics, VCU Institute of Molecular Medicine, Massey Cancer Center, Virginia Commonwealth University School of Medicine, Richmond, Virginia, USA
| | - Zhijun Qiu
- Department of Human and Molecular Genetics, VCU Institute of Molecular Medicine, Massey Cancer Center, Virginia Commonwealth University School of Medicine, Richmond, Virginia, USA
| | - Aiman Alhazmi
- Department of Human and Molecular Genetics, VCU Institute of Molecular Medicine, Massey Cancer Center, Virginia Commonwealth University School of Medicine, Richmond, Virginia, USA
| | - Joseph W Landry
- Department of Human and Molecular Genetics, VCU Institute of Molecular Medicine, Massey Cancer Center, Virginia Commonwealth University School of Medicine, Richmond, Virginia, USA.
| |
Collapse
|
|
19
|
Desai MA, Webb HD, Sinanan LM, Scarsdale JN, Walavalkar NM, Ginder GD, Williams DC. An intrinsically disordered region of methyl-CpG binding domain protein 2 (MBD2) recruits the histone deacetylase core of the NuRD complex. Nucleic Acids Res 2015; 43:3100-13. [PMID: 25753662 PMCID: PMC4381075 DOI: 10.1093/nar/gkv168] [Citation(s) in RCA: 57] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2014] [Revised: 02/13/2015] [Accepted: 02/20/2015] [Indexed: 12/20/2022] Open
Abstract
The MBD2-NuRD (Nucleosome Remodeling and Deacetylase) complex is an epigenetic reader of DNA methylation that regulates genes involved in normal development and neoplastic diseases. To delineate the architecture and functional interactions of the MBD2-NuRD complex, we previously solved the structures of MBD2 bound to methylated DNA and a coiled-coil interaction between MBD2 and p66α that recruits the CHD4 nucleosome remodeling protein to the complex. The work presented here identifies novel structural and functional features of a previously uncharacterized domain of MBD2 (MBD2IDR). Biophysical analyses show that the MBD2IDR is an intrinsically disordered region (IDR). However, despite this inherent disorder, MBD2IDR increases the overall binding affinity of MBD2 for methylated DNA. MBD2IDR also recruits the histone deacetylase core components (RbAp48, HDAC2 and MTA2) of NuRD through a critical contact region requiring two contiguous amino acid residues, Arg(286) and Leu(287). Mutating these residues abrogates interaction of MBD2 with the histone deacetylase core and impairs the ability of MBD2 to repress the methylated tumor suppressor gene PRSS8 in MDA-MB-435 breast cancer cells. These findings expand our knowledge of the multi-dimensional interactions of the MBD2-NuRD complex that govern its function.
Collapse
Affiliation(s)
- Megha A Desai
- Department of Human and Molecular Genetics and Massey Cancer Center, Virginia Commonwealth University, Richmond, VA 23298, USA
| | - Heather D Webb
- Department of Pathology and Massey Cancer Center, Virginia Commonwealth University, Richmond, VA 23298, USA
| | - Leander M Sinanan
- Department of Pathology and Laboratory Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
| | - J Neel Scarsdale
- Institute of Structural Biology and Drug Design, Center for the Study of Biological Complexity, and Massey Cancer Center, Virginia Commonwealth University, Richmond, VA 23298, USA
| | - Ninad M Walavalkar
- Department of Pathology and Laboratory Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
| | - Gordon D Ginder
- Departments of Internal Medicine, Human and Molecular Genetics, and Microbiology and Immunology and Massey Cancer Center, Virginia Commonwealth University, Richmond, VA 23298, USA
| | - David C Williams
- Department of Pathology and Laboratory Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
| |
Collapse
|
|
20
|
Alteration of Scn3a expression is mediated via CpG methylation and MBD2 in mouse hippocampus during postnatal development and seizure condition. BIOCHIMICA ET BIOPHYSICA ACTA-GENE REGULATORY MECHANISMS 2014; 1849:1-9. [PMID: 25459751 DOI: 10.1016/j.bbagrm.2014.11.004] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/27/2014] [Revised: 10/13/2014] [Accepted: 11/12/2014] [Indexed: 12/21/2022]
Abstract
Increased expression of sodium channel SCN3A, an embryonic-expressed gene, has been identified in epileptic tissues, which is believed to contribute to the development of epilepsy. However, the regulatory mechanism of SCN3A expression under epileptic condition is still unknown. Here we showed a high level of Scn3a mRNA expression in mouse embryonic hippocampus with gradually decreasing to a low level during the postnatal development and a methylation of a specific CpG site (-39C) in the Scn3a promoter was increased in hippocampus during postnatal development, corresponding to the downregulation of Scn3a expression. Furthermore, in vitro methylation and -39C>T mutation of the Scn3a promoter decreased the reporter gene expression, suggesting an important role of the -39C site in regulating gene expression. We then demonstrated that the sequence containing -39C was a MBD2-binding motif and the CpG methylation of the promoter region increased the capability of MBD2's binding to the motif. Knockdown of MBD2 in mouse N1E-115 cells led to the -39C methylation and the downregulation of Scn3a transcription by decreasing the Scn3a promoter activity. In the hippocampus of seizure mice, the expressions of Scn3a and Mbd2 were upregulated after 10-day KA treatment. At the same time point, the -39C site was demethylated and the capability of MBD2's binding to the Scn3a promoter motif was decreased. Taken together, these findings suggest that CpG methylation and MBD2 are involved in altering Scn3a expression during postnatal development and seizure condition.
Collapse
|
|
21
|
Cheishvili D, Chik F, Li CC, Bhattacharya B, Suderman M, Arakelian A, Hallett M, Rabbani SA, Szyf M. Synergistic effects of combined DNA methyltransferase inhibition and MBD2 depletion on breast cancer cells; MBD2 depletion blocks 5-aza-2'-deoxycytidine-triggered invasiveness. Carcinogenesis 2014; 35:2436-46. [PMID: 25178277 DOI: 10.1093/carcin/bgu181] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
5-Aza-2'-deoxycytidine (5-azaCdR) not only inhibits growth of non-invasive breast cancer cells but also increases their invasiveness through induction of pro-metastatic genes. Methylated DNA binding protein 2 (MBD2) is involved in silencing methylated tumor suppressor genes as well as activation of pro-metastatic genes. In this study, we show that a combination of MBD2 depletion and DNA methyltransferases (DNMT) inhibition in breast cancer cells results in a combined effect in vitro and in vivo, enhancing tumor growth arrest on one hand, while inhibiting invasiveness triggered by 5-azaCdR on the other hand. The combined treatment of MBD2 depletion and 5-azaCdR suppresses and augments distinct gene networks that are induced by DNMT inhibition alone. These data point to a potential new approach in targeting the DNA methylation machinery by combination of MBD2 and DNMT inhibitors.
Collapse
Affiliation(s)
- David Cheishvili
- Department of Pharmacology and Therapeutics, McGill University and
| | - Flora Chik
- Department of Pharmacology and Therapeutics, McGill University and
| | - Chen Chen Li
- Department of Pharmacology and Therapeutics, McGill University and
| | - Bishnu Bhattacharya
- Department of Pharmacology and Therapeutics, McGill University and Sackler Program for Epigenetics and Developmental Psychobiology, McGill University, 3655 Promenade Sir William Osler, Montreal, Quebec H3G 1Y6, Canada, McGill Centre for Bioinformatics, McGill University, 3649 Promenade Sir William Osler, Montreal, Quebec H3G 0B1, Canada and
| | - Matthew Suderman
- Department of Pharmacology and Therapeutics, McGill University and Sackler Program for Epigenetics and Developmental Psychobiology, McGill University, 3655 Promenade Sir William Osler, Montreal, Quebec H3G 1Y6, Canada, McGill Centre for Bioinformatics, McGill University, 3649 Promenade Sir William Osler, Montreal, Quebec H3G 0B1, Canada and
| | - Ani Arakelian
- Department of Medicine, McGill University Health Centre, 687 Pine Avenue West, Room H4.67, Montreal, Quebec H3A 1A1, Canada
| | - Michael Hallett
- McGill Centre for Bioinformatics, McGill University, 3649 Promenade Sir William Osler, Montreal, Quebec H3G 0B1, Canada and
| | - Shafaat A Rabbani
- Department of Medicine, McGill University Health Centre, 687 Pine Avenue West, Room H4.67, Montreal, Quebec H3A 1A1, Canada
| | - Moshe Szyf
- Department of Pharmacology and Therapeutics, McGill University and Sackler Program for Epigenetics and Developmental Psychobiology, McGill University, 3655 Promenade Sir William Osler, Montreal, Quebec H3G 1Y6, Canada,
| |
Collapse
|
|
22
|
Recillas-Targa F. Interdependency between genetic and epigenetic regulatory defects in cancer. Methods Mol Biol 2014; 1165:33-52. [PMID: 24839017 DOI: 10.1007/978-1-4939-0856-1_4] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/05/2023]
Abstract
Epigenetic regulation is understood as heritable changes in gene expression and genome function that can occur without affecting the DNA sequence. In its in vivo context DNA is coupled to a group of small basic proteins that together with the DNA form the chromatin. The organization and regulation of the chromatin alliance with multiple nuclear functions are inconceivable without genetic information. With the advance on the understanding of the chromatin organization of the eukaryotic genome, it has been clear that not only genetics but also epigenetics influence both normal human biology and diseases. As a consequence, the basic concepts and mechanisms of cancer need to be readdressed and viewed not only locally but also at the whole genome scale or even, in the three-dimensional context of the cell nucleus space. Such a vision has a larger impact than has been previously predicted, since phenomena like aging, senescence, the entail of nutrition, stem cell biology, and cancer are orchestrated by epigenetic and genetic processes. Here I describe the relevance and central role of genetic and epigenetic defects in cancer.
Collapse
Affiliation(s)
- Félix Recillas-Targa
- Departamento de Genética Molecular, Instituto de Fisiología Celular, Universidad Nacional Autónoma de México, Apartado Postal 70-242, México, 04510, D.F, México,
| |
Collapse
|
|
23
|
DNA promoter and histone H3 methylation downregulate NGX6 in gastric cancer cells. Med Oncol 2013; 31:817. [PMID: 24338274 DOI: 10.1007/s12032-013-0817-z] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2013] [Accepted: 12/06/2013] [Indexed: 12/27/2022]
Abstract
Nasopharyngeal carcinoma-associated gene 6 (NGX6) is a novel candidate tumor metastasis suppressor gene. Our study was to determine whether DNA hypermethylation and histone modification at the NGX6 gene promoter play important roles in silencing NGX6 expression in gastric cancer. NGX6 expression was downregulated in all gastric cancer cells and 76.19 % tissues. In three GC cell lines, hypermethylated NGX6 loci were characterized by histone H3-K9 hypoacetylation and hypermethylation. Trichostatin A treatment could moderately increase H3-K9 acetylation at the silenced loci; however, it had no effect on DNA and H3-K9 methylation and minimal effects on NGX6 expression. In contrast, 5'aza-2'-deoxycytidine treatment could rapidly decrease DNA and H3-K9 methylation at the silenced loci, leading to the reexpression of NGX6. Combined treatment with 5'aza-2'-deoxycytidine and trichostatin A had synergistic effects on the reexpression of NGX6 at the hypermethylation loci. Our current study shows that NGX6 expression is downregulated in GC cancer cells and tissues due to NGX6 promoter methylation and H3-K9 methylation, but not H3-K9 acetylation. Our findings indicate that the downregulation of NGX6 expression contributes to the development and progression of gastric cancer. More studies are needed to determine the precise mechanism of NGX6 in the progression of gastric cancer.
Collapse
|
|
24
|
Abstract
Cancer has been considered a genetic disease with a wide array of well-characterized gene mutations and chromosomal abnormalities. Of late, aberrant epigenetic modifications have been elucidated in cancer, and together with genetic alterations, they have been helpful in understanding the complex traits observed in neoplasia. "Cancer Epigenetics" therefore has contributed substantially towards understanding the complexity and diversity of various cancers. However, the positioning of epigenetic events during cancer progression is still not clear, though there are some reports implicating aberrant epigenetic modifications in very early stages of cancer. Amongst the most studied aberrant epigenetic modifications are the DNA methylation differences at the promoter regions of genes affecting their expression. Hypomethylation mediated increased expression of oncogenes and hypermethylation mediated silencing of tumor suppressor genes are well known examples. This chapter also explores the correlation of DNA methylation and demethylation enzymes with cancer.
Collapse
Affiliation(s)
- Gopinathan Gokul
- Laboratory of Mammalian Genetics, CDFD, Hyderabad, 500001, India
| | | |
Collapse
|
|
25
|
Koike K, Kasamatsu A, Iyoda M, Saito Y, Kouzu Y, Koike H, Sakamoto Y, Ogawara K, Tanzawa H, Uzawa K. High prevalence of epigenetic inactivation of the human four and a half LIM domains 1 gene in human oral cancer. Int J Oncol 2012; 42:141-50. [PMID: 23123766 DOI: 10.3892/ijo.2012.1677] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2012] [Accepted: 09/28/2012] [Indexed: 11/06/2022] Open
Abstract
The four and a half LIM domains 1 (FHL1) gene has been related to carcinogenesis. However, the expression status of FHL1 in human oral squamous cell carcinoma (OSCC) remains unclear and the detailed mechanism of gene silencing is poorly understood. The aim of this study was to examine the FHL1 expression level and its regulatory mechanism in OSCCs. Quantitative reverse-transcriptase-polymerase chain reaction (PCR) and western blotting showed significant downregulation of FHL1 in all OSCC-derived cell lines (Sa3, HSC-2, HSC-3, HSC-4, HO-1-u-1, HO-1-N-1, KON and Ca9-22) compared to human normal oral keratinocytes. We also found that FHL1 mRNA expression was frequently downregulated (P<0.01) in 51 (86.4%) of 59 primary OSCCs compared with the corresponding normal oral tissues, while there was no significant difference between the status of the FHL1 protein expression in OSCCs and the clinicopathological features. Using methylation-specific PCR, we detected methylated FHL1 in all cell lines and treatment with the DNA methyltransferase inhibitor, 5-aza-2'-deoxycytidine restored the FHL1 expression. However, no significant restoration of FHL1 expression was observed using sodium butyrate, an inhibitor of histone deacetylase and chromatin immunoprecipitation showed that histone H3 lysine 9 in the FHL1 promoter region was significantly acetylated. In addition, no mutation in the entire coding region of the FHL1 gene was found. Therefore, our data suggested that inactivation of the FHL1 gene is a frequent event during oral carcinogenesis and that the mechanism of FHL1 downregulation in OSCCs is through DNA methylation of the promoter region rather than histone deacetylation or mutation.
Collapse
Affiliation(s)
- Kazuyuki Koike
- Department of Clinical Molecular Biology, Chiba University, Chuo-ku, Chiba, Japan
| | | | | | | | | | | | | | | | | | | |
Collapse
|
|
26
|
MBD2 and multiple domains of CHD4 are required for transcriptional repression by Mi-2/NuRD complexes. Mol Cell Biol 2012; 32:5078-88. [PMID: 23071088 DOI: 10.1128/mcb.00819-12] [Citation(s) in RCA: 39] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/02/2023] Open
Abstract
Mi-2/nucleosome remodeling and deacetylase (NuRD) chromatin remodeling complexes are important regulators of chromatin structure and DNA accessibility. We examined requirements for individual domains of chromodomain helicase DNA-binding protein 4 (CHD4), a core catalytic component of NuRD complexes, as well as the NuRD subunit methyl-binding domain protein 2 (MBD2) and methylated DNA, for NuRD function in the context of tissue-specific transcription. By itself, loss of NuRD activity is not sufficient for transcriptional activation. However, NuRD complexes greatly reduce activation of the B cell-specific mb-1 (Cd79a) gene by the transcription factors EBF1 and Pax5. Using our B cell model system, we determined that the two chromodomains and ATPase/helicase and C-terminal domains (CTD) of CHD4 are all necessary for repression of mb-1 promoters by NuRD. All of these domains except the CTD are required for efficient association of CHD4 with mb-1 promoter chromatin. Loss of MBD2 expression or of DNA methylation impaired association of CHD4 with mb-1 promoter chromatin and enhanced its transcription. We conclude that repressive functions of MBD2-containing NuRD complexes are dependent on cooperative interactions between the major domains of CHD4 with histones and DNA and on binding of methylated DNA by MBD2.
Collapse
|
|
27
|
Transcriptional regulation of hTREX84 in human cancer cells. PLoS One 2012; 7:e43610. [PMID: 22952718 PMCID: PMC3428327 DOI: 10.1371/journal.pone.0043610] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2012] [Accepted: 07/23/2012] [Indexed: 11/19/2022] Open
Abstract
TREX (transcription/export) is a multiprotein complex that plays a key role in the transcriptional elongation and transport of mRNA from the nucleus to the cytoplasm. We previously reported the purification of the human TREX protein and found that expression of a member of this complex, p84N5 (referred to as hTREX84 or hHPR1), a RB binding protein, correlated with breast tumor size and metastasis. Here we examine the mechanisms of aberrant expression of hTREX84 in breast and ovarian cancer cells and evaluate its role in tumorigenesis. We show that ovarian tumor cells over-express hTREX84 4-fold and 10-fold compared to immortal, non-tumorigenic and primary ovarian surface epithelial cells, respectively. Reduction of hTREX84 levels by small interfering RNA result in inhibition of cellular proliferation and G(2/M) arrest. Even though we observed that hTREX84 expression was induced by treatment with a demethylation agent, 5-aza-2'-deoxycytidine (5-aza-dC), sodium bisulfite DNA sequencing and methylation specific PCR found no evidence of changes in DNA methylation in the CpG islands in the regulator region of hTREX84. We subsequently identify several transcriptional factors, including NF-κB binding sites in the hTREX84 gene promoter and demonstrate by chromatin immunoprecipation (ChIP) and site directed mutagenesis that RelA/p65 binds the NF-kB binding sites and induces hTREX84 expression. Finally, we show by immunohistochemistry (IHC) that RelA/p65 is abundantly expressed in malignant cells that aberrantly express hTREX84 indicating that RelA/p65 might play a pivotal role in regulating hTREX84 expression in cancer. Our results indicate that overexpression of hTREX84 is associated with cancer cell transformation, proliferation and may be regulated by RelA/p65.
Collapse
|
|
28
|
Gargalionis AN, Piperi C, Adamopoulos C, Papavassiliou AG. Histone modifications as a pathogenic mechanism of colorectal tumorigenesis. Int J Biochem Cell Biol 2012; 44:1276-1289. [PMID: 22583735 DOI: 10.1016/j.biocel.2012.05.002] [Citation(s) in RCA: 37] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2012] [Revised: 05/02/2012] [Accepted: 05/02/2012] [Indexed: 12/16/2022]
Abstract
Epigenetic regulation of gene expression has provided colorectal cancer (CRC) pathogenesis with an additional trait during the past decade. In particular, histone post-translational modifications set up a major component of this process dictating chromatin status and recruiting non-histone proteins in complexes formed to "handle DNA". In CRC, histone marks of aberrant acetylation and methylation levels on specific residues have been revealed, along with a plethora of deregulated enzymes that catalyze these reactions. Mutations, deletions or altered expression patterns transform the function of several histone-modifying proteins, further supporting the crucial role of epigenetic effectors in CRC oncogenesis, being closely associated to inactivation of tumor suppressor genes. Elucidation of the biochemical basis of these new tumorigenic mechanisms allows novel potential prognostic factors to come into play. Moreover, the detection of these changes even in early stages of the multistep CRC process, along with the reversible nature of these mechanisms and the technical capability to detect such alterations in cancer cells, places this group of covalent modifications as a further potential asset for clinical diagnosis or treatment of CRC. This review underlines the biochemistry of histone modifications and the potential regulatory role of histone-modifying proteins in CRC pathogenesis, to date. Furthermore, the underlying mechanisms of the emerging epigenetic interplay along with the chemical compounds that are candidates for clinical use are discussed, offering new insights for further investigation of key histone enzymes and new therapeutic targets.
Collapse
Affiliation(s)
- Antonios N Gargalionis
- Department of Biological Chemistry, University of Athens, Medical School, 11527 Athens, Greece.
| | | | | | | |
Collapse
|
|
29
|
Sun WJ, Zhou X, Zheng JH, Lu MD, Nie JY, Yang XJ, Zheng ZQ. Histone acetyltransferases and deacetylases: molecular and clinical implications to gastrointestinal carcinogenesis. Acta Biochim Biophys Sin (Shanghai) 2012; 44:80-91. [PMID: 22194016 DOI: 10.1093/abbs/gmr113] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
Histone acetyltransferases and deacetylases are two groups of enzymes whose opposing activities govern the dynamic levels of reversible acetylation on specific lysine residues of histones and many other proteins. Gastrointestinal (GI) carcinogenesis is a major cause of morbidity and mortality worldwide. In addition to genetic and environmental factors, the role of epigenetic abnormalities such as aberrant histone acetylation has been recognized to be pivotal in regulating benign tumorigenesis and eventual malignant transformation. Here we provide an overview of histone acetylation, list the major groups of histone acetyltransferases and deacetylases, and cover in relatively more details the recent studies that suggest the links of these enzymes to GI carcinogenesis. As potential novel therapeutics for GI and other cancers, histone deacetylase inhibitors are also discussed.
Collapse
Affiliation(s)
- Wei-Jian Sun
- The 2nd Affiliated Hospital, Wenzhou Medical College, China
| | | | | | | | | | | | | |
Collapse
|
|
30
|
Papoutsis AJ, Borg JL, Selmin OI, Romagnolo DF. BRCA-1 promoter hypermethylation and silencing induced by the aromatic hydrocarbon receptor-ligand TCDD are prevented by resveratrol in MCF-7 cells. J Nutr Biochem 2011; 23:1324-32. [PMID: 22197621 DOI: 10.1016/j.jnutbio.2011.08.001] [Citation(s) in RCA: 55] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2011] [Revised: 07/17/2011] [Accepted: 08/03/2011] [Indexed: 01/26/2023]
Abstract
Epigenetic mechanisms may contribute to reduced expression of the tumor suppressor gene BRCA-1 in sporadic breast cancers. Through environmental exposure and diet, humans are exposed to xenobiotics and food compounds that bind the aromatic hydrocarbon receptor (AhR). AhR-ligands include the dioxin-like and tumor promoter 2,3,7,8 tetrachlorodibenzo-p-dioxin (TCDD). The activated AhR regulates transcription through binding to xenobiotic response elements (XREs=GCGTG) and interactions with transcription cofactors. Previously, we reported on the presence of several XREs in the proximal BRCA-1 promoter and that the expression of endogenous AhR was required for silencing of BRCA-1 expression by TCDD. Here, we document that in estrogen receptor-α-positive and BRCA-1 wild-type MCF-7 breast cancer cells, the treatment with TCDD attenuated 17β-estradiol-dependent stimulation of BRCA-1 protein and induced hypermethylation of a CpG island spanning the BRCA-1 transcriptional start site of exon-1a. Additionally, we found that TCDD enhanced the association of the AhR; DNA methyl transferase (DNMT)1, DNMT3a and DNMT3b; methyl binding protein (MBD)2; and trimethylated H3K9 (H3K9me3) with the BRCA-1 promoter. Conversely, the phytoalexin resveratrol, selected as a prototype dietary AhR antagonist, antagonized at physiologically relevant doses (1 μmol/L) the TCDD-induced repression of BRCA-1 protein, BRCA-1 promoter methylation and the recruitment of the AhR, MBD2, H3K9me3 and DNMTs (1, 3a and 3b). Taken together, these observations provide mechanistic evidence for AhR agonists in the establishment of BRCA-1 promoter hypermethylation and the basis for the development of prevention strategies based on AhR antagonists.
Collapse
Affiliation(s)
- Andreas J Papoutsis
- Department of Nutritional Sciences, The University of Arizona, Tucson, AZ 85721, USA
| | | | | | | |
Collapse
|
|
31
|
Normal Japanese individuals harbor polymorphisms in the p14 ARF /INK4 locus promoters and/or other gene introns. — Variation in nucleotide sequences in each individual. Genes Genomics 2011. [DOI: 10.1007/s13258-011-0085-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/14/2022]
|
|
32
|
Katiyar SK, Singh T, Prasad R, Sun Q, Vaid M. Epigenetic alterations in ultraviolet radiation-induced skin carcinogenesis: interaction of bioactive dietary components on epigenetic targets. Photochem Photobiol 2011; 88:1066-74. [PMID: 22017262 DOI: 10.1111/j.1751-1097.2011.01020.x] [Citation(s) in RCA: 45] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
The importance of epigenetic alterations in the development of various diseases including the cancers has been realized. As epigenetic changes are reversible heritable changes, these can be utilized as an effective strategy for the prevention of cancers. DNA methylation is the most characterized epigenetic mechanism that can be inherited without changing the DNA sequence. Although limited available data suggest that silencing of tumor suppressor genes in ultraviolet (UV) radiation-exposed epidermis leads to photocarcinogenesis and is associated with a network of epigenetic modifications including alterations in DNA methylation, DNA methyltransferases and histone acetylations. Various bioactive dietary components have been shown to protect skin from UV radiation-induced skin tumors in animal models. The role of bioactive dietary components, such as, (-)-epicatechins from green tea and proanthocyanidins from grape seeds has been assessed in chemoprevention of UV-induced skin carcinogenesis and underlying epigenetic mechanism in vitro and in vivo animal models. These bioactive components have the ability to block UV-induced DNA hypermethylation and histone modifications in the skin required for the silencing of tumor suppressor genes (e.g. Cip1/p21, p16(INK4a) ). This information is of importance for understanding the role of epigenetic modulation in UV-induced skin tumor and the chemopreventive mechanism of bioactive dietary components.
Collapse
|
|
33
|
Zhu D, Hunter SB, Vertino PM, Van Meir EG. Overexpression of MBD2 in glioblastoma maintains epigenetic silencing and inhibits the antiangiogenic function of the tumor suppressor gene BAI1. Cancer Res 2011; 71:5859-70. [PMID: 21724586 PMCID: PMC3165103 DOI: 10.1158/0008-5472.can-11-1157] [Citation(s) in RCA: 57] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
Brain angiogenesis inhibitor 1 (BAI1) is a putative G protein-coupled receptor with potent antiangiogenic and antitumorigenic properties that is mutated in certain cancers. BAI1 is expressed in normal human brain, but it is frequently silenced in glioblastoma multiforme. In this study, we show that this silencing event is regulated by overexpression of methyl-CpG-binding domain protein 2 (MBD2), a key mediator of epigenetic gene regulation, which binds to the hypermethylated BAI1 gene promoter. In glioma cells, treatment with the DNA demethylating agent 5-aza-2'-deoxycytidine (5-Aza-dC) was sufficient to reactivate BAI1 expression. Chromatin immunoprecipitation showed that MBD2 was enriched at the promoter of silenced BAI1 in glioma cells and that MBD2 binding was released by 5-Aza-dC treatment. RNA interference-mediated knockdown of MBD2 expression led to reactivation of BAI1 gene expression and restoration of BAI1 functional activity, as indicated by increased antiangiogenic activity in vitro and in vivo. Taken together, our results suggest that MBD2 overexpression during gliomagenesis may drive tumor growth by suppressing the antiangiogenic activity of a key tumor suppressor. These findings have therapeutic implications because inhibiting MBD2 could offer a strategy to reactivate BAI1 and suppress glioma pathobiology.
Collapse
Affiliation(s)
- Dan Zhu
- Laboratory of Molecular Neuro-Oncology, Department of Neurosurgery, School of Medicine, Emory University, Atlanta, Georgia, USA
| | | | | | | |
Collapse
|
|
34
|
Mossman D, Scott RJ. Long term transcriptional reactivation of epigenetically silenced genes in colorectal cancer cells requires DNA hypomethylation and histone acetylation. PLoS One 2011; 6:e23127. [PMID: 21829702 PMCID: PMC3150411 DOI: 10.1371/journal.pone.0023127] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2010] [Accepted: 07/12/2011] [Indexed: 11/18/2022] Open
Abstract
UNLABELLED Epigenetic regulation of genes involves the coordination of DNA methylation and histone modifications to maintain transcriptional status. These two features are frequently disrupted in malignancy such that critical genes succumb to inactivation. 5-aza-2'-deoxycytidine (5-aza-dC) is an agent which inhibits DNA methyltransferase, and holds great potential as a treatment for cancer, yet the extent of its effectiveness varies greatly between tumour types. Previous evidence suggests expression status after 5-aza-dC exposure cannot be explained by the DNA methylation status alone. AIM We sought to identify chromatin changes involved with short and long term gene reactivation following 5-aza-dC exposure. Two colorectal cancer cell lines, HCT116 and SW480, were treated with 5-aza-dC and then grown in drug-free media to allow DNA re-methylation. DNA methylation and chromatin modifications were assessed with bisulfite sequencing and Chromatin Immuno-Precipitation analysis. RESULTS Increased H3 acetylation, H3K4 tri-methylation and loss of H3K27 tri-methylation were associated with reactivation. Hypermethylated genes that did not show increased acetylation were transiently expressed with 5-aza-dC treatment before reverting to an inactive state. Three reactivated genes, CDO1, HSPC105 and MAGEA3, were still expressed 10 days post 5-aza-dC treatment and displayed localised hypomethylation at the transcriptional start site, and also an increased enrichment of histone H3 acetylation. CONCLUSIONS These observations suggest that hypomethylation alone is insufficient to reactivate silenced genes and that increased Histone H3 acetylation in unison with localised hypomethylation allows long term reversion of these epigenetically silenced genes. This study suggests that combined DNA methyltransferase and histone deacetylase inhibitors may aid long term reactivation of silenced genes.
Collapse
Affiliation(s)
- David Mossman
- Discipline of Medical Genetics, School of Biomedical Sciences, Faculty of Health, University of Newcastle, Callaghan, New South Wales, Australia
- Hunter Medical Research Institute, New Lambton Heights, New South Wales, Australia
| | - Rodney J. Scott
- Discipline of Medical Genetics, School of Biomedical Sciences, Faculty of Health, University of Newcastle, Callaghan, New South Wales, Australia
- Hunter Medical Research Institute, New Lambton Heights, New South Wales, Australia
- Division of Genetics, Hunter Area Pathology Service, John Hunter Hospital, Newcastle, New South Wales, Australia
- * E-mail:
| |
Collapse
|
|
35
|
Abstract
The nucleosome remodelling and histone deacetylase (NuRD; also known as Mi-2) complex regulates gene expression at the level of chromatin. The NuRD complex has been identified - using both genetic and molecular analyses - as a key determinant of differentiation in mouse embryonic stem cells and during development in various model systems. Similar to other chromatin remodellers, such as SWI/SNF and Polycomb complexes, NuRD has also been implicated in the regulation of transcriptional events that are integral to oncogenesis and cancer progression. Emerging molecular details regarding the recruitment of NuRD to specific loci during development, and the modulation of these events in cancer, are used to illustrate how the inappropriate localization of the complex could contribute to tumour biology.
Collapse
Affiliation(s)
- Anne Y Lai
- Laboratory of Molecular Carcinogenesis, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina NC 27709, USA.
| | | |
Collapse
|
|
36
|
Ohsaka Y, Nishino H. Polymorphisms in promoter sequences of MDM2, p53, and p16 genes in normal Japanese individuals. Genet Mol Biol 2011; 33:615-26. [PMID: 21637567 PMCID: PMC3036159 DOI: 10.1590/s1415-47572010000400004] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2010] [Accepted: 07/02/2010] [Indexed: 02/11/2023] Open
Abstract
Research has been conducted to identify sequence polymorphisms of gene promoter regions in patients and control subjects, including normal individuals, and to determine the influence of these polymorphisms on transcriptional regulation in cells that express wild-type or mutant p53. In this study we isolated genomic DNA from whole blood of healthy Japanese individuals and sequenced the promoter regions of the MDM2, p53, and p16(INK4a) genes. We identified polymorphisms comprising 3 nucleotide substitutions at exon 1 and intron 1 regions of the MDM2 gene and 1 nucleotide insertion at a poly(C) nucleotide position in the p53 gene. The Japanese individuals also exhibited p16(INK4a) polymorphisms at several positions, including position -191. Reporter gene analysis by using luciferase revealed that the polymorphisms of MDM2, p53, and p16(INK4a) differentially altered luciferase activities in several cell lines, including the Colo320DM, U251, and T98G cell lines expressing mutant p53. Our results indicate that the promoter sequences of these genes differ among normal Japanese individuals and that polymorphisms can alter gene transcription activity.
Collapse
Affiliation(s)
- Yasuhito Ohsaka
- Department of Biochemistry and Molecular Biology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto Japan
| | | |
Collapse
|
|
37
|
Scarsdale JN, Webb HD, Ginder GD, Williams DC. Solution structure and dynamic analysis of chicken MBD2 methyl binding domain bound to a target-methylated DNA sequence. Nucleic Acids Res 2011; 39:6741-52. [PMID: 21531701 PMCID: PMC3159451 DOI: 10.1093/nar/gkr262] [Citation(s) in RCA: 80] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022] Open
Abstract
The epigenetic code of DNA methylation is interpreted chiefly by methyl cytosine binding domain (MBD) proteins which in turn recruit multiprotein co-repressor complexes. We previously isolated one such complex, MBD2-NuRD, from primary erythroid cells and have shown it contributes to embryonic/fetal β-type globin gene silencing during development. This complex has been implicated in silencing tumor suppressor genes in a variety of human tumor cell types. Here we present structural details of chicken MBD2 bound to a methylated DNA sequence from the ρ-globin promoter to which it binds in vivo and mediates developmental transcriptional silencing in normal erythroid cells. While previous studies have failed to show sequence specificity for MBD2 outside of the symmetric mCpG, we find that this domain binds in a single orientation on the ρ-globin target DNA sequence. Further, we show that the orientation and affinity depends on guanine immediately following the mCpG dinucleotide. Dynamic analyses show that DNA binding stabilizes the central β-sheet, while the N- and C-terminal regions of the protein maintain mobility. Taken together, these data lead to a model in which DNA binding stabilizes the MBD2 structure and that binding orientation and affinity is influenced by the DNA sequence surrounding the central mCpG.
Collapse
Affiliation(s)
- J Neel Scarsdale
- Institute of Structural Biology and Drug Design, Virginia Commonwealth University, Richmond, VA 23298-0035, USA
| | | | | | | |
Collapse
|
|
38
|
Nandakumar V, Vaid M, Tollefsbol TO, Katiyar SK. Aberrant DNA hypermethylation patterns lead to transcriptional silencing of tumor suppressor genes in UVB-exposed skin and UVB-induced skin tumors of mice. Carcinogenesis 2011; 32:597-604. [PMID: 21186298 PMCID: PMC3066413 DOI: 10.1093/carcin/bgq282] [Citation(s) in RCA: 67] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2010] [Revised: 12/13/2010] [Accepted: 12/20/2010] [Indexed: 12/31/2022] Open
Abstract
Overexposure of the human skin to solar ultraviolet (UV) radiation is the major etiologic factor for development of skin cancers. Here, we report the results of epigenetic modifications in UV-exposed skin and skin tumors in a systematic manner. The skin and tumor samples were collected after chronic exposure of the skin of SKH-1 hairless mice to UVB radiation using a well-established photocarcinogenesis protocol. We found a distinct DNA hypermethylation pattern in the UVB-exposed epidermal skin and UVB-induced skin tumors that was associated with the elevated expression and activity of the DNA methyltransferases (Dnmt) 1, Dnmt3a and Dnmt3b. To explore the role of hypermethylation in skin photocarcinogenesis, we focused on the p16(INK4a) and RASSF1A tumor suppressor genes, which are transcriptionally silenced on methylation. We established that the silencing of these genes in UVB-exposed epidermis and UVB-induced skin tumors is associated with a network of epigenetic modifications, including hypoacetylation of histone H3 and H4 and increased histone deacetylation, as well as recruitment of methyl-binding proteins, including MeCP2 and MBD1, to the methylated CpGs. Higher levels of DNA methylation and DNMT activity in human squamous cell carcinoma specimens than in normal human skin suggest that the data are relevant clinically. Our data indicate for the first time that UVB-induced DNA hypermethylation, enhanced Dnmt activity and histone modifications occur in UVB-exposed skin and UVB-induced skin tumors and suggest that these events are involved in the silencing of tumor suppressor genes and in skin tumor development.
Collapse
Affiliation(s)
| | | | - Trygve O. Tollefsbol
- Department of Biology, University of Alabama at Birmingham, 1670, University Boulevard, Volker Hall 557, AL 35294,USA
| | - Santosh K. Katiyar
- Department ofDermatology
- Birmingham Veterans Affairs Medical Center, Birmingham, AL 35294, USA
| |
Collapse
|
|
39
|
Pérot G, Chibon F, Montero A, Lagarde P, de Thé H, Terrier P, Guillou L, Ranchère D, Coindre JM, Aurias A. Constant p53 pathway inactivation in a large series of soft tissue sarcomas with complex genetics. THE AMERICAN JOURNAL OF PATHOLOGY 2011; 177:2080-90. [PMID: 20884963 DOI: 10.2353/ajpath.2010.100104] [Citation(s) in RCA: 85] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Abstract] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Alterations of the p53 pathway are among the most frequent aberrations observed in human cancers. We have performed an exhaustive analysis of TP53, p14, p15, and p16 status in a large series of 143 soft tissue sarcomas, rare tumors accounting for around 1% of all adult cancers, with complex genetics. For this purpose, we performed genomic studies, combining sequencing, copy number assessment, and expression analyses. TP53 mutations and deletions are more frequent in leiomyosarcomas than in undifferentiated pleomorphic sarcomas. Moreover, 50% of leiomyosarcomas present TP53 biallelic inactivation, whereas most undifferentiated pleomorphic sarcomas retain one wild-type TP53 allele (87.2%). The spectrum of mutations between these two groups of sarcomas is different, particularly with a higher rate of complex mutations in undifferentiated pleomorphic sarcomas. Most tumors without TP53 alteration exhibit a deletion of p14 and/or lack of mRNA expression, suggesting that p14 loss could be an alternative genotype for direct TP53 inactivation. Nevertheless, the fact that even in tumors altered for TP53, we could not detect p14 protein suggests that other p14 functions, independent of p53, could be implicated in sarcoma oncogenesis. In addition, both p15 and p16 are frequently codeleted or transcriptionally co-inhibited with p14, essentially in tumors with two wild-type TP53 alleles. Conversely, in TP53-altered tumors, p15 and p16 are well expressed, a feature not incompatible with an oncogenic process.
Collapse
Affiliation(s)
- Gaëlle Pérot
- Institut Curie, Genetics and Biology of Cancers, Paris, France
| | | | | | | | | | | | | | | | | | | |
Collapse
|
|
40
|
Zhang Y. Biology of the Mi-2/NuRD Complex in SLAC (Stemness, Longevity/Ageing, and Cancer). GENE REGULATION AND SYSTEMS BIOLOGY 2011; 5:1-26. [PMID: 21523247 PMCID: PMC3080740 DOI: 10.4137/grsb.s6510] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
The dynamic chromatin activities of Mi-2/Nucleosome Remodeling and Histone deacetylation (Mi-2/NuRD) complexes in mammals are at the basis of current research on stemness, longevity/ageing, and cancer (4-2-1/SLAC), and have been widely studied over the past decade in mammals and the elegant model organism, Caenorhabditis elegans. Interestingly, a common emergent theme from these studies is that of distinct coregulator-recruited Mi-2/NuRD complexes largely orchestrating the 4-2-1/SLAC within a unique paradigm by maintaining genome stability via DNA repair and controlling three types of transcriptional programs in concert in a number of cellular, tissue, and organism contexts. Thus, the core Mi-2/NuRD complex plays a central role in 4-2-1/SLAC. The plasticity and robustness of 4-2-1/SLAC can be interpreted as modulation of specific coregulator(s) within cell-specific, tissue-specific, stage-specific, or organism-specific niches during stress induction, ie, a functional module and its networking, thereby conferring differential responses to different environmental cues. According to “Occam’s razor”, a simple theory is preferable to a complex one, so this simplified notion might be useful for exploring 4-2-1/SLAC with a holistic view. This thought could also be valuable in forming strategies for future research, and could open up avenues for cancer prevention and antiageing strategies.
Collapse
Affiliation(s)
- Yue Zhang
- Department of Radiation Oncology, Beth Israel Deaconess Medical Center, Harvard Medical School, 99 Brookline Avenue, Boston, MA 02215, USA
| |
Collapse
|
|
41
|
Abstract
Plasma cell leukemia (PCL) is a rare, yet aggressive plasma cell (PC) neoplasm, variant of multiple myeloma (MM), characterized by high levels of PCs circulating in the peripheral blood. PCL can either originate de novo (primary PCL) or as a secondary leukemic transformation of MM (secondary PCL). Presenting signs and symptoms are similar to those seen in MM such as renal insufficiency, hypercalcemia, lytic bone lesions, anemia, and thrombocytopenia, but can also include hepatomegaly and splenomegaly. The diagnostic evaluation of a patient with suspected PCL should include a review of the peripheral blood smear, bone marrow aspiration and biopsy, serum protein electrophoresis (SPEP) with immunofixation, and protein electrophoresis of an aliquot from a 24h urine collection (UPEP). The diagnosis is made when a monoclonal population of PCs is present in the peripheral blood with an absolute PC count exceeding 2000/μL and PC comprising 20% or more of the peripheral blood white cells. The prognosis of PCL is poor with a median survival of 7 to 11 months. Survival is even shorter (2 to 7 months) when PCL occurs in the context of refractory or relapsing MM. There have been no prospective randomized trials investigating the treatment of PCL. Recommendations are primarily based upon data from small retrospective series, case reports, and extrapolation of data from patients with MM. In general, patients are treated with induction therapy followed by hematopoietic cell transplantation (HCT) in those who are appropriate candidates for this approach. The best induction regimen for PCL is not known and there is great variability in clinical practice. Newer agents that are being incorporated into frontline and salvage therapy for MM have also demonstrated activity in PCL such as Immunomodulatory agents and the use of bortezomib with different combinations.
Collapse
|
|
42
|
Adkins NL, Georgel PT. MeCP2: structure and functionThis paper is one of a selection of papers published in a Special Issue entitled 31st Annual International Asilomar Chromatin and Chromosomes Conference, and has undergone the Journal’s usual peer review process. Biochem Cell Biol 2011; 89:1-11. [DOI: 10.1139/o10-112] [Citation(s) in RCA: 73] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/05/2023] Open
Abstract
Despite a vast body of literature linking chromatin structure to regulation of gene expression, the role of architectural proteins in higher order chromatin transitions required for transcription activation and repression has remained an under-studied field. To demonstrate the current knowledge of the role of such proteins, we have focused our attention on the methylated DNA binding and chromatin-associated protein MeCP2. Structural studies using chromatin assembled in vitro have revealed that MeCP2 can associate with nucleosomes in an N-terminus dependent manner and efficiently condense nucleosome arrays. The present review attempts to match MeCP2 structural domains, or lack thereof, and specific chromatin features needed for the proper recruitment of MeCP2 to its multiple functions as either activator or repressor. We specifically focused on MeCP2’s role in Rett syndrome, a neurological disorder associated with specific MeCP2 mutations.
Collapse
Affiliation(s)
- Nicholas L. Adkins
- Byrd Biotechnology Building, Department of Biological Sciences, Marshall University, 1 John Marshall Drive, Huntington, WV 25755, USA
| | - Philippe T. Georgel
- Byrd Biotechnology Building, Department of Biological Sciences, Marshall University, 1 John Marshall Drive, Huntington, WV 25755, USA
| |
Collapse
|
|
43
|
Chatagnon A, Ballestar E, Esteller M, Dante R. A role for methyl-CpG binding domain protein 2 in the modulation of the estrogen response of pS2/TFF1 gene. PLoS One 2010; 5:e9665. [PMID: 20300195 PMCID: PMC2837351 DOI: 10.1371/journal.pone.0009665] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2010] [Accepted: 02/18/2010] [Indexed: 12/20/2022] Open
Abstract
BACKGROUND In human Estrogen Receptor alpha (ERalpha)-positive breast cancers, 5' end dense methylation of the estrogen-regulated pS2/TFF1 gene correlates with its transcriptional inhibition. However, in some ERalpha-rich biopsies, pS2 expression is observed despite the methylation of its TATA-box region. Herein, we investigated the methylation-dependent mechanism of pS2 regulation. METHODOLOGY/PRINCIPAL FINDINGS We observed interplay between Methyl-CpG Binding Domain protein 2 (MBD2) transcriptional repressor and ERalpha transactivator: (i) the pS2 gene is poised for transcription upon demethylation limited to the enhancer region containing the estrogen responsive element (ERE); (ii) MBD2-binding sites overlapped with the methylation status of the pS2 5' end; (iii) MBD2 depletion elevated pS2 expression and ectopic expression of ERalpha partially overcame the inhibitory effect of MBD2 when the ERE is unmethylated. Furthermore, serial chromatin immunoprecipitation assays indicated that MBD2 and ERalpha could simultaneously occupy the same pS2 DNA molecule; (iv) concomitant ectopic ERalpha expression and MBD2 depletion resulted in synergistic transcriptional stimulation, while the pS2 promoter remains methylated. CONCLUSIONS/SIGNIFICANCE MBD2 and ERalpha drive opposite effects on pS2 expression, which are associated with specific steady state levels of histone H3 acetylation and methylation marks. Thus, epigenetic silencing of pS2 could be dependent on balance of the relative intracellular concentrations of ERalpha and MBD2.
Collapse
Affiliation(s)
| | - Esteban Ballestar
- Cancer Epigenetics and Biology Programme (PEBC), Catalan Institute of Oncology (ICO-IDIBELL), L'Hospitalet de Llobregat, Barcelona, Spain
| | - Manel Esteller
- Cancer Epigenetics and Biology Programme (PEBC), Catalan Institute of Oncology (ICO-IDIBELL), L'Hospitalet de Llobregat, Barcelona, Spain
| | | |
Collapse
|
|
44
|
Wu Y, Alvarez M, Slamon DJ, Koeffler P, Vadgama JV. Caspase 8 and maspin are downregulated in breast cancer cells due to CpG site promoter methylation. BMC Cancer 2010; 10:32. [PMID: 20132554 PMCID: PMC2824712 DOI: 10.1186/1471-2407-10-32] [Citation(s) in RCA: 60] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2009] [Accepted: 02/04/2010] [Indexed: 12/29/2022] Open
Abstract
Background Epigenetic changes associated with promoter DNA methylation results in silencing of several tumor suppressor genes that lead to increased risk for tumor formation and for progression of the cancer. Methods Methylation specific PCR (MSP) and bisulfite sequencing were used for determination of proapoptotic gene Caspase 8 (CASP8) and the tumor suppressor gene maspin promoter methylation in four breast cancer and two non-tumorigenic breast cell lines. Involvement of histone H3 methylation in those cell lines were examined by CHIP assay. Results The CpG sites in the promoter region of CASP8 and maspin were methylated in all four breast cancer cell lines but not in two non-tumorigenic breast cell lines. Demethylation agent 5-aza-2'-deoxycytidine (5-aza-dc) selectively inhibits DNA methyltransferases, DNMT3a and DNMT3b, and restored CASP8 and maspin gene expression in breast cancer cells. 5-aza-dc also reduced histone H3k9me2 occupancy on CASP8 promoter in SKBR3cells, but not in MCF-7 cells. Combination of histone deacetylase inhibitor Trichostatin A (TSA) and 5-aza-dc significant decrease in nuclear expression of Di-methyl histone H3-Lys27 and slight increase in acetyl histone H3-Lys9 in MCF-7 cells. CASP8 mRNA and protein level in MCF-7 cells were increased by the 5-aza-dc in combination with TSA. Data from our study also demonstrated that treatment with 5-FU caused a significant increase in unmethylated CASP8 and in CASP8 mRNA in all 3 cancer lines. Conclusions CASP8 and maspin expression were reduced in breast cancer cells due to promoter methylation. Selective application of demethylating agents could offer novel therapeutic opportunities in breast cancer.
Collapse
Affiliation(s)
- Yanyuan Wu
- Division of Cancer Research and Training, Department of Internal Medicine, Charles R, Drew University of Medicine and Science, Los Angeles, CA 90059, USA
| | | | | | | | | |
Collapse
|
|
45
|
Plasma cell leukemia: a highly aggressive monoclonal gammopathy with a very poor prognosis. Int J Hematol 2009; 89:259-268. [PMID: 19326058 DOI: 10.1007/s12185-009-0288-3] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2008] [Revised: 01/27/2009] [Accepted: 02/23/2009] [Indexed: 10/21/2022]
Abstract
Plasma cell leukemia (PCL) is an aggressive variant of multiple myeloma and is characterized by the presence of >20% and/or an absolute number of greater 2 x 10(9)/L plasma cells circulating in the peripheral blood. PCL represents approximately 2-4% of all MM diagnosis and exists in two forms: primary PCL (PPCL, 60% of cases) presents de novo, whereas secondary PCL (SPCL, accounts for the remaining 40%) consists of a leukemic transformation in patients with a previously diagnosed MM. Because the mechanisms contributing to the pathogenesis of PCL are not fully understood, immunophenotyping, genetic evaluation (conventional karyotype, FISH, GEP and array-CGH), and immunohistochemistry are really important tools to investigate why plasma cells escape from bone marrow and become highly aggressive. Since treatment with standard agents and steroids is poorly effective, a combination of new drugs as part of the induction regimens and bone marrow transplant (autologous and allogeneic approaches) could nearly overcome the poor prognosis exhibited by PCL patients.
Collapse
|
|
46
|
Vallian S, Sedaghat M, Nassiri I, Frazmand A. Methylation status of p16 INK4A tumor suppressor gene in Iranian patients with sporadic breast cancer. J Cancer Res Clin Oncol 2009; 135:991-6. [PMID: 19125298 DOI: 10.1007/s00432-008-0534-8] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2008] [Accepted: 12/08/2008] [Indexed: 11/27/2022]
Abstract
INTRODUCTION p16(INK4A) is a tumor suppressor encoding the Cdk inhibitor protein, which acts to repress Cdk4/6 and pRb phosphorylation. p16(INK4A) gene can be inactivated by a variety of events, including promoter hypermethylation. MATERIALS AND METHODS To investigate the methylation status of the p16(INK4A) gene in Iranian patients with breast carcinoma, promoter methylation was studied by methylation-specific PCR (MSP) and restriction enzyme-related PCR (REP). In addition, p16(INK4A) promoter was analyzed by PCR-SSCP in order to detection of mutation and single nucleotide polymorphisms. RESULTS Analysis of 70 patients by MPS and REP showed hypermethylation of p16(INK4A) promoter in 35.7% (25/70) and 40% (28/70) of samples, respectively. Comparison of the molecular data and pathological information of the samples suggested that p16(INK4A) gene might be inactivated at the early stages in breast cancer. CONCLUSION Therefore, it could be suggested that hypermethylation of p16(INK4A) promoter is one of the epigenetic factors affecting the progress of sporadic breast carcinogenesis in Iranian patients.
Collapse
Affiliation(s)
- Sadeq Vallian
- Division of Genetics, Department of Biology, Faculty of Science, The University of Isfahan, Hezarjerib St., Isfahan, Islamic Republic of Iran.
| | | | | | | |
Collapse
|
|
47
|
Lu B, Ma Y, Wu G, Tong X, Guo H, Liang A, Cong W, Liu C, Wang H, Wu M, Zhao J, Guo Y. Methylation of Tip30 promoter is associated with poor prognosis in human hepatocellular carcinoma. Clin Cancer Res 2009; 14:7405-12. [PMID: 19010857 DOI: 10.1158/1078-0432.ccr-08-0409] [Citation(s) in RCA: 37] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/15/2023]
Abstract
PURPOSE To investigate Tip30 promoter methylation status in human hepatocellular carcinoma (HCC) and the correlation with clinicopathologic features and prognosis. EXPERIMENTAL DESIGN The methylation status of CpG islands in Tip30 promoter was examined in 15 HCC cell lines as well as 59 paired HCC and adjacent nontumor tissues. The associations between Tip30 methylation status and the survival of patients were analyzed. RESULTS Tip30 promoter was hypermethylated in 6 of 10 HCC cell lines with reduced Tip30 mRNA. DNA methyltransferase inhibitor, 5-aza-2'-deoxycytidine, greatly enhanced TIP30 expression and sensitized HCC cells to cytotoxic drug-induced cell death. The promoter region of Tip30 was identified and the main promoter activity was located in the -135 to -45 region sited within a CpG island. The minimal promoter element contained four Sp1 binding sites, which were hypermethylated in HCC cell-derived promoters. Moreover, analyses of Tip30 promoter methylation status in 59 paired HCC tissues showed that 47% of the cases were hypermethylated. Recurrence rate (95% versus 67%; P = 0.011) and mortality (82% versus 53%; P = 0.033) were significantly higher in patients with methylated Tip30. Disease-free survival was significantly higher in patients with unmethylated Tip30 (33.3% versus 4.5%; P = 0.036). CONCLUSIONS Our results show that epigenetic silencing of Tip30 gene expression by CpG island DNA hypermethylation is associated with poor prognosis in patients with HCC.
Collapse
Affiliation(s)
- Bin Lu
- International Cancer Institute and Eastern Hospital of Hepatobiliary Surgery, Second Military Medical University, Shanghai, People's Republic of China
| | | | | | | | | | | | | | | | | | | | | | | |
Collapse
|
|
48
|
Karrasch S, Holz O, Jörres RA. Aging and induced senescence as factors in the pathogenesis of lung emphysema. Respir Med 2008; 102:1215-30. [PMID: 18617381 DOI: 10.1016/j.rmed.2008.04.013] [Citation(s) in RCA: 81] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/16/2007] [Revised: 03/21/2008] [Accepted: 04/04/2008] [Indexed: 12/17/2022]
Abstract
Classically, the development of emphysema in chronic obstructive pulmonary disease is believed to involve inflammation induced by cigarette smoke and leukocyte activation, including oxidant-antioxidant and protease-antiprotease imbalances. While there is substantial evidence for this, additional aspects have been suggested by a number of clinical and experimental observations. Smokers exhibit signs of premature aging, particularly obvious in the skin. The link between aging and chronic disease is well-known, e.g., for the brain and musculoskeletal or cardiovascular system, as well as the clinical link between malnutrition and emphysema, and the experimental link to caloric restriction. Interestingly, this intervention also increases lifespan, in parallel with alterations in metabolism, oxidant burden and endocrine signaling. Of special interest is the observation that, even in the absence of an inflammatory environment, lung fibroblasts from patients with emphysema show persistent alterations, possibly based on epigenetic mechanisms. The importance of these mechanisms for cellular reprogramming and response patterns, individual risk profile and therapeutic options is becoming increasingly recognized. The same applies to cellular senescence. Recent findings from patients and experimental models open novel views into the arena of gene-environment interactions, including the role of systemic alterations, cellular stress, telomeres, CDK inhibitors such as p16, p21, pRb, PI3K, mTOR, FOXO transcription factors, histone modifications, and sirtuins. This article aims to outline this emerging picture and to stimulate the identification of challenging questions. Such insights also bear implications for the long-term course of the disease in relation to existing or future therapies and the exploration of potential lung regeneration.
Collapse
Affiliation(s)
- Stefan Karrasch
- Institute for Inhalation Biology, Helmholtz Zentrum München - German Research Center for Environmental Health, Neuherberg/Munich, Germany
| | | | | |
Collapse
|
|
49
|
Tiedemann RE, Gonzalez-Paz N, Kyle RA, Santana-Davila R, Price-Troska T, Van Wier SA, Chng WJ, Ketterling RP, Gertz MA, Henderson K, Greipp PR, Dispenzieri A, Lacy MQ, Rajkumar SV, Bergsagel PL, Stewart AK, Fonseca R. Genetic aberrations and survival in plasma cell leukemia. Leukemia 2008; 22:1044-52. [PMID: 18216867 PMCID: PMC3893817 DOI: 10.1038/leu.2008.4] [Citation(s) in RCA: 226] [Impact Index Per Article: 13.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2007] [Revised: 12/05/2007] [Accepted: 01/03/2008] [Indexed: 12/27/2022]
Abstract
Plasma cell leukemia (PCL) is an aggressive and rare hematological malignancy that originates either as primary disease (pPCL) or as a secondary leukemic transformation (sPCL) of multiple myeloma (MM). We report here the genetic aberrations and survival of 80 patients with pPCL or sPCL and make comparisons with 439 cases of MM. pPCL presents a decade earlier than sPCL (54.7 vs 65.3 years) and is associated with longer median overall survival (11.1 vs 1.3 months; P<0.001). 14q32 (IgH) translocations are highly prevalent in both sPCL and pPCL (82-87%); in pPCL IgH translocations almost exclusively involve 11q13 (CCND1), supporting a central etiological role, while in sPCL multiple partner oncogenes are involved, including 11q13, 4p16 (FGFR3/MMSET) and 16q23 (MAF), recapitulating MM. Both show ubiquitous inactivation of TP53 (pPCL 56%; sPCL 83%) by coding mutation or 17p13 deletion; complemented by p14ARF epigenetic silencing in sPCL (29%). Both show frequent N-RAS or K-RAS mutation. Poor survival in pPCL was predicted by MYC translocation (P=0.006). Survival in sPCL was consistently short. Overall pPCL and sPCL are different disorders with distinct natural histories, genetics and survival.
Collapse
Affiliation(s)
- RE Tiedemann
- Division of Hematology and Oncology, Mayo Clinic, Scottsdale, AZ, USA
| | | | - RA Kyle
- Division of Hematology, Mayo Clinic, Rochester, MN, USA
| | - R Santana-Davila
- Department of Medicine, University of Minnesota, Minneapolis, MN, USA
| | | | - SA Van Wier
- Division of Hematology and Oncology, Mayo Clinic, Scottsdale, AZ, USA
| | - WJ Chng
- Division of Hematology and Oncology, Mayo Clinic, Scottsdale, AZ, USA
| | - RP Ketterling
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA
| | - MA Gertz
- Division of Hematology, Mayo Clinic, Rochester, MN, USA
| | - K Henderson
- Division of Hematology, Mayo Clinic, Rochester, MN, USA
| | - PR Greipp
- Division of Hematology, Mayo Clinic, Rochester, MN, USA
| | - A Dispenzieri
- Division of Hematology, Mayo Clinic, Rochester, MN, USA
| | - MQ Lacy
- Division of Hematology, Mayo Clinic, Rochester, MN, USA
| | - SV Rajkumar
- Division of Hematology, Mayo Clinic, Rochester, MN, USA
| | - PL Bergsagel
- Division of Hematology and Oncology, Mayo Clinic, Scottsdale, AZ, USA
| | - AK Stewart
- Division of Hematology and Oncology, Mayo Clinic, Scottsdale, AZ, USA
| | - R Fonseca
- Division of Hematology and Oncology, Mayo Clinic, Scottsdale, AZ, USA
| |
Collapse
|
|
50
|
Unmasking of epigenetically silenced candidate tumor suppressor genes by removal of methyl-CpG-binding domain proteins. Oncogene 2008; 27:3556-66. [PMID: 18223687 DOI: 10.1038/sj.onc.1211022] [Citation(s) in RCA: 46] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
Methyl-cytosine-phosphate-guanine (CpG)-binding domain (MBD) proteins are bound to hypermethylated promoter CpG islands of tumor suppressor genes in human cancer cells, although a direct causal relationship at the genome-wide level between MBD presence and gene silencing remains to be demonstrated. To this end, we have inhibited the expression of MBD proteins in HeLa cells by short hairpin RNAs; and studied the functional consequences of MBD depletion using microarray-based expression analysis in conjunction with extensive bisulfite genomic sequencing and chromatin immunoprecipitation. The removal of MBDs results in a release of gene silencing associated with a loss of MBD occupancy in 5'-CpG islands without any change in the DNA methylation pattern. Our results unveil new targets for epigenetic inactivation mediated by MBDs in transformed cells, such as the cell adhesion protein gamma-parvin and the fibroblast growth factor 19, where we also demonstrate their bona fide tumor suppressor features. Our data support a fundamental role for MBD proteins in the direct maintenance of transcriptional repression of tumor suppressors and identify new candidate genes for epigenetic disruption in cancer cells.
Collapse
|