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Wang Y, Liu Z, Lv Y, Long J, Lu Y, Huang P. Mechanisms of radioresistance and radiosensitization strategies for Triple Negative Breast Cancer. Transl Oncol 2025; 55:102351. [PMID: 40112501 PMCID: PMC11964565 DOI: 10.1016/j.tranon.2025.102351] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2024] [Revised: 03/02/2025] [Accepted: 03/04/2025] [Indexed: 03/22/2025] Open
Abstract
Breast cancer is one of the most common malignant tumors in women. Triple-negative breast cancer (TNBC) is a molecular subtype of breast cancer that is characterized by a high risk of recurrence and poor prognosis. With the increasingly prominent role of radiotherapy in TNBC treatment, patient resistance to radiotherapy is an attractive area of clinical research. Gene expression changes induced by multiple mechanisms can affect the radiosensitivity of TNBC cells to radiotherapy through a variety of ways, and the enhancement of radioresistance is an important factor in the malignant progression of TNBC. The above pathways mainly include DNA damage repair, programmed cell death, cancer stem cells (CSC), antioxidant function, tumor microenvironment, and epithelial-mesenchymal transition (EMT) pathway. Tumor cells can reduce the damage of radiotherapy to themselves through the above ways, resulting in radioresistance. Therefore, in this review, we aim to summarize the strategies for immunotherapy combined with radiotherapy, targeted therapy combined with radiotherapy, and epigenetic therapy combined with radiotherapy to identify the best treatment for TNBC and improve the cure and survival rates of patients with TNBC. This review will provide important guidance and inspiration for the clinical practice of radiotherapy for TNBC, which will help deepen our understanding of this field and promote its development.
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Affiliation(s)
- Yuxuan Wang
- School of Basic Medicine, Gannan Medical University, Ganzhou, Jiangxi, 341000, China
| | - Zhiwei Liu
- School of Basic Medicine, Gannan Medical University, Ganzhou, Jiangxi, 341000, China
| | - Yulu Lv
- School of Basic Medicine, Gannan Medical University, Ganzhou, Jiangxi, 341000, China
| | - Jiayang Long
- School of Basic Medicine, Gannan Medical University, Ganzhou, Jiangxi, 341000, China
| | - Yao Lu
- School of Basic Medicine, Gannan Medical University, Ganzhou, Jiangxi, 341000, China.
| | - Panpan Huang
- School of Basic Medicine, Gannan Medical University, Ganzhou, Jiangxi, 341000, China.
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Tahghighi A, Seyedhashemi E, Mohammadi J, Moradi A, Esmaeili A, Pornour M, Jafarifar K, Ganji SM. Epigenetic marvels: exploring the landscape of colorectal cancer treatment through cutting-edge epigenetic-based drug strategies. Clin Epigenetics 2025; 17:34. [PMID: 39987205 PMCID: PMC11847397 DOI: 10.1186/s13148-025-01844-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2024] [Accepted: 02/14/2025] [Indexed: 02/24/2025] Open
Abstract
Epigenetics is currently considered the investigation of inheritable changes in gene expression that do not rely on DNA sequence alteration. Significant epigenetic procedures are involved, such as DNA methylations, histone modifications, and non-coding RNA actions. It is confirmed through several investigations that epigenetic changes are associated with the formation, development, and metastasis of various cancers, such as colorectal cancer (CRC). The difference between epigenetic changes and genetic mutations is that the former could be reversed or prevented; therefore, cancer treatment and prevention could be achieved by restoring abnormal epigenetic events within the neoplastic cells. These treatments, consequently, cause the anti-tumour effects augmentation, drug resistance reduction, and host immune response stimulation. In this article, we begin our survey by exploring basic epigenetic mechanisms to understand epigenetic tools and strategies for treating colorectal cancer in monotherapy and combination with chemotherapy or immunotherapy.
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Affiliation(s)
- Azar Tahghighi
- Medicinal Chemistry Laboratory, Clinical Research Department, Pasteur Institute of Iran, Tehran, Iran
| | - Effat Seyedhashemi
- Department of Molecular Medicine, Department of Medical Biotechnology, National Institute of Genetic Engineering and Biotechnology (NIGEB), Shahrak-E Pajoohesh, Km 15, P.O. Box 14965/161, Tehran, Iran
| | - Javad Mohammadi
- Department of Molecular Medicine, Department of Medical Biotechnology, National Institute of Genetic Engineering and Biotechnology (NIGEB), Shahrak-E Pajoohesh, Km 15, P.O. Box 14965/161, Tehran, Iran
- Department of Life Science Engineering, Faculty of New Sciences and Technologies, University of Tehran, Tehran, Iran
| | - Arash Moradi
- Department of Molecular Medicine, Department of Medical Biotechnology, National Institute of Genetic Engineering and Biotechnology (NIGEB), Shahrak-E Pajoohesh, Km 15, P.O. Box 14965/161, Tehran, Iran
| | - Aria Esmaeili
- Department of Molecular Medicine, Department of Medical Biotechnology, National Institute of Genetic Engineering and Biotechnology (NIGEB), Shahrak-E Pajoohesh, Km 15, P.O. Box 14965/161, Tehran, Iran
| | - Majid Pornour
- Department of Biochemistry and Molecular Biology, University of Maryland, Baltimore, MD, USA
| | - Kimia Jafarifar
- Department of Molecular Medicine, University of Pavia, Pavia, Italy
| | - Shahla Mohammad Ganji
- Department of Molecular Medicine, Department of Medical Biotechnology, National Institute of Genetic Engineering and Biotechnology (NIGEB), Shahrak-E Pajoohesh, Km 15, P.O. Box 14965/161, Tehran, Iran.
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Surendran K, Pradeep S, Pillai PP. Comparative transcriptome and metabolite profiling reveal diverse pattern of CYP-TS gene expression during corosolic acid biosynthesis in Lagerstroemia speciosa (L.) Pers. PLANT CELL REPORTS 2024; 43:122. [PMID: 38642121 DOI: 10.1007/s00299-024-03203-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/09/2024] [Accepted: 03/19/2024] [Indexed: 04/22/2024]
Abstract
KEY MESSAGE Extensive leaf transcriptome profiling and differential gene expression analysis of field grown and elicited shoot cultures of L. speciosa suggest that differential synthesis of CRA is mediated primarily by CYP and TS genes, showing functional diversity. Lagerstroemia speciosa L. is a tree species with medicinal and horticultural attributes. The pentacyclic triterpene, Corosolic acid (CRA) obtained from this species is widely used for the management of diabetes mellitus in traditional medicine. The high mercantile value of the compound and limited availability of innate resources entail exploration of alternative sources for CRA production. Metabolic pathway engineering for enhanced bioproduction of plant secondary metabolites is an attractive proposition for which, candidate genes in the pathway need to be identified and characterized. Therefore, in the present investigation, we focused on the identification of cytochrome P450 (CYP450) and oxidosqualene cyclases (OSC) genes and their differential expression during biosynthesis of CRA. The pattern of differential expression of these genes in the shoot cultures of L. speciosa, elicited with different epigenetic modifiers (azacytidine (AzaC), sodium butyrate (NaBu) and anacardic acid (AA)), was studied in comparison with field grown plant. Further, in vitro cultures with varying (low to high) concentrations of CRA were systematically assessed for the expression of CYP-TS and associated genes involved in CRA biosynthesis by transcriptome sequencing. The sequenced samples were de novo assembled into 180,290 transcripts of which, 92,983 transcripts were further annotated by UniProt. The results are collectively given in co-occurrence heat maps to identify the differentially expressed genes. The combined transcript and metabolite profiles along with RT-qPCR analysis resulted in the identification of CYP-TS genes with high sequence variation. Further, instances of concordant/discordant relation between CRA biosynthesis and CYP-TS gene expression were observed, indicating functional diversity in genes.
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Affiliation(s)
- Karuna Surendran
- Department of Genomic Science, Central University of Kerala, Kasaragod, 671320, India
| | - Siya Pradeep
- Department of Genomic Science, Central University of Kerala, Kasaragod, 671320, India
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Camero S, Vitali G, Pontecorvi P, Ceccarelli S, Anastasiadou E, Cicchetti F, Flex E, Pomella S, Cassandri M, Rota R, Marampon F, Marchese C, Schiavetti A, Megiorni F. DNMT3A and DNMT3B Targeting as an Effective Radiosensitizing Strategy in Embryonal Rhabdomyosarcoma. Cells 2021; 10:2956. [PMID: 34831178 PMCID: PMC8616246 DOI: 10.3390/cells10112956] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2021] [Revised: 10/21/2021] [Accepted: 10/28/2021] [Indexed: 01/10/2023] Open
Abstract
Rhabdomyosarcoma (RMS) is the most common soft tissue sarcoma in childhood. Recently, we demonstrated the overexpression of both DNA methyltransferase 3A (DNMT3A) and 3B (DNMT3B) in RMS tumour biopsies and cell lines compared to normal skeletal muscle. Radiotherapy may often fail due to the abnormal expression of some molecules able to drive resistance mechanisms. The aim of this study was to analyse the involvement of DNMT3A and DNMT3B in radioresistance in RMS. RNA interference experiments against DNMT3A/3B were performed in embryonal RMS cells, upon ionizing radiation (IR) exposure and the effects of the combined treatment on RMS cells were analysed. DNMT3A and DNMT3B knocking down increased the sensitivity of RMS cells to IR, as indicated by the drastic decrease of colony formation ability. Interestingly, DNMT3A/3B act in two different ways: DNMT3A silencing triggers the cellular senescence program by up-regulating p16 and p21, whilst DNMT3B depletion induces significant DNA damage and impairs the DNA repair machinery (ATM, DNA-PKcs and Rad51 reduction). Our findings demonstrate for the first time that DNMT3A and DNMT3B overexpression may contribute to radiotherapy failure, and their inhibition might be a promising radiosensitizing strategy, mainly in the treatment of patients with metastatic or recurrent RMS tumours.
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Affiliation(s)
- Simona Camero
- Department of Maternal, Infantile and Urological Sciences, Sapienza University of Rome, Viale Regina Elena 324, 00161 Rome, Italy; (S.C.); (A.S.)
| | - Giulia Vitali
- Department of Experimental Medicine, Sapienza University of Rome, Viale Regina Elena 324, 00161 Rome, Italy; (G.V.); (P.P.); (S.C.); (E.A.); (C.M.)
| | - Paola Pontecorvi
- Department of Experimental Medicine, Sapienza University of Rome, Viale Regina Elena 324, 00161 Rome, Italy; (G.V.); (P.P.); (S.C.); (E.A.); (C.M.)
| | - Simona Ceccarelli
- Department of Experimental Medicine, Sapienza University of Rome, Viale Regina Elena 324, 00161 Rome, Italy; (G.V.); (P.P.); (S.C.); (E.A.); (C.M.)
| | - Eleni Anastasiadou
- Department of Experimental Medicine, Sapienza University of Rome, Viale Regina Elena 324, 00161 Rome, Italy; (G.V.); (P.P.); (S.C.); (E.A.); (C.M.)
| | - Francesca Cicchetti
- Policlinico Umberto I Hospital, Viale del Policlinico 155, 00161 Rome, Italy;
| | - Elisabetta Flex
- Department of Oncology and Molecular Medicine, Istituto Superiore di Sanità, Viale Regina Elena 299, 00161 Rome, Italy;
| | - Silvia Pomella
- Group of Epigenetics of Pediatric Sarcomas, Department of Oncohematology, Bambino Gesù Children’s Hospital, IRCCS, Via San Paolo 15, 00146 Rome, Italy; (S.P.); (M.C.); (R.R.)
| | - Matteo Cassandri
- Group of Epigenetics of Pediatric Sarcomas, Department of Oncohematology, Bambino Gesù Children’s Hospital, IRCCS, Via San Paolo 15, 00146 Rome, Italy; (S.P.); (M.C.); (R.R.)
| | - Rossella Rota
- Group of Epigenetics of Pediatric Sarcomas, Department of Oncohematology, Bambino Gesù Children’s Hospital, IRCCS, Via San Paolo 15, 00146 Rome, Italy; (S.P.); (M.C.); (R.R.)
| | - Francesco Marampon
- Department of Radiological, Oncological and Pathological Sciences, Sapienza University of Rome, Viale Regina Elena 324, 00161 Rome, Italy
| | - Cinzia Marchese
- Department of Experimental Medicine, Sapienza University of Rome, Viale Regina Elena 324, 00161 Rome, Italy; (G.V.); (P.P.); (S.C.); (E.A.); (C.M.)
| | - Amalia Schiavetti
- Department of Maternal, Infantile and Urological Sciences, Sapienza University of Rome, Viale Regina Elena 324, 00161 Rome, Italy; (S.C.); (A.S.)
| | - Francesca Megiorni
- Department of Experimental Medicine, Sapienza University of Rome, Viale Regina Elena 324, 00161 Rome, Italy; (G.V.); (P.P.); (S.C.); (E.A.); (C.M.)
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Wu YS, Lee ZY, Chuah LH, Mai CW, Ngai SC. Epigenetics in Metastatic Breast Cancer: Its Regulation and Implications in Diagnosis, Prognosis and Therapeutics. Curr Cancer Drug Targets 2019; 19:82-100. [PMID: 29714144 DOI: 10.2174/1568009618666180430130248] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2017] [Revised: 02/21/2018] [Accepted: 04/03/2018] [Indexed: 02/06/2023]
Abstract
Despite advances in the treatment regimen, the high incidence rate of breast cancer (BC) deaths is mostly caused by metastasis. Recently, the aberrant epigenetic modifications, which involve DNA methylation, histone modifications and microRNA (miRNA) regulations become attractive targets to treat metastatic breast cancer (MBC). In this review, the epigenetic alterations of DNA methylation, histone modifications and miRNA regulations in regulating MBC are discussed. The preclinical and clinical trials of epigenetic drugs such as the inhibitor of DNA methyltransferase (DNMTi) and the inhibitor of histone deacetylase (HDACi), as a single or combined regimen with other epigenetic drug or standard chemotherapy drug to treat MBCs are discussed. The combined regimen of epigenetic drugs or with standard chemotherapy drugs enhance the therapeutic effect against MBC. Evidences that epigenetic changes could have implications in diagnosis, prognosis and therapeutics for MBC are also presented. Several genes have been identified as potential epigenetic biomarkers for diagnosis and prognosis, as well as therapeutic targets for MBC. Endeavors in clinical trials of epigenetic drugs against MBC should be continued although limited success has been achieved. Future discovery of epigenetic drugs from natural resources would be an attractive natural treatment regimen for MBC. Further research is warranted in translating research into clinical practice with the ultimate goal of treating MBC by epigenetic therapy in the near future.
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Affiliation(s)
- Yuan Seng Wu
- School of Biosciences, Faculty of Science, University of Nottingham Malaysia Campus, Selangor, Malaysia
- School of Pharmacy, Monash University Malaysia, Bandar Sunway, Selangor, Malaysia
| | - Zhong Yang Lee
- School of Biosciences, Faculty of Science, University of Nottingham Malaysia Campus, Selangor, Malaysia
| | - Lay-Hong Chuah
- School of Pharmacy, Monash University Malaysia, Bandar Sunway, Selangor, Malaysia
- Advanced Engineering Platform, Monash University Malaysia, Bandar Sunway, Selangor, Malaysia
| | - Chun Wai Mai
- Department of Pharmaceutical Chemistry, International Medical University, Bukit Jalil, Kuala Lumpur, Malaysia
| | - Siew Ching Ngai
- School of Biosciences, Faculty of Science, University of Nottingham Malaysia Campus, Selangor, Malaysia
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Kerns SL, Chuang KH, Hall W, Werner Z, Chen Y, Ostrer H, West C, Rosenstein B. Radiation biology and oncology in the genomic era. Br J Radiol 2018; 91:20170949. [PMID: 29888979 PMCID: PMC6475928 DOI: 10.1259/bjr.20170949] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2017] [Revised: 06/01/2018] [Accepted: 06/05/2018] [Indexed: 12/25/2022] Open
Abstract
Radiobiology research is building the foundation for applying genomics in precision radiation oncology. Advances in high-throughput approaches will underpin increased understanding of radiosensitivity and the development of future predictive assays for clinical application. There is an established contribution of genetics as a risk factor for radiotherapy side effects. An individual's radiosensitivity is an inherited polygenic trait with an architecture that includes rare mutations in a few genes that confer large effects and common variants in many genes with small effects. Current thinking is that some will be tissue specific, and future tests will be tailored to the normal tissues at risk. The relationship between normal and tumor cell radiosensitivity is poorly understood. Data are emerging suggesting interplay between germline genetic variation and epigenetic modification with growing evidence that changes in DNA methylation regulate the radiosensitivity of cancer cells and histone acetyltransferase inhibitors have radiosensitizing effects. Changes in histone methylation can also impair DNA damage response signaling and alter radiosensitivity. An important effort to advance radiobiology in the genomic era was establishment of the Radiogenomics Consortium to enable the creation of the large radiotherapy cohorts required to exploit advances in genomics. To address challenges in harmonizing data from multiple cohorts, the consortium established the REQUITE project to collect standardized data and genotyping for ~5,000 patients. The collection of detailed dosimetric data is important to produce validated multivariable models. Continued efforts will identify new genes that impact on radiosensitivity to generate new knowledge on toxicity pathogenesis and tests to incorporate into the clinical decision-making process.
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Affiliation(s)
| | - Kuang-Hsiang Chuang
- Department of Radiation Oncology, University of Rochester Medical Center, Rochester, NY, USA
| | - William Hall
- Department of Radiation Oncology, Medical College of Wisconsin and Clement J Zablocki VA Medical Center Milwaukee, Milwaukee, WI, USA
| | | | - Yuhchyau Chen
- Department of Radiation Oncology, University of Rochester Medical Center, Rochester, NY, USA
| | - Harry Ostrer
- Departments of Pathology and Pediatrics, Albert Einstein College of Medicine, Bronx, NY, USA
| | - Catharine West
- Division of Cancer Sciences, University of Manchester, Christie Hospital, Manchester, UK
| | - Barry Rosenstein
- Departments of Radiation Oncology, Genetics and Genomic Sciences, and Dermatology, Icahn School of Medicine at Mount Sinai, New York, NY, USA
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Methylation of promoter of RBL1 enhances the radioresistance of three dimensional cultured carcinoma cells. Oncotarget 2018; 8:4422-4435. [PMID: 27779109 PMCID: PMC5354843 DOI: 10.18632/oncotarget.12647] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2016] [Accepted: 09/29/2016] [Indexed: 12/04/2022] Open
Abstract
Three dimensional (3D) culture in vitro is a new cell culture model that more closely mimics the physiology features of the in vivo environment and is being used widely in the field of medical and biological research. It has been demonstrated that cancer cells cultured in 3D matrices are more radioresistant compared with cells in monolayer (2D). However, the mechanisms causing this difference remain largely unclear. Here we found that the cell cycle distribution and expression of cell cycle regulation genes in 3D A549 cells are different from the 2D. The higher levels of the promotor methylation of cell cycle regulation genes such as RBL1 were observed in 3D A549 cells compared with cells in 2D. The treatments of irradiation or 5-Aza-CdR activated the demethylation of RBL1 promotor and resulted in the increased expression of RBL1 only in 3D A549 cells. Inhibition of RBL1 enhanced the radioresistance and decreased the G2/M phase arrest induced by irradiation in 2D A549 and MCF7 cells. Overexpression of RBL1 sensitized 3D cultured A549 and MCF7 cells to irradiation. Taken together, to our knowledge, it is the first time to revealthat the low expression of RBL1 due to itself promotor methylation in 3D cells enhances the radioresistance. Our finding sheds a new light on understanding the features of the 3D cultured cell model and its application in basic research into cancer radiotherapy and medcine development.
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Potential of DNA methylation in rectal cancer as diagnostic and prognostic biomarkers. Br J Cancer 2015; 113:1035-45. [PMID: 26335606 PMCID: PMC4651135 DOI: 10.1038/bjc.2015.303] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2015] [Revised: 06/17/2015] [Accepted: 07/30/2015] [Indexed: 12/15/2022] Open
Abstract
Background: Aberrant DNA methylation is more prominent in proximal compared with distal colorectal cancers. Although a number of methylation markers were identified for colon cancer, yet few are available for rectal cancer. Methods: DNA methylation differences were assessed by a targeted DNA microarray for 360 marker candidates between 22 fresh frozen rectal tumour samples and 8 controls and validated by microfluidic high-throughput and methylation-sensitive qPCR in fresh frozen and formalin-fixed paraffin-embedded (FFPE) samples, respectively. The CpG island methylator phenotype (CIMP) was assessed by MethyLight in FFPE material from 78 patients with pT2 and pT3 rectal adenocarcinoma. Results: We identified and confirmed two novel three-gene signatures in fresh frozen samples that can distinguish tumours from adjacent tissue as well as from blood with a high sensitivity and specificity of up to 1 and an AUC of 1. In addition, methylation of individual CIMP markers was associated with specific clinical parameters such as tumour stage, therapy or patients' age. Methylation of CDKN2A was a negative prognostic factor for overall survival of patients. Conclusions: The newly defined methylation markers will be suitable for early disease detection and monitoring of rectal cancer.
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Karsli-Ceppioglu S, Dagdemir A, Judes G, Ngollo M, Penault-Llorca F, Pajon A, Bignon YJ, Bernard-Gallon D. Epigenetic mechanisms of breast cancer: an update of the current knowledge. Epigenomics 2015; 6:651-64. [PMID: 25531258 DOI: 10.2217/epi.14.59] [Citation(s) in RCA: 76] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
Epigenetic alterations are heritable changes in gene expression that occur without causing any change in DNA sequence. They are important key factors for cancer development and prognosis. Breast cancer is induced by the accumulation of altered gene regulation. Besides genetic mutations, epigenetics mechanisms have an important role in breast cancer tumorigenesis. Investigations related with aberrant epigenetic regulations in breast cancer focus on initiating molecular mechanisms in cancer development, identification of new biomarkers to predict breast cancer aggressiveness and the potential of epigenetic therapy. In this review, we will summarize the recent knowledge about the role of epigenetic alterations related with DNA methylation and histone modification in breast cancer. In addition, altered regulation of breast cancer specific genes and the potential of epigenetic therapy will be discussed according to epigenetic mechanisms.
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Lattanzio L, Lo Nigro C. Epigenetics and DNA methylation in cancer. World J Transl Med 2015; 4:11-24. [DOI: 10.5528/wjtm.v4.i1.11] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/08/2014] [Revised: 11/10/2014] [Accepted: 03/20/2015] [Indexed: 02/05/2023] Open
Abstract
Epigenetic is the study of those alterations regulating gene expression without altering DNA sequence and inherited by transmission through cell division. Mutational and epimutational events that alterate cellular growth and division are combined in carcinogenesis. Advances in genome and epigenome-wide analysis identify DNA hypomethylation, hypermethylation of tumor suppressor genes, aberrant histone modifications and/or specific miRNA expression profiles to contribute to tumor initiation and progression. The major challenge for cancer researchers is to enlighten the complex relationship between the epigenetic and genetic machinery in order to optimize combined therapies, reducing chemoresistance and minimizing adverse effects in cancer patients. In this review we will cover many distinct aspects of epigenetic phenomenon. Firstly, we will globally explain the most common epigenetic events and their effects on gene expression regulation. Secondly, we will review the evidence of the correlation between epigenetics and cancer progression, focusing in particular on the effect of aberrant hypo- and hyper-methylation. We will also consider the main methods currently used for methylation analysis, covering both locus-specific technologies and genome-wide analysis. Finally, we will discuss the introduction of novel epigenetic drugs in combination with conventional treatments in order to develop more effective cancer therapies. Such information could help in understanding the important role of epigenetics in cancer.
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Li X, Mei Q, Nie J, Fu X, Han W. Decitabine: a promising epi-immunotherapeutic agent in solid tumors. Expert Rev Clin Immunol 2015; 11:363-75. [DOI: 10.1586/1744666x.2015.1002397] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
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Smits KM, Melotte V, Niessen HE, Dubois L, Oberije C, Troost EG, Starmans MH, Boutros PC, Vooijs M, van Engeland M, Lambin P. Epigenetics in radiotherapy: Where are we heading? Radiother Oncol 2014; 111:168-77. [DOI: 10.1016/j.radonc.2014.05.001] [Citation(s) in RCA: 33] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2013] [Revised: 03/17/2014] [Accepted: 05/01/2014] [Indexed: 12/20/2022]
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13
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Kitazono M, Shinchi H, Ishigami S, Ueno S, Natsugoe S. Effects of a histone deacetylase inhibitor, sodium butyrate, on 53-kDa protein expression and sensitivity to anticancer drugs of pancreatic cancer cells. Curr Ther Res Clin Exp 2014; 71:162-72. [PMID: 24683262 DOI: 10.1016/j.curtheres.2010.06.002] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 03/16/2010] [Indexed: 11/25/2022] Open
Abstract
BACKGROUND Several tumor-suppressor genes, such as 53-kDa protein (p53), are inactivated in some pancreatic cancers. The lack of a functional p53 has been proposed to be a component of resistance to chemotherapy, resulting in the inhibition of apoptosis. Therefore, reintroduction of wild-type p53 is a commonly used gene therapy strategy for the treatment of various types of cancer, including pancreatic cancer. OBJECTIVE The aim of this study was to examine the ability of the histone deacetylase inhibitor, sodium butyrate (NaB), to modulate the expression of p53. METHODS Five human pancreatic carcinoma cell lines (SW-1990, BxPC-3, PANC-1, MIA PaCa-2, JHP-1) were utilized. Two of the cell lines (SW-1990 and JHP-1) lacked p53 expression, as determined by Western blot analysis, and were investigated further. Expression of p53 was determined by densitometry of all bands present in the Western blot. Drug sensitivity was measured with a tetrazolium-based assay by exposing the cells to graded concentrations of NaB and/or anticancer drugs (cisplatin, fluorouracil, SN-38, and paclitaxel). Apoptosis was observed using gel electrophoresis. RESULTS In the SW-1990 and JHP-1 cell lines, use of 1 mM NaB was found to induce histone acetylation and p53 expression compared with those not treated with NaB (P = 0.01 and P = 0.018, respectively). Sensitivity to cisplatin (P = 0.021), fluorouracil (P = 0.046), and SN-38 (P = 0.039) was significantly enhanced by NaB treatment compared with nontreatment. However, sensitivity to paclitaxel was not significantly different between untreated and NaB-treated cells. A higher frequency of apoptosis was observed in NaB-treated cells compared with that of control cells. CONCLUSION This in vitro study found that NaB induced p53 expression in 2 pancreatic cancer cell lines (SW-1990 and JHP-1). Moreover, NaB acted on a biochemical modulator for antieuplastic therapy. Future research is necessary to assess the value of these findings.
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Affiliation(s)
- Masaki Kitazono
- Department of Surgical Oncology and Digestive Surgery, Kagoshima University Graduate School, Kagoshima, Japan
| | - Hiroyuki Shinchi
- Department of Surgical Oncology and Digestive Surgery, Kagoshima University Graduate School, Kagoshima, Japan
| | - Sumiya Ishigami
- Department of Surgical Oncology and Digestive Surgery, Kagoshima University Graduate School, Kagoshima, Japan
| | - Shinichi Ueno
- Department of Surgical Oncology and Digestive Surgery, Kagoshima University Graduate School, Kagoshima, Japan
| | - Shoji Natsugoe
- Department of Surgical Oncology and Digestive Surgery, Kagoshima University Graduate School, Kagoshima, Japan
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Li Y, Geng P, Jiang W, Wang Y, Yao J, Lin X, Liu J, Huang L, Su B, Chen H. Enhancement of radiosensitivity by 5-Aza-CdR through activation of G2/M checkpoint response and apoptosis in osteosarcoma cells. Tumour Biol 2014; 35:4831-9. [PMID: 24474250 DOI: 10.1007/s13277-014-1634-5] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2013] [Accepted: 01/07/2014] [Indexed: 02/07/2023] Open
Abstract
Radiation resistance is a major problem preventing successful treatment. Therefore, identifying sensitizers is vitally important for radiotherapy success. Epigenetic events such as DNA methylation have been proposed to mediate the sensitivity of tumor therapy. In this study, we investigated the influence of demethylating agent 5-Aza-2'-deoxycytidine (5-Aza-CdR) on the radiosensitivity of human osteosarcoma cell lines. 5-Aza-CdR was capable of sensitizing three osteosarcoma cells to irradiation in a time-dependent manner, with the maximum effect attained by 48 h. Pretreatment with 5-Aza-CdR synchronized cells in G2/M phase of the cell cycle and enhanced irradiation-induced apoptosis compared with irradiation alone in SaOS2, HOS, and U2OS cells. Moreover, 5-Aza-CdR restored mRNA expressions of 14-3-3σ, CHK2, and DAPK-1 in the three cells, accompanied with demethylation of their promoters. These findings demonstrate that demethylation with 5-Aza-CdR increases radiosensitivity in some osteosarcoma cells through arresting cells at G2/M phase and increasing apoptosis, which is partly mediated by upregulation of 14-3-3σ, CHK2, and DAPK-1 genes, suggesting that 5-Aza-CdR may be a potential radiosensitizer to improve the therapy effect in osteosarcoma.
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Affiliation(s)
- Yi Li
- Key Laboratory of Oncology, Cancer Center, Division of Internal Medicine, Chinese PLA General Hospital and Chinese PLA Medical School, Beijing, 100853, China
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15
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Ye S, Yuan D, Xie Y, Pan Y, Shao C. Role of DNA methylation in long-term low-dose γ-rays induced adaptive response in human B lymphoblast cells. Int J Radiat Biol 2013; 89:898-906. [PMID: 23692433 DOI: 10.3109/09553002.2013.806832] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022]
Abstract
PURPOSE With widespread use of ionizing radiation, more attention has been attracted to low-dose radiation (LDR); however, the mechanisms of long-term LDR-induced bio-effects are unclear. Here, we applied human B lymphoblast cell line HMy2.CIR to monitor the effects of long-term LDR and the potential involvement of DNA methylation. MATERIALS AND METHODS HMy2.CIR cells were irradiated with 0.032 Gy γ-rays three times per week for 1-4 weeks. Some of these primed cells were further challenged with 2 Gy γ-rays. Cell proliferation, micronuclei formation, gene expression of DNA methyltransferases (DNMT), levels of global genomic DNA methylation and protein expression of methyl CpG binding protein 2 (MeCP2) and heterochromatin protein-1 (HP1) were measured. RESULTS Long-term LDR enhanced cell proliferation and clonogenicity and triggered a cellular adaptive response (AR). Furthermore, global genomic DNA methylation was increased in HMy2.CIR cells after long-term LDR, accompanied with an increase of gene expression of DNMT1 and protein expression of MeCP2 and HP1. After treatment with 5-aza-2'-deoxycytidine (5-aza-dC), a DNA methyltransferase inhibitor, the long-term LDR-induced global genomic DNA hypermethylation was decreased and the AR was eliminated. CONCLUSION Global genomic DNA hypermethylation accompanied with increases of DNMT1 and MeCP2 expression and heterochromatin formation might be involved in long-term LDR-induced adaptive response.
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Affiliation(s)
- Shuang Ye
- Institute of Radiation Medicine, Fudan University , Shanghai , P. R. China
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16
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Perona M, Rodríguez C, Carpano M, Thomasz L, Nievas S, Olivera M, Thorp S, Curotto P, Pozzi E, Kahl S, Pisarev M, Juvenal G, Dagrosa A. Improvement of the boron neutron capture therapy (BNCT) by the previous administration of the histone deacetylase inhibitor sodium butyrate for the treatment of thyroid carcinoma. RADIATION AND ENVIRONMENTAL BIOPHYSICS 2013; 52:363-373. [PMID: 23636505 DOI: 10.1007/s00411-013-0470-0] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/29/2012] [Accepted: 04/10/2013] [Indexed: 06/02/2023]
Abstract
We have shown that boron neutron capture therapy (BNCT) could be an alternative for the treatment of poorly differentiated thyroid carcinoma (PDTC). Histone deacetylase inhibitors (HDACI) like sodium butyrate (NaB) cause hyperacetylation of histone proteins and show capacity to increase the gamma irradiation effect. The purpose of these studies was to investigate the use of the NaB as a radiosensitizer of the BNCT for PDTC. Follicular thyroid carcinoma cells (WRO) and rat thyroid epithelial cells (FRTL-5) were incubated with 1 mM NaB and then treated with boronophenylalanine ¹⁰BPA (10 μg ¹⁰B ml⁻¹) + neutrons, or with 2, 4-bis (α,β-dihydroxyethyl)-deutero-porphyrin IX ¹⁰BOPP (10 μg ¹⁰B ml⁻¹) + neutrons, or with a neutron beam alone. The cells were irradiated in the thermal column facility of the RA-3 reactor (flux = (1.0 ± 0.1) × 10¹⁰ n cm⁻² s⁻¹). Cell survival decreased as a function of the physical absorbed dose in both cell lines. Moreover, the addition of NaB decreased cell survival (p < 0.05) in WRO cells incubated with both boron compounds. NaB increased the percentage of necrotic and apoptotic cells in both BNCT groups (p < 0.05). An accumulation of cells in G2/M phase at 24 h was observed for all the irradiated groups and the addition of NaB increased this percentage. Biodistribution studies of BPA (350 mg kg⁻¹ body weight) 24 h after NaB injection were performed. The in vivo studies showed that NaB treatment increases the amount of boron in the tumor at 2-h post-BPA injection (p < 0.01). We conclude that NaB could be used as a radiosensitizer for the treatment of thyroid carcinoma by BNCT.
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Affiliation(s)
- M Perona
- Department of Radiobiology, National Atomic Energy Commission-CNEA, Avenida General Paz 1499, San Martín 1650, Buenos Aires, Argentina
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17
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Epigenetics meets radiation biology as a new approach in cancer treatment. Int J Mol Sci 2013; 14:15059-73. [PMID: 23873297 PMCID: PMC3742287 DOI: 10.3390/ijms140715059] [Citation(s) in RCA: 33] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2013] [Revised: 07/10/2013] [Accepted: 07/15/2013] [Indexed: 02/06/2023] Open
Abstract
Cancer is a disease that results from both genetic and epigenetic changes. In recent decades, a number of people have investigated the disparities in gene expression resulting from variable DNA methylation alteration and chromatin structure modification in response to the environment. Especially, colon cancer is a great model system for investigating the epigenetic mechanism for aberrant gene expression alteration. Ionizing radiation (IR) could affect a variety of processes within exposed cells and, in particular, cause changes in gene expression, disruption of cell cycle arrest, and apoptotic cell death. Even though there is growing evidence on the importance of epigenetics and biological processes induced by radiation exposure in various cancer types including colon cancer, specific epigenetic alterations induced by radiation at the molecular level are incompletely defined. This review focuses on discussing possible IR-mediated changes of DNA methylation and histone modification in cancer.
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18
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Zhang S, Bai J, Ren S, Wang R, Zhang L, Zuo Y. Sodium butyrate restores ASC expression and induces apoptosis in LS174T cells. Int J Mol Med 2012; 30:1431-7. [PMID: 23064206 DOI: 10.3892/ijmm.2012.1156] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2012] [Accepted: 09/14/2012] [Indexed: 11/06/2022] Open
Abstract
Sodium butyrate (NaBu) is a short-chain fatty acid (SCFA), which has been proposed as a potential anticancer agent. Apoptosis-associated speck-like protein (ASC) is a pro-apoptotic signaling factor that is subjected to epigenetic silencing in human cancers. Modulation by the aberrant methylation of CpG islands of ASC is a well-characterized epigenetic mechanism, and the methylation-induced silencing of ASC has been observed in several types of tumors. NaBu induces cell cycle arrest, markers of cell differentiation and apoptosis in colon cancer. NaBu promotes transcriptional activation by relaxing the DNA conformation and displays anti-proliferative and differentiating activity in a wide variety of cancers. Thus, we used NaBu to investigate the relationship between the status of cell proliferation and the re-expression of ASC in colon carcinoma LS174T cells. Our experiments determined ASC re-expression at the protein level using western blotting. In addition, we used reverse transcription-polymerase chain reaction to detect the expression levels of ASC mRNA and an MTT assay to detect the inhibitory rate of cell growth. The apoptosis rate was also detected for further validation of the re-expression of ASC. The results showed that ASC re-expression was significantly increased in the LS174 cells following NaBu treatment in a time- and dose-dependent manner. The expression of ASC also induced the apoptosis of LS174T cells. These results suggest that NaBu plays a role in the reactivation of ASC expression and that the latter promotes the apoptosis of LS174T cells.
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Affiliation(s)
- Shuai Zhang
- Department of Clinical Biochemistry, Dalian Medical University, Dalian 116044, P.R. China
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19
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Wang L, Zhang Y, Li R, Chen Y, Pan X, Li G, Dai F, Yang J. 5-aza-2'-Deoxycytidine enhances the radiosensitivity of breast cancer cells. Cancer Biother Radiopharm 2012; 28:34-44. [PMID: 22917213 DOI: 10.1089/cbr.2012.1170] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/12/2022] Open
Abstract
PURPOSE To investigate the effect of the DNA methyltransferase inhibitor, 5-aza-2'-deoxycytidine (DAC), on radiosensitivity in breast cancer cells. MATERIALS AND METHODS Two breast cancer cell lines, MDA-MB-231 and MDA-MB-435, were evaluated. The methylation status and the mRNA expression of three genes (ER, PR, and HIC-1) that were frequently hypermethylated in these cell lines were determined as a function of DAC exposure. 3-(4,5)-dimethylthiahiazo-(-z-y1)-3,5-di-phenytetrazoliumromide (MTT) absorbance and a colony-forming assay were used to estimate cell viability and radiosensitivity. Using cell-cycle analysis, γ-histone H2A (γ-H2AX) formation assays and methylation-specific polymerase chain reaction (MSP) analysis of three genes correlated with radiosensitivity (BRCA1, 14-3-3σ, and E-cadherin), the mechanism of DAC enhancement of radiosensitivity was explored. RESULTS DAC induced the demethylation and reactivation of silent genes in both cell lines. The combination of DAC and irradiation induced growth suppression in vitro. DAC, 5 μM, enhanced sensitivity to ionizing radiation. DAC followed by irradiation correlated with G2/M arrest and the retardation of repair of radiation-induced double strand breaks. DAC reversed the methylation status of genes connected with radiosensitization. The different radiosensitization effects observed with different breast cancers cells may correlate with the primary methylation status of radiosensitizing genes. CONCLUSIONS Treatment strategies that include DAC present promising options for sensitizing breast cancer cells to irradiation.
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Affiliation(s)
- Li Wang
- Department of Pathology, Kunming General Hospital, Kunming, Yunnan, China
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20
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Akilov OE, Grant C, Frye R, Bates S, Piekarz R, Geskin LJ. Low-dose electron beam radiation and romidepsin therapy for symptomatic cutaneous T-cell lymphoma lesions. Br J Dermatol 2012; 167:194-7. [PMID: 22372971 PMCID: PMC3386371 DOI: 10.1111/j.1365-2133.2012.10905.x] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
BACKGROUND Romidepsin is a structurally unique histone deacetylase inhibitor approved by the U.S. Food and Drug Administration for therapy of relapsed or refractory cutaneous T-cell lymphoma (CTCL). Localized electron beam radiation therapy (LEBT) is standard practice in the care of patients with chronically traumatized and painful lesions. Combination therapy of those two modalities may be beneficial for the therapy of CTCL. OBJECTIVES To report observations on supportive LEBT utilized for isolated refractory lesions in patients on romidepsin. METHODS Observations were made during a phase II clinical trial sponsored by the National Cancer Institute (NCI-1312) examining the efficacy of romidepsin for patients with relapsed, refractory or advanced CTCL, stage IB-IVA mycosis fungoides (MF) or Sézary syndrome. Skin responses were assessed by evaluation of five target lesions only. Patients with objective clinical responses in target lesions who had symptomatic nontarget lesions were allowed limited LEBT to isolated lesions for symptomatic relief. Patients who received localized radiation were not considered complete responders at any point. RESULTS Five patients with advanced MF (three stage IIB and two stage IVA2) received LEBT to symptomatic nontarget lesions while on a protocol with romidepsin. None of these patients experienced additional or unexpected toxicity. Four of the five patients demonstrated fast and durable responses. We noted that significantly lower than standard doses of LEBT effectively treated symptomatic lesions in these patients. CONCLUSIONS LEBT demonstrated significant responses at very low doses without additional toxicity in patients on protocol treatment with the histone deacetylase inhibitor romidepsin. This merits formal investigation in a clinical trial for potential synergy in patients with CTCL.
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Affiliation(s)
- O E Akilov
- Department of Dermatology, University of Pittsburgh, 200 Lothrop Street, Presby South Tower, Suite 3880, Pittsburgh, PA 15213, USA
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21
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Ikehata M, Ueda K, Iwakawa S. Different involvement of DNA methylation and histone deacetylation in the expression of solute-carrier transporters in 4 colon cancer cell lines. Biol Pharm Bull 2012; 35:301-7. [PMID: 22382314 DOI: 10.1248/bpb.35.301] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
The purpose of this study on the involvement of epigenetic control of the expression of solute carrier (SLC) transporters by DNA methylation and histone deacetylation in 4 colon cancer cells is to find the epigenetic control mechanisms of drug transporters in colon cancers. Human colon cancer cell lines (HCT116, HT29, SW48, SW480) were treated with 5-aza-2'-deoxycytidine (DAC), as a DNA methyltransferase inhibitor, followed by trichostatin A (TSA), as a histone deacetylase inhibitor. The mRNA expression and DNA methylation of several SLC transporters were analyzed by real-time polymerase chain reaction (PCR) and methylation-specific PCR, respectively. Among 12 SLC transporters possessing cytosine-phosphate-guanine (CpG) islands, thiamine transporter 2 (THTR2) (SLC19A3) gene showed a correlation between its mRNA expression level and DNA methylation status. TSA treatment increased histone H3 acetylation of THTR2 promoter region in all 4 colon cancer cell lines examined. HCT116 and SW48 cells showed a lack of THTR2 mRNA expression and methylation of its promoter, and DAC treatment induced its re-expression. In addition, the co-treatment with DAC and TSA increased THTR2 mRNA expression more markedly than DAC treatment in HCT116 and SW48 cells. In HT29 and SW480 cells that showed little methylation of THTR2 promoter, TSA treatment induced THTR2 mRNA expression markedly, but DAC treatment did not. In the 4 colon cancer cells examined, THTR2 mRNA expression is down-regulated by DNA methylation and/or histone deacetylation.
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Affiliation(s)
- Mika Ikehata
- Department of Pharmaceutics, Kobe Pharmaceutical University, Higashinada-ku, Japan.
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22
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Artacho-Cordón F, Ríos-Arrabal S, Lara PC, Artacho-Cordón A, Calvente I, Núñez MI. Matrix metalloproteinases: potential therapy to prevent the development of second malignancies after breast radiotherapy. Surg Oncol 2012; 21:e143-51. [PMID: 22749313 DOI: 10.1016/j.suronc.2012.06.001] [Citation(s) in RCA: 60] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2012] [Revised: 05/25/2012] [Accepted: 06/02/2012] [Indexed: 12/24/2022]
Abstract
Radiotherapy is widely used in the treatment of patients with breast cancer, but ionizing radiation-induced carcinogenesis has been described in several studies. Matrix metalloproteinases (MMPs) are a wide family of proteases secreted by tumour and microenvironmental cells that are directly linked with invasion and metastasis through complete extracellular matrix (ECM) breakage. In the past decade, MMPs have been associated with other carcinogenesis steps, including tumour growth and angiogenesis promotion. Moreover, in vitro studies have demonstrated an enhanced migration, invasiveness, and angiogenic ability of cancer cells after radiation exposure through an increase in MMP activity. These findings are consistent with clinical observations of breast cancer metastases raised in bone, lung and brain tissues after radiotherapy. The aim of this review was to analyse the current state of research on MMPs and report new insights into the potential of MMP-targeted therapy in combination with radiotherapy to decrease the risk of radiation-induced second malignancies and to improve the overall survival of breast cancer patients.
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Affiliation(s)
- F Artacho-Cordón
- Departamento de Radiología y Medicina Física, Universidad de Granada, Av. Madrid s/n, 18012 Granada, Spain
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23
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Kim HJ, Kim JH, Chie EK, Da Young P, Kim IA, Kim IH. DNMT (DNA methyltransferase) inhibitors radiosensitize human cancer cells by suppressing DNA repair activity. Radiat Oncol 2012; 7:39. [PMID: 22429326 PMCID: PMC3375186 DOI: 10.1186/1748-717x-7-39] [Citation(s) in RCA: 95] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2011] [Accepted: 03/20/2012] [Indexed: 12/30/2022] Open
Abstract
BACKGROUND Histone modifications and DNA methylation are two major factors in epigenetic phenomenon. Unlike the histone deacetylase inhibitors, which are known to exert radiosensitizing effects, there have only been a few studies thus far concerning the role of DNA methyltransferase (DNMT) inhibitors as radiosensitizers. The principal objective of this study was to evaluate the effects of DNMT inhibitors on the radiosensitivity of human cancer cell lines, and to elucidate the mechanisms relevant to that process. METHODS A549 (lung cancer) and U373MG (glioblastoma) cells were exposed to radiation with or without six DNMT inhibitors (5-azacytidine, 5-aza-2'-deoxycytidine, zebularine, hydralazine, epigallocatechin gallate, and psammaplin A) for 18 hours prior to radiation, after which cell survival was evaluated via clonogenic assays. Cell cycle and apoptosis were analyzed via flow cytometry. Expressions of DNMT1, 3A/3B, and cleaved caspase-3 were detected via Western blotting. Expression of γH2AX, a marker of radiation-induced DNA double-strand break, was examined by immunocytochemistry. RESULTS Pretreatment with psammaplin A, 5-aza-2'-deoxycytidine, and zebularine radiosensitized both A549 and U373MG cells. Pretreatment with psammaplin A increased the sub-G1 fraction of A549 cells, as compared to cells exposed to radiation alone. Prolongation of γH2AX expression was observed in the cells treated with DNMT inhibitors prior to radiation as compared with those treated by radiation alone. CONCLUSIONS Psammaplin A, 5-aza-2'-deoxycytidine, and zebularine induce radiosensitivity in both A549 and U373MG cell lines, and suggest that this effect might be associated with the inhibition of DNA repair.
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Affiliation(s)
- Hak Jae Kim
- Department of Radiation Oncology, Seoul National University College of Medicine, Seoul, Republic of Korea
| | - Jin Ho Kim
- Department of Radiation Oncology, Seoul National University College of Medicine, Seoul, Republic of Korea
| | - Eui Kyu Chie
- Department of Radiation Oncology, Seoul National University College of Medicine, Seoul, Republic of Korea
| | - Park Da Young
- Cancer Research Institute, Seoul National University College of Medicine, Seoul, Republic of Korea
| | - In Ah Kim
- Department of Radiation Oncology, Seoul National University College of Medicine, Seoul, Republic of Korea
- Cancer Research Institute, Seoul National University College of Medicine, Seoul, Republic of Korea
- Department of Radiation Oncology, Seoul National University Bundang Hospital, Seongnam, Republic of Korea
| | - Il Han Kim
- Department of Radiation Oncology, Seoul National University College of Medicine, Seoul, Republic of Korea
- Cancer Research Institute, Seoul National University College of Medicine, Seoul, Republic of Korea
- Institute of Radiation Medicine, Medical Research Center, Seoul National University, Seoul, Republic of Korea
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24
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Theoretical studies on the chemical decomposition of 5-aza-2′-deoxycytidine: DFT study and Monte Carlo simulation. Theor Chem Acc 2012. [DOI: 10.1007/s00214-012-1108-z] [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]
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25
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HLA-G regulators in cancer medicine: an outline of key requirements. Tumour Biol 2011; 32:1071-86. [DOI: 10.1007/s13277-011-0213-2] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2011] [Accepted: 07/08/2011] [Indexed: 02/07/2023] Open
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Gonçalves P, Gregório I, Martel F. The short-chain fatty acid butyrate is a substrate of breast cancer resistance protein. Am J Physiol Cell Physiol 2011; 301:C984-94. [PMID: 21775706 DOI: 10.1152/ajpcell.00146.2011] [Citation(s) in RCA: 30] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023]
Abstract
Colorectal cancer is one of the most common cancers worldwide. Butyrate (BT) plays a key role in colonic epithelium homeostasis. The aim of this work was to investigate the possibility of BT being transported by P-glycoprotein (MDR1), multidrug resistance proteins (MRPs), or breast cancer resistance protein (BCRP). Uptake and efflux of (14)C-BT and (3)H-folic acid were measured in Caco-2, IEC-6, and MDA-MB-231 cell lines. mRNA expression of BCRP was detected by RT-PCR. Cell viability, proliferation, and differentiation were quantified with the lactate dehydrogenase, sulforhodamine B, and alkaline phosphatase activity assays, respectively. In both IEC-6 cells and Caco-2 cells, no evidence was found for the involvement of either MDR1 or MRPs in (14)C-BT efflux from the cells. In contrast, several lines of evidence support the conclusion that BT is a substrate of both rat and human BCRP. Indeed, BCRP inhibitors reduced (14)C-BT efflux in IEC-6 cells, both BT and BCRP inhibitors significantly decreased the efflux of the known BCRP substrate (3)H-folic acid in IEC-6 cells, and BCRP inhibitors reduced (14)C-BT efflux in the BCRP-expressing MDA-MB-231 cell line. In IEC-6 cells, combination of BT with a BCRP inhibitor significantly potentiated the effect of BT on cell proliferation. The results of this study, showing for the first time that BT is a BCRP substrate, are very important in the context of the high levels of BCRP expression in the human colon and the anticarcinogenic and anti-inflammatory role of BT at that level. So, interaction of BT with BCRP and with other BCRP substrates/inhibitors is clearly of major importance.
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Affiliation(s)
- Pedro Gonçalves
- Department of Biochemistry, Faculty of Medicine, University of Porto, Porto, Portugal
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27
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Cai FF, Kohler C, Zhang B, Wang MH, Chen WJ, Zhong XY. Epigenetic therapy for breast cancer. Int J Mol Sci 2011; 12:4465-87. [PMID: 21845090 PMCID: PMC3155363 DOI: 10.3390/ijms12074465] [Citation(s) in RCA: 32] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2011] [Revised: 06/30/2011] [Accepted: 07/01/2011] [Indexed: 01/21/2023] Open
Abstract
Both genetic and epigenetic alterations can control the progression of cancer. Genetic alterations are impossible to reverse, while epigenetic alterations are reversible. This advantage suggests that epigenetic modifications should be preferred in therapy applications. DNA methyltransferases and histone deacetylases have become the primary targets for studies in epigenetic therapy. Some DNA methylation inhibitors and histone deacetylation inhibitors are approved by the US Food and Drug Administration as anti-cancer drugs. Therefore, the uses of epigenetic targets are believed to have great potential as a lasting favorable approach in treating breast cancer.
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Affiliation(s)
- Feng-Feng Cai
- Laboratory for Gynecological Oncology, Department of Biomedicine, Women’s Hospital, University of Basel, Hebelstrasse 20, Room 420, Basel, CH 4031, Switzerland; E-Mails: (F.-F.C.); (C.K.); (B.Z.); (W.-J.C.)
| | - Corina Kohler
- Laboratory for Gynecological Oncology, Department of Biomedicine, Women’s Hospital, University of Basel, Hebelstrasse 20, Room 420, Basel, CH 4031, Switzerland; E-Mails: (F.-F.C.); (C.K.); (B.Z.); (W.-J.C.)
| | - Bei Zhang
- Laboratory for Gynecological Oncology, Department of Biomedicine, Women’s Hospital, University of Basel, Hebelstrasse 20, Room 420, Basel, CH 4031, Switzerland; E-Mails: (F.-F.C.); (C.K.); (B.Z.); (W.-J.C.)
| | - Ming-Hong Wang
- Department of General Practice Medicine, Zhongda Hospital of Southeast University, Nanjing 210009, Jiangsu, China; E-Mail:
| | - Wei-Jie Chen
- Laboratory for Gynecological Oncology, Department of Biomedicine, Women’s Hospital, University of Basel, Hebelstrasse 20, Room 420, Basel, CH 4031, Switzerland; E-Mails: (F.-F.C.); (C.K.); (B.Z.); (W.-J.C.)
| | - Xiao-Yan Zhong
- Laboratory for Gynecological Oncology, Department of Biomedicine, Women’s Hospital, University of Basel, Hebelstrasse 20, Room 420, Basel, CH 4031, Switzerland; E-Mails: (F.-F.C.); (C.K.); (B.Z.); (W.-J.C.)
- Author to whom correspondence should be addressed; E-Mail: ; Tel.: +41-612-659-248; Fax: +41-612-659-399
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Brodská B, Otevřelová P, Holoubek A. Decitabine-induced apoptosis is derived by Puma and Noxa induction in chronic myeloid leukemia cell line as well as in PBL and is potentiated by SAHA. Mol Cell Biochem 2010; 350:71-80. [PMID: 21153863 DOI: 10.1007/s11010-010-0683-3] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2010] [Accepted: 12/02/2010] [Indexed: 10/18/2022]
Abstract
Restoration of cellular apoptotic pathways plays a crucial role in cancer therapy strategies. In a broad spectrum of anticancer drugs, epigenetic effectors are in the center of interest mostly because of potential reversibility of their action. Methylation status of the cells is influenced by methyltransferase inhibitor 2-deoxy-5'-azacytidine (decitabine, DAC), but higher concentrations of this agent cause a DNA-damage. In our study, tumor supressor p53-apoptotic pathway was activated in decitabine-induced cell death. Expression of p53-inducible BH3-only apoptotic proteins Puma and Noxa was elevated and large activation of executive caspases was observed. The extent of acetylation in the cell is affected by histonedeacetylase inhibitor suberoylanilide hydroxamic acid (SAHA). Combination of SAHA with decitabine brought synergistic effect on apoptosis triggering in CML-T1 cell line, but apoptosis as well as necrosis occurred also in normal peripheral blood lymphocytes. Therefore, promising potential of such combined therapy calls for more detailed investigation of unwanted effects in normal cells.
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Affiliation(s)
- Barbora Brodská
- Institute of Hematology and Blood Transfusion, Prague 2, Czech Republic.
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29
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Abstract
Epigenetic mechanisms involving DNA methylation, histone modifications and noncoding RNAs regulate and maintain gene-expression states. Similar to genetic mutations, alterations in epigenetic regulation can lead to uncontrolled cell division, tumor initiation and growth, invasiveness and metastasis. Research in brain cancer, particularly gliomas, has uncovered global and gene-specific DNA hypomethylation, local DNA hypermethylation of gene promoters and the de-regulation of microRNA expression. Understanding epigenetic dysregulation in brain cancers has provided new tools for prognostication, as well as suggesting new approaches to therapy. There is significant interest in new sequencing-based technologies that map genetic and epigenetic alterations comprehensively and at high resolution. These methods are being applied to brain tumors, and will better define the contribution of epigenetic defects to tumorigenesis.
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Affiliation(s)
- Shaun D Fouse
- Brain Tumor Research Center, Department of Neurosurgery, Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, CA 94158, USA
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