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1
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Duan X, Xing Z, Qiao L, Qin S, Zhao X, Gong Y, Li X. The role of histone post-translational modifications in cancer and cancer immunity: functions, mechanisms and therapeutic implications. Front Immunol 2024; 15:1495221. [PMID: 39620228 PMCID: PMC11604627 DOI: 10.3389/fimmu.2024.1495221] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2024] [Accepted: 10/18/2024] [Indexed: 12/11/2024] Open
Abstract
Histones play crucial roles in both promoting and repressing gene expression, primarily regulated through post-translational modifications (PTMs) at specific amino acid residues. Histone PTMs, including methylation, acetylation, ubiquitination, phosphorylation, lactylation, butyrylation, and propionylation, act as important epigenetic markers. These modifications influence not only chromatin compaction but also gene expression. Their importance extends to the treatment and prevention of various human diseases, particularly cancer, due to their involvement in key cellular processes. Abnormal histone modifications and the enzymes responsible for these alterations often serve as critical drivers in tumor cell proliferation, invasion, apoptosis, and stemness. This review introduces key histone PTMs and the enzymes responsible for these modifications, examining their impact on tumorigenesis and cancer progression. Furthermore, it explores therapeutic strategies targeting histone PTMs and offers recommendations for identifying new potential therapeutic targets.
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Affiliation(s)
- Xiaohong Duan
- School of Disaster and Emergency Medicine, Faculty of Medicine, Tianjin University, Tianjin, China
- Institute of Disaster and Emergency Medicine, Faculty of Medicine, Tianjin University, Tianjin, China
- Medical School, Faculty of Medicine, Tianjin University, Tianjin, China
| | - Zhiyao Xing
- Tianjin University and Health-Biotech United Group Joint Laboratory of Innovative Drug Development and Translational Medicine, School of Pharmaceutical Science and Technology, Faculty of Medicine, Tianjin University, Tianjin, China
- Department of Respiratory Medicine, Jinnan Hospital, Tianjin University, Tianjin, China
- Department of Respiratory Medicine, Tianjin Jinnan Hospital, Tianjin, China
| | - Lu Qiao
- The Province and Ministry Co-sponsored Collaborative Innovation Center for Medical Epigenetics, Key Laboratory of Immune Microenvironment and Disease (Ministry of Education), Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Tianjin Medical University, Tianjin, China
| | - Shan Qin
- Tianjin University and Health-Biotech United Group Joint Laboratory of Innovative Drug Development and Translational Medicine, School of Pharmaceutical Science and Technology, Faculty of Medicine, Tianjin University, Tianjin, China
| | - Xuejing Zhao
- Tianjin University and Health-Biotech United Group Joint Laboratory of Innovative Drug Development and Translational Medicine, School of Pharmaceutical Science and Technology, Faculty of Medicine, Tianjin University, Tianjin, China
| | - Yanhua Gong
- School of Disaster and Emergency Medicine, Faculty of Medicine, Tianjin University, Tianjin, China
- Institute of Disaster and Emergency Medicine, Faculty of Medicine, Tianjin University, Tianjin, China
- Medical School, Faculty of Medicine, Tianjin University, Tianjin, China
| | - Xueren Li
- Department of Respiratory Medicine, Jinnan Hospital, Tianjin University, Tianjin, China
- Department of Respiratory Medicine, Tianjin Jinnan Hospital, Tianjin, China
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2
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Farrokhi Yekta R, Farahani M, Koushki M, Amiri-Dashatan N. Deciphering the potential role of post-translational modifications of histones in gastrointestinal cancers: a proteomics-based review with therapeutic challenges and opportunities. Front Oncol 2024; 14:1481426. [PMID: 39497715 PMCID: PMC11532047 DOI: 10.3389/fonc.2024.1481426] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2024] [Accepted: 09/30/2024] [Indexed: 11/07/2024] Open
Abstract
Oncogenesis is a complex and multi-step process, controlled by several factors including epigenetic modifications. It is considered that histone modifications are critical components in the regulation of gene expression, protein functions, and molecular interactions. Dysregulated post-translationally modified histones and the related enzymatic systems are key players in the control of cell proliferation and differentiation, which are associated with the onset and progression of cancers. The most of traditional investigations on cancer have focused on mutations of oncogenes and tumor suppressor genes. However, increasing evidence indicates that epigenetics, especially histone post-translational modifications (PTMs) play important roles in various cancer types. Mass spectrometry-based proteomic approaches have demonstrated tremendous potential in PTMs profiling and quantitation in different biological systems. In this paper, we have made a proteomics-based review on the role of histone modifications involved in gastrointestinal cancers (GCs) tumorigenesis processes. These alterations function not only as diagnostic or prognostic biomarkers for GCs, but a deeper comprehension of the epigenetic regulation of GCs could facilitate the treatment of this prevalent malignancy through the creation of more effective targeted therapies.
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Affiliation(s)
- Reyhaneh Farrokhi Yekta
- Proteomics Research Center, System Biology Institute, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Masoumeh Farahani
- Proteomics Research Center, System Biology Institute, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Mehdi Koushki
- Cancer Gene Therapy Research Center, Zanjan University of Medical Sciences, Zanjan, Iran
- Department of Clinical Biochemistry, School of Medicine, Zanjan University of Medical Sciences, Zanjan, Iran
| | - Nasrin Amiri-Dashatan
- Zanjan Metabolic Diseases Research Center, Zanjan University of Medical Sciences, Zanjan, Iran
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Tan WY, Nagabhyrava S, Ang-Olson O, Das P, Ladel L, Sailo B, He L, Sharma A, Ahuja N. Translation of Epigenetics in Cell-Free DNA Liquid Biopsy Technology and Precision Oncology. Curr Issues Mol Biol 2024; 46:6533-6565. [PMID: 39057032 PMCID: PMC11276574 DOI: 10.3390/cimb46070390] [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: 05/27/2024] [Revised: 06/21/2024] [Accepted: 06/23/2024] [Indexed: 07/28/2024] Open
Abstract
Technological advancements in cell-free DNA (cfDNA) liquid biopsy have triggered exponential growth in numerous clinical applications. While cfDNA-based liquid biopsy has made significant strides in personalizing cancer treatment, the exploration and translation of epigenetics in liquid biopsy to clinical practice is still nascent. This comprehensive review seeks to provide a broad yet in-depth narrative of the present status of epigenetics in cfDNA liquid biopsy and its associated challenges. It highlights the potential of epigenetics in cfDNA liquid biopsy technologies with the hopes of enhancing its clinical translation. The momentum of cfDNA liquid biopsy technologies in recent years has propelled epigenetics to the forefront of molecular biology. We have only begun to reveal the true potential of epigenetics in both our understanding of disease and leveraging epigenetics in the diagnostic and therapeutic domains. Recent clinical applications of epigenetics-based cfDNA liquid biopsy revolve around DNA methylation in screening and early cancer detection, leading to the development of multi-cancer early detection tests and the capability to pinpoint tissues of origin. The clinical application of epigenetics in cfDNA liquid biopsy in minimal residual disease, monitoring, and surveillance are at their initial stages. A notable advancement in fragmentation patterns analysis has created a new avenue for epigenetic biomarkers. However, the widespread application of cfDNA liquid biopsy has many challenges, including biomarker sensitivity, specificity, logistics including infrastructure and personnel, data processing, handling, results interpretation, accessibility, and cost effectiveness. Exploring and translating epigenetics in cfDNA liquid biopsy technology can transform our understanding and perception of cancer prevention and management. cfDNA liquid biopsy has great potential in precision oncology to revolutionize conventional ways of early cancer detection, monitoring residual disease, treatment response, surveillance, and drug development. Adapting the implementation of liquid biopsy workflow to the local policy worldwide and developing point-of-care testing holds great potential to overcome global cancer disparity and improve cancer outcomes.
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Affiliation(s)
- Wan Ying Tan
- Department of Surgery, Yale School of Medicine, New Haven, CT 06520-8000, USA; (W.Y.T.); (P.D.); (L.L.); (B.S.); (L.H.)
- Department of Internal Medicine, Norwalk Hospital, Norwalk, CT 06850, USA
- Hematology & Oncology, Neag Comprehensive Cancer Center, UConn Health, Farmington, CT 06030, USA
| | | | - Olivia Ang-Olson
- Department of Surgery, Yale School of Medicine, New Haven, CT 06520-8000, USA; (W.Y.T.); (P.D.); (L.L.); (B.S.); (L.H.)
| | - Paromita Das
- Department of Surgery, Yale School of Medicine, New Haven, CT 06520-8000, USA; (W.Y.T.); (P.D.); (L.L.); (B.S.); (L.H.)
| | - Luisa Ladel
- Department of Surgery, Yale School of Medicine, New Haven, CT 06520-8000, USA; (W.Y.T.); (P.D.); (L.L.); (B.S.); (L.H.)
- Department of Internal Medicine, Norwalk Hospital, Norwalk, CT 06850, USA
| | - Bethsebie Sailo
- Department of Surgery, Yale School of Medicine, New Haven, CT 06520-8000, USA; (W.Y.T.); (P.D.); (L.L.); (B.S.); (L.H.)
| | - Linda He
- Department of Surgery, Yale School of Medicine, New Haven, CT 06520-8000, USA; (W.Y.T.); (P.D.); (L.L.); (B.S.); (L.H.)
| | - Anup Sharma
- Department of Surgery, Yale School of Medicine, New Haven, CT 06520-8000, USA; (W.Y.T.); (P.D.); (L.L.); (B.S.); (L.H.)
| | - Nita Ahuja
- Department of Surgery, Yale School of Medicine, New Haven, CT 06520-8000, USA; (W.Y.T.); (P.D.); (L.L.); (B.S.); (L.H.)
- Department of Pathology, Yale School of Medicine, New Haven, CT 06520-8000, USA
- Biological and Biomedical Sciences Program (BBS), Yale University, New Haven, CT 06520-8084, USA
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Christodoulidis G, Koumarelas KE, Kouliou MN, Thodou E, Samara M. Gastric Cancer in the Era of Epigenetics. Int J Mol Sci 2024; 25:3381. [PMID: 38542354 PMCID: PMC10970362 DOI: 10.3390/ijms25063381] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2023] [Revised: 03/12/2024] [Accepted: 03/13/2024] [Indexed: 11/11/2024] Open
Abstract
Gastric cancer (GC) remains a significant contributor to cancer-related mortality. Novel high-throughput techniques have enlightened the epigenetic mechanisms governing gene-expression regulation. Epigenetic characteristics contribute to molecular taxonomy and give rise to cancer-specific epigenetic patterns. Helicobacter pylori (Hp) infection has an impact on aberrant DNA methylation either through its pathogenic CagA protein or by inducing chronic inflammation. The hypomethylation of specific repetitive elements generates an epigenetic field effect early in tumorigenesis. Epstein-Barr virus (EBV) infection triggers DNA methylation by dysregulating DNA methyltransferases (DNMT) enzyme activity, while persistent Hp-EBV co-infection leads to aggressive tumor behavior. Distinct histone modifications are also responsible for oncogene upregulation and tumor-suppressor gene silencing in gastric carcinomas. While histone methylation and acetylation processes have been extensively studied, other less prevalent alterations contribute to the development and migration of gastric cancer via a complex network of interactions. Enzymes, such as Nicotinamide N-methyltransferase (NNMT), which is involved in tumor's metabolic reprogramming, interact with methyltransferases and modify gene expression. Non-coding RNA molecules, including long non-coding RNAs, circular RNAs, and miRNAs serve as epigenetic regulators contributing to GC development, metastasis, poor outcomes and therapy resistance. Serum RNA molecules hold the potential to serve as non-invasive biomarkers for diagnostic, prognostic or therapeutic applications. Gastric fluids represent a valuable source to identify potential biomarkers with diagnostic use in terms of liquid biopsy. Ongoing clinical trials are currently evaluating the efficacy of next-generation epigenetic drugs, displaying promising outcomes. Various approaches including multiple miRNA inhibitors or targeted nanoparticles carrying epigenetic drugs are being designed to enhance existing treatment efficacy and overcome treatment resistance.
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Affiliation(s)
- Grigorios Christodoulidis
- Department of General Surgery, University Hospital of Larissa, University of Thessaly, Biopolis Campus, 41110 Larissa, Greece; (G.C.); (K.-E.K.); (M.-N.K.)
| | - Konstantinos-Eleftherios Koumarelas
- Department of General Surgery, University Hospital of Larissa, University of Thessaly, Biopolis Campus, 41110 Larissa, Greece; (G.C.); (K.-E.K.); (M.-N.K.)
| | - Marina-Nektaria Kouliou
- Department of General Surgery, University Hospital of Larissa, University of Thessaly, Biopolis Campus, 41110 Larissa, Greece; (G.C.); (K.-E.K.); (M.-N.K.)
| | - Eleni Thodou
- Department of Pathology, Faculty of Medicine, School of Health Sciences, University of Thessaly, Biopolis Campus, 41110 Larissa, Greece;
| | - Maria Samara
- Department of Pathology, Faculty of Medicine, School of Health Sciences, University of Thessaly, Biopolis Campus, 41110 Larissa, Greece;
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Archana B, D'Cruze L, Sundaram S, Ramanathan K, Ganesh K. Immunohistochemical expression of histone modification pattern in adult glioblastoma. J Cancer Res Ther 2024; 20:52-56. [PMID: 38554298 DOI: 10.4103/jcrt.jcrt_257_22] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2022] [Accepted: 08/29/2022] [Indexed: 11/19/2022]
Abstract
BACKGROUND Despite the growing advances in molecular research and therapeutics, glioblastomas are still considered highly invasive aggressive tumors with a median survival of 15 months. Genetic alterations have been studied in detail; however, additionally, there is now growing evidence on the role of epigenetic alterations in glioblastoma. Recently, histone modification patterns have been found to have a significant part in gene expression and prognosis. However, further research in this field is warranted to establish its role for the betterment of these patients with the deadly disease. AIMS To determine the immunohistochemical expression of histone modifications like histone-3-lysine-18 acetylation (H3K18Ac) and histone-4-lysine 20 trimethylation (H4K20triMe) in glioblastoma patients. MATERIALS AND METHODS This is a retrospective study of 48 glioblastoma patients who underwent surgery. Immunohistochemistry (IHC) for tri-methyl-histone-H4 (Lys20) (H4K20triMe) and acetyl-histone-H3 (Lys18) (H3K18Ac) was performed in paraffin-embedded tissues manually, and the expression was noted. Data on the mitotic index and overall survival was collected and statistically analyzed. RESULTS The mean age was 50 years with a M: F ratio of 1.6:1. Out of 48 cases, 60% (28 cases) demonstrated positivity for H3K18Ac and 98% (46 cases) for H4K20triMe. The pattern of expression was nuclear with increased expression adjacent to necrosis and at the invasive front. The overall median Q score for H3K18Ac was 1/12 and for H4K20triMe was 6/12. No significant statistical significance was observed between histone expression, Ki67%, and overall survival. CONCLUSION Histone modification patterns are being explored in detail in an array of tumors. They also have a potential role in glioblastoma for risk stratification and instituting appropriate treatment based on the prognosis. Epigenetic changes like histone modification patterns, in addition to genetics, can pave the way for a better molecular understanding of glioblastomas and provide hope in the future to improve the survival of these patients with deadly diseases.
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Affiliation(s)
- B Archana
- Department of Pathology, Sri Ramachandra Institute of Higher Education and Research, Porur, Chennai, Tamil Nadu, India
| | - Lawrence D'Cruze
- Department of Pathology, Sri Ramachandra Institute of Higher Education and Research, Porur, Chennai, Tamil Nadu, India
| | - Sandhya Sundaram
- Department of Pathology, Sri Ramachandra Institute of Higher Education and Research, Porur, Chennai, Tamil Nadu, India
| | - Krishnakumar Ramanathan
- Department of Pathology, Sri Ramachandra Institute of Higher Education and Research, Porur, Chennai, Tamil Nadu, India
| | - Krishnamurthy Ganesh
- Department of Neurosurgery, Sri Ramachandra Institute of Higher Education and Research, Porur, Chennai, Tamil Nadu, India
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Gaggioli V, Lo CSY, Reverón-Gómez N, Jasencakova Z, Domenech H, Nguyen H, Sidoli S, Tvardovskiy A, Uruci S, Slotman JA, Chai Y, Gonçalves JGSCS, Manolika EM, Jensen ON, Wheeler D, Sridharan S, Chakrabarty S, Demmers J, Kanaar R, Groth A, Taneja N. Dynamic de novo heterochromatin assembly and disassembly at replication forks ensures fork stability. Nat Cell Biol 2023; 25:1017-1032. [PMID: 37414849 PMCID: PMC10344782 DOI: 10.1038/s41556-023-01167-z] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2022] [Accepted: 05/16/2023] [Indexed: 07/08/2023]
Abstract
Chromatin is dynamically reorganized when DNA replication forks are challenged. However, the process of epigenetic reorganization and its implication for fork stability is poorly understood. Here we discover a checkpoint-regulated cascade of chromatin signalling that activates the histone methyltransferase EHMT2/G9a to catalyse heterochromatin assembly at stressed replication forks. Using biochemical and single molecule chromatin fibre approaches, we show that G9a together with SUV39h1 induces chromatin compaction by accumulating the repressive modifications, H3K9me1/me2/me3, in the vicinity of stressed replication forks. This closed conformation is also favoured by the G9a-dependent exclusion of the H3K9-demethylase JMJD1A/KDM3A, which facilitates heterochromatin disassembly upon fork restart. Untimely heterochromatin disassembly from stressed forks by KDM3A enables PRIMPOL access, triggering single-stranded DNA gap formation and sensitizing cells towards chemotherapeutic drugs. These findings may help in explaining chemotherapy resistance and poor prognosis observed in patients with cancer displaying elevated levels of G9a/H3K9me3.
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Affiliation(s)
- Vincent Gaggioli
- Department of Molecular Genetics, Erasmus University Medical Center, Erasmus MC Cancer Institute, Rotterdam, the Netherlands
- Oncode Institute, Erasmus University Medical Center, Erasmus MC Cancer Institute, Rotterdam, the Netherlands
| | - Calvin S Y Lo
- Department of Molecular Genetics, Erasmus University Medical Center, Erasmus MC Cancer Institute, Rotterdam, the Netherlands
| | - Nazaret Reverón-Gómez
- Novo Nordisk Foundation Center for Protein Research (CPR), Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
- Biotech Research and Innovation Centre (BRIC), Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Zuzana Jasencakova
- Novo Nordisk Foundation Center for Protein Research (CPR), Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
- Biotech Research and Innovation Centre (BRIC), Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Heura Domenech
- Department of Molecular Genetics, Erasmus University Medical Center, Erasmus MC Cancer Institute, Rotterdam, the Netherlands
| | - Hong Nguyen
- Department of Molecular Genetics, Erasmus University Medical Center, Erasmus MC Cancer Institute, Rotterdam, the Netherlands
| | - Simone Sidoli
- Department of Biochemistry & Molecular Biology, VILLUM Centre for Bioanalytical Sciences and Centre for Epigenetics, University of Southern Denmark, Odense, Denmark
- Department of Biochemistry, Albert Einstein College of Medicine, Bronx, NY, USA
| | - Andrey Tvardovskiy
- Department of Biochemistry & Molecular Biology, VILLUM Centre for Bioanalytical Sciences and Centre for Epigenetics, University of Southern Denmark, Odense, Denmark
- Institute of Functional Epigenetics (IFE), Helmholtz Zentrum Munchen, Neuherberg, Germany
| | - Sidrit Uruci
- Department of Molecular Genetics, Erasmus University Medical Center, Erasmus MC Cancer Institute, Rotterdam, the Netherlands
| | - Johan A Slotman
- Department of Pathology, Erasmus Optical Imaging Centre, Erasmus Medical Center, Rotterdam, the Netherlands
| | - Yi Chai
- Cancer Science Institute of Singapore, Yong Loo Lin School of Medicine, National University of Singapore (NUS), Singapore, Singapore
| | | | - Eleni Maria Manolika
- Department of Molecular Genetics, Erasmus University Medical Center, Erasmus MC Cancer Institute, Rotterdam, the Netherlands
| | - Ole N Jensen
- Department of Biochemistry & Molecular Biology, VILLUM Centre for Bioanalytical Sciences and Centre for Epigenetics, University of Southern Denmark, Odense, Denmark
| | - David Wheeler
- Laboratory of Biochemistry and Molecular Biology, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
| | - Sriram Sridharan
- Cancer Science Institute of Singapore, Yong Loo Lin School of Medicine, National University of Singapore (NUS), Singapore, Singapore
| | - Sanjiban Chakrabarty
- Department of Cell and Molecular Biology, Manipal School of Life Sciences, Manipal Academy of Higher Education, Manipal, India
| | - Jeroen Demmers
- Proteomics Center and Department of Biochemistry, Erasmus University Medical Centre, Rotterdam, the Netherlands
| | - Roland Kanaar
- Department of Molecular Genetics, Erasmus University Medical Center, Erasmus MC Cancer Institute, Rotterdam, the Netherlands
- Oncode Institute, Erasmus University Medical Center, Erasmus MC Cancer Institute, Rotterdam, the Netherlands
| | - Anja Groth
- Novo Nordisk Foundation Center for Protein Research (CPR), Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
- Biotech Research and Innovation Centre (BRIC), Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Nitika Taneja
- Department of Molecular Genetics, Erasmus University Medical Center, Erasmus MC Cancer Institute, Rotterdam, the Netherlands.
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Liu R, Wu J, Guo H, Yao W, Li S, Lu Y, Jia Y, Liang X, Tang J, Zhang H. Post-translational modifications of histones: Mechanisms, biological functions, and therapeutic targets. MedComm (Beijing) 2023; 4:e292. [PMID: 37220590 PMCID: PMC10200003 DOI: 10.1002/mco2.292] [Citation(s) in RCA: 53] [Impact Index Per Article: 26.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2022] [Revised: 05/05/2023] [Accepted: 05/09/2023] [Indexed: 05/25/2023] Open
Abstract
Histones are DNA-binding basic proteins found in chromosomes. After the histone translation, its amino tail undergoes various modifications, such as methylation, acetylation, phosphorylation, ubiquitination, malonylation, propionylation, butyrylation, crotonylation, and lactylation, which together constitute the "histone code." The relationship between their combination and biological function can be used as an important epigenetic marker. Methylation and demethylation of the same histone residue, acetylation and deacetylation, phosphorylation and dephosphorylation, and even methylation and acetylation between different histone residues cooperate or antagonize with each other, forming a complex network. Histone-modifying enzymes, which cause numerous histone codes, have become a hot topic in the research on cancer therapeutic targets. Therefore, a thorough understanding of the role of histone post-translational modifications (PTMs) in cell life activities is very important for preventing and treating human diseases. In this review, several most thoroughly studied and newly discovered histone PTMs are introduced. Furthermore, we focus on the histone-modifying enzymes with carcinogenic potential, their abnormal modification sites in various tumors, and multiple essential molecular regulation mechanism. Finally, we summarize the missing areas of the current research and point out the direction of future research. We hope to provide a comprehensive understanding and promote further research in this field.
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Affiliation(s)
- Ruiqi Liu
- Cancer CenterDepartment of Radiation OncologyZhejiang Provincial People's HospitalAffiliated People's HospitalHangzhou Medical CollegeHangzhouZhejiangChina
- Graduate DepartmentBengbu Medical College, BengbuAnhuiChina
| | - Jiajun Wu
- Graduate DepartmentBengbu Medical College, BengbuAnhuiChina
- Otolaryngology & Head and Neck CenterCancer CenterDepartment of Head and Neck SurgeryZhejiang Provincial People's HospitalAffiliated People's Hospital, Hangzhou Medical CollegeHangzhouZhejiangChina
| | - Haiwei Guo
- Otolaryngology & Head and Neck CenterCancer CenterDepartment of Head and Neck SurgeryZhejiang Provincial People's HospitalAffiliated People's Hospital, Hangzhou Medical CollegeHangzhouZhejiangChina
| | - Weiping Yao
- Cancer CenterDepartment of Radiation OncologyZhejiang Provincial People's HospitalAffiliated People's HospitalHangzhou Medical CollegeHangzhouZhejiangChina
- Graduate DepartmentBengbu Medical College, BengbuAnhuiChina
| | - Shuang Li
- Cancer CenterDepartment of Radiation OncologyZhejiang Provincial People's HospitalAffiliated People's HospitalHangzhou Medical CollegeHangzhouZhejiangChina
- Graduate DepartmentJinzhou Medical UniversityJinzhouLiaoningChina
| | - Yanwei Lu
- Cancer CenterDepartment of Radiation OncologyZhejiang Provincial People's HospitalAffiliated People's HospitalHangzhou Medical CollegeHangzhouZhejiangChina
| | - Yongshi Jia
- Cancer CenterDepartment of Radiation OncologyZhejiang Provincial People's HospitalAffiliated People's HospitalHangzhou Medical CollegeHangzhouZhejiangChina
| | - Xiaodong Liang
- Cancer CenterDepartment of Radiation OncologyZhejiang Provincial People's HospitalAffiliated People's HospitalHangzhou Medical CollegeHangzhouZhejiangChina
- Graduate DepartmentBengbu Medical College, BengbuAnhuiChina
| | - Jianming Tang
- Department of Radiation OncologyThe First Hospital of Lanzhou UniversityLanzhou UniversityLanzhouGansuChina
| | - Haibo Zhang
- Cancer CenterDepartment of Radiation OncologyZhejiang Provincial People's HospitalAffiliated People's HospitalHangzhou Medical CollegeHangzhouZhejiangChina
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8
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Bhattacharya A. Epigenetic modifications and regulations in gastrointestinal diseases. EPIGENETICS IN ORGAN SPECIFIC DISORDERS 2023:497-543. [DOI: 10.1016/b978-0-12-823931-5.00005-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/04/2025]
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9
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Yang Y, Zhang M, Wang Y. The roles of histone modifications in tumorigenesis and associated inhibitors in cancer therapy. JOURNAL OF THE NATIONAL CANCER CENTER 2022; 2:277-290. [PMID: 39036551 PMCID: PMC11256729 DOI: 10.1016/j.jncc.2022.09.002] [Citation(s) in RCA: 42] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2022] [Revised: 09/19/2022] [Accepted: 09/26/2022] [Indexed: 11/25/2022] Open
Abstract
Histone modifications are key factors in chromatin packaging, and are responsible for gene regulation during cell fate determination and development. Abnormal alterations in histone modifications potentially affect the stability of the genome and disrupt gene expression patterns, leading to many diseases, including cancer. In recent years, mounting evidence has shown that various histone modifications altered by aberrantly expressed modifier enzymes contribute to tumor development and metastasis through the induction of epigenetic, transcriptional, and phenotypic changes. In this review, we will discuss the existing histone modifications, both well-studied and rare ones, and their roles in solid tumors and hematopoietic cancers, to identify the molecular pathways involved and investigate targeted therapeutic drugs to reorganize the chromatin and enhance cancer treatment efficiency. Finally, clinical inhibitors of histone modifications are summarized to better understand the developmental stage of cancer therapy in using these drugs to inhibit the histone modification enzymes.
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Affiliation(s)
| | | | - Yan Wang
- Key Laboratory of Cancer and Microbiome, State Key Laboratory of Molecular Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
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10
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Lei ZN, Teng QX, Tian Q, Chen W, Xie Y, Wu K, Zeng Q, Zeng L, Pan Y, Chen ZS, He Y. Signaling pathways and therapeutic interventions in gastric cancer. Signal Transduct Target Ther 2022; 7:358. [PMID: 36209270 PMCID: PMC9547882 DOI: 10.1038/s41392-022-01190-w] [Citation(s) in RCA: 121] [Impact Index Per Article: 40.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2022] [Revised: 08/14/2022] [Accepted: 09/07/2022] [Indexed: 11/23/2022] Open
Abstract
Gastric cancer (GC) ranks fifth in global cancer diagnosis and fourth in cancer-related death. Despite tremendous progress in diagnosis and therapeutic strategies and significant improvements in patient survival, the low malignancy stage is relatively asymptomatic and many GC cases are diagnosed at advanced stages, which leads to unsatisfactory prognosis and high recurrence rates. With the recent advances in genome analysis, biomarkers have been identified that have clinical importance for GC diagnosis, treatment, and prognosis. Modern molecular classifications have uncovered the vital roles that signaling pathways, including EGFR/HER2, p53, PI3K, immune checkpoint pathways, and cell adhesion signaling molecules, play in GC tumorigenesis, progression, metastasis, and therapeutic responsiveness. These biomarkers and molecular classifications open the way for more precise diagnoses and treatments for GC patients. Nevertheless, the relative significance, temporal activation, interaction with GC risk factors, and crosstalk between these signaling pathways in GC are not well understood. Here, we review the regulatory roles of signaling pathways in GC potential biomarkers, and therapeutic targets with an emphasis on recent discoveries. Current therapies, including signaling-based and immunotherapies exploited in the past decade, and the development of treatment for GC, particularly the challenges in developing precision medications, are discussed. These advances provide a direction for the integration of clinical, molecular, and genomic profiles to improve GC diagnosis and treatments.
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Affiliation(s)
- Zi-Ning Lei
- Guangdong Provincial Key Laboratory of Digestive Cancer Research, Digestive Diseases Center, Scientific Research Center, The Seventh Affiliated Hospital of Sun Yat-Sen University, 518107, Shenzhen, Guangdong, China
- Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John's University, Queens, NY, 11439, USA
| | - Qiu-Xu Teng
- Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John's University, Queens, NY, 11439, USA
| | - Qin Tian
- Guangdong Provincial Key Laboratory of Digestive Cancer Research, Digestive Diseases Center, Scientific Research Center, The Seventh Affiliated Hospital of Sun Yat-Sen University, 518107, Shenzhen, Guangdong, China
| | - Wei Chen
- Guangdong Provincial Key Laboratory of Digestive Cancer Research, Digestive Diseases Center, Scientific Research Center, The Seventh Affiliated Hospital of Sun Yat-Sen University, 518107, Shenzhen, Guangdong, China
| | - Yuhao Xie
- Institute for Biotechnology, St. John's University, Queens, NY, 11439, USA
| | - Kaiming Wu
- Guangdong Provincial Key Laboratory of Digestive Cancer Research, Digestive Diseases Center, Scientific Research Center, The Seventh Affiliated Hospital of Sun Yat-Sen University, 518107, Shenzhen, Guangdong, China
| | - Qianlin Zeng
- Guangdong Provincial Key Laboratory of Digestive Cancer Research, Digestive Diseases Center, Scientific Research Center, The Seventh Affiliated Hospital of Sun Yat-Sen University, 518107, Shenzhen, Guangdong, China
| | - Leli Zeng
- Guangdong Provincial Key Laboratory of Digestive Cancer Research, Digestive Diseases Center, Scientific Research Center, The Seventh Affiliated Hospital of Sun Yat-Sen University, 518107, Shenzhen, Guangdong, China.
| | - Yihang Pan
- Guangdong Provincial Key Laboratory of Digestive Cancer Research, Digestive Diseases Center, Scientific Research Center, The Seventh Affiliated Hospital of Sun Yat-Sen University, 518107, Shenzhen, Guangdong, China.
| | - Zhe-Sheng Chen
- Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John's University, Queens, NY, 11439, USA.
- Institute for Biotechnology, St. John's University, Queens, NY, 11439, USA.
| | - Yulong He
- Guangdong Provincial Key Laboratory of Digestive Cancer Research, Digestive Diseases Center, Scientific Research Center, The Seventh Affiliated Hospital of Sun Yat-Sen University, 518107, Shenzhen, Guangdong, China.
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11
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Lam-Ubol A, Phattarataratip E. Distinct histone H3 modification profiles correlate with aggressive characteristics of salivary gland neoplasms. Sci Rep 2022; 12:15063. [PMID: 36064736 PMCID: PMC9445049 DOI: 10.1038/s41598-022-19174-9] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2022] [Accepted: 08/25/2022] [Indexed: 11/09/2022] Open
Abstract
Post-translational modification of histones is the crucial event that affect many tumor-specific traits. A diverse type of histone modifications had been reported in different cancers with prognostic implications. This study aimed to examine the degree of histone H3 modifications in salivary gland neoplasms and their associations with tumor pathologic characteristics and proliferative activity. The expression of H3K9Ac, H3K18Ac, H3K9Me3 and Ki-67 in 70 specimens of salivary gland neoplasms, consisting of 30 mucoepidermoid carcinoma (MEC), 20 adenoid cystic carcinoma (ACC) and 20 pleomorphic adenoma (PA), were investigated immunohistochemically. The immunohistochemical scoring of 3 histone modification types and Ki-67 labeling index were determined. Overall, MEC demonstrated elevated H3K9Ac level compared with benign PA. Increased H3K9Me3 in MEC was positively correlated with small nest invasion at tumor front, advanced pathologic grade, and elevated proliferative index. In addition, the significant upregulation of all 3 types of histone H3 modification was noted in solid subtype of ACC and associated with increased cell proliferation. This study indicates that salivary gland neoplasms differentially acquire distinct patterns of histone H3 modification, which impact prognostically relevant cancer phenotypes. The hyperacetylation and methylation of histone H3 could be underpinning the prognostically worsen solid type of ACC, and the trimethylation of H3K9 may be involved in aggressive characteristics of MEC.
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Affiliation(s)
- Aroonwan Lam-Ubol
- Department of Oral Surgery and Oral Medicine, Faculty of Dentistry, Srinakharinwirot University, 114 Sukhumvit 23 Wattana, Bangkok, 10110, Thailand
| | - Ekarat Phattarataratip
- Department of Oral Pathology, Faculty of Dentistry, Chulalongkorn University, Henri-Dunant Road, Pathumwan, Bangkok, 10330, Thailand.
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12
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Pogribna M, Word B, Lyn-Cook B, Hammons G. Effect of titanium dioxide nanoparticles on histone modifications and histone modifying enzymes expression in human cell lines. Nanotoxicology 2022; 16:409-424. [DOI: 10.1080/17435390.2022.2085206] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/16/2022]
Affiliation(s)
- Marta Pogribna
- Division of Biochemical Toxicology, National Center for Toxicological Research, U.S. Food & Drug Administration, Jefferson, AR, USA
| | - Beverly Word
- Division of Biochemical Toxicology, National Center for Toxicological Research, U.S. Food & Drug Administration, Jefferson, AR, USA
| | - Beverly Lyn-Cook
- Division of Biochemical Toxicology, National Center for Toxicological Research, U.S. Food & Drug Administration, Jefferson, AR, USA
| | - George Hammons
- Division of Biochemical Toxicology, National Center for Toxicological Research, U.S. Food & Drug Administration, Jefferson, AR, USA
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13
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Zhao W, Jiang X, Weisenthal K, Ma J, Botticelli EM, Zhou Y, Hedley-Whyte ET, Wang B, Swearingen B, Soberman RJ, Klibanski A, Zhang X. High Histone Deacetylase 2/3 Expression in Non-Functioning Pituitary Tumors. Front Oncol 2022; 12:875122. [PMID: 35646715 PMCID: PMC9136140 DOI: 10.3389/fonc.2022.875122] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2022] [Accepted: 04/13/2022] [Indexed: 11/21/2022] Open
Abstract
Epigenetic modification of chromatin is involved in non-malignant pituitary neoplasia by causing abnormal expression of tumor suppressors and oncogenes. These changes are potentially reversible, suggesting the possibility of targeting tumor cells by restoring the expression of epigenetically silenced tumor suppressors. The role of the histone deacetylase (HDAC) family in pituitary tumorigenesis is not known. We report that HDAC2 and 3, Class I HDAC members, are highly expressed in clinically non-functioning pituitary adenomas (NFPAs) compared to normal pituitary (NP) samples as determined by RT-PCR and immunohistochemical staining (IHC). Treatment of a human NFPA derived folliculostellate cell line, PDFS, with the HDAC3 inhibitor RGFP966 for 96 hours resulted in inhibition of cell proliferation by 70%. Furthermore, the combination of RGFP966 with a methyltransferase/DNMT inhibitor, 5’-aza-2’-deoxycytidine, led to the restoration of the expression of several tumor suppressor genes, including STAT1, P16, PTEN, and the large non-coding RNA tumor suppressor MEG3, in PDFS cells. Our data support the hypothesis that both histone modification and DNA methylation are involved in the pathogenesis of human NFPAs and suggest that targeting HDACs and DNA methylation can be incorporated into future therapies.
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Affiliation(s)
- Wenxiu Zhao
- Neuroendocrine Unit, Massachusetts General Hospital and Harvard Medical School, Boston, MA, United States
| | - Xiaobin Jiang
- Neuroendocrine Unit, Massachusetts General Hospital and Harvard Medical School, Boston, MA, United States
| | - Karrin Weisenthal
- Neuroendocrine Unit, Massachusetts General Hospital and Harvard Medical School, Boston, MA, United States
| | - Jun Ma
- Neuroendocrine Unit, Massachusetts General Hospital and Harvard Medical School, Boston, MA, United States
| | - Erin M. Botticelli
- Neuroendocrine Unit, Massachusetts General Hospital and Harvard Medical School, Boston, MA, United States
| | - Yunli Zhou
- Neuroendocrine Unit, Massachusetts General Hospital and Harvard Medical School, Boston, MA, United States
| | - E. Tessa Hedley-Whyte
- Neuropathology Unit, Massachusetts General Hospital and Harvard Medical School, Boston, MA, United States
| | - Baiyao Wang
- Neuroendocrine Unit, Massachusetts General Hospital and Harvard Medical School, Boston, MA, United States
| | - Brooke Swearingen
- Neurosurgical Service, Massachusetts General Hospital and Harvard Medical School, Boston, MA, United States
| | - Roy J. Soberman
- Nephrology Division, Massachusetts General Hospital and Harvard Medical School, Boston, MA, United States
| | - Anne Klibanski
- Neuroendocrine Unit, Massachusetts General Hospital and Harvard Medical School, Boston, MA, United States
| | - Xun Zhang
- Neuroendocrine Unit, Massachusetts General Hospital and Harvard Medical School, Boston, MA, United States
- *Correspondence: Xun Zhang,
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14
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Tang SY, Zhou PJ, Meng Y, Zeng FR, Deng GT. Gastric cancer: An epigenetic view. World J Gastrointest Oncol 2022; 14:90-109. [PMID: 35116105 PMCID: PMC8790429 DOI: 10.4251/wjgo.v14.i1.90] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/21/2021] [Revised: 05/17/2021] [Accepted: 12/23/2021] [Indexed: 02/06/2023] Open
Abstract
Gastric cancer (GC) poses a serious threat worldwide with unfavorable prognosis mainly due to late diagnosis and limited therapies. Therefore, precise molecular classification and search for potential targets are required for diagnosis and treatment, as GC is complicated and heterogeneous in nature. Accumulating evidence indicates that epigenetics plays a vital role in gastric carcinogenesis and progression, including histone modifications, DNA methylation and non-coding RNAs. Epigenetic biomarkers and drugs are currently under intensive evaluations to ensure efficient clinical utility in GC. In this review, key epigenetic alterations and related functions and mechanisms are summarized in GC. We focus on integration of existing epigenetic findings in GC for the bench-to-bedside translation of some pivotal epigenetic alterations into clinical practice and also describe the vacant field waiting for investigation.
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Affiliation(s)
- Si-Yuan Tang
- Department of Gastroenterology, Xiangya Hospital, Central South University, Changsha 410008, Hunan Province, China
| | - Pei-Jun Zhou
- Cancer Research Institute, School of Basic Medicine Science, Central South University, School of Basic Medicine Science, Central South University 410008, Hunan Province, China
| | - Yu Meng
- Department of Dermatology, Xiangya Hospital, Central South University, Changsha 410008, Hunan Province, China
| | - Fu-Rong Zeng
- Department of Dermatology, Xiangya Hospital, Central South University, Changsha 410008, Hunan Province, China
| | - Guang-Tong Deng
- Department of Dermatology, Xiangya Hospital, Central South University, Changsha 410008, Hunan Province, China
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15
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Holdgate GA, Bardelle C, Lanne A, Read J, O'Donovan DH, Smith JM, Selmi N, Sheppard R. Drug discovery for epigenetics targets. Drug Discov Today 2021; 27:1088-1098. [PMID: 34728375 DOI: 10.1016/j.drudis.2021.10.020] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2021] [Revised: 09/19/2021] [Accepted: 10/27/2021] [Indexed: 12/28/2022]
Abstract
Dysregulation of the epigenome is associated with the onset and progression of several diseases, including cancer, autoimmune, cardiovascular, and neurological disorders. Members from the three families of epigenetic proteins (readers, writers, and erasers) have been shown to be druggable using small-molecule inhibitors. Increasing knowledge of the role of epigenetics in disease and the reversibility of these modifications explain why pharmacological intervention is an attractive strategy for tackling epigenetic-based disease. In this review, we provide an overview of epigenetics drug targets, focus on approaches used for initial hit identification, and describe the subsequent role of structure-guided chemistry optimisation of initial hits to clinical candidates. We also highlight current challenges and future potential for epigenetics-based therapies.
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Affiliation(s)
- Geoffrey A Holdgate
- High-throughput Screening, Discovery Sciences, BioPharmaceuticals R&D, AstraZeneca, Alderley Park, UK.
| | - Catherine Bardelle
- High-throughput Screening, Discovery Sciences, BioPharmaceuticals R&D, AstraZeneca, Alderley Park, UK
| | - Alice Lanne
- High-throughput Screening, Discovery Sciences, BioPharmaceuticals R&D, AstraZeneca, Alderley Park, UK
| | - Jon Read
- Structure and Biophysics, Discovery Sciences, BioPharmaceuticals R&D, AstraZeneca, Cambridge, UK
| | | | | | - Nidhal Selmi
- iLAB, Discovery Sciences, BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden
| | - Robert Sheppard
- Medicinal Chemistry, Cardiovascular, Renal, Metabolism R&D, BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden
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16
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Reyes DA, Sarría VMS, Salazar-Viedma M, D'Afonseca V. Histone Methyltransferases Useful in Gastric Cancer Research. Cancer Inform 2021; 20:11769351211039862. [PMID: 34413625 PMCID: PMC8369960 DOI: 10.1177/11769351211039862] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2021] [Accepted: 07/26/2021] [Indexed: 11/29/2022] Open
Abstract
Gastric cancer (GC) is one of the most frequent tumors in the world. Stomach adenocarcinoma is a heterogeneous tumor, turning the prognosis prediction and patients’ clinical management difficult. Some diagnosis tests for GC are been development using knowledge based in polymorphisms, somatic copy number alteration (SCNA) and aberrant histone methylation. This last event, a posttranslational modification that occurs at the chromatin level, is an important epigenetic alteration seen in several tumors including stomach adenocarcinoma. Histone methyltransferases (HMT) are the proteins responsible for the methylation in specific amino acids residues of histones tails. Here, were presented several HMTs that could be relating to GC process. We use public data from 440 patients with stomach adenocarcinoma. We evaluated the alterations as SCNAs, mutations, and genes expression level of HMTs in these aforementioned samples. As results, it was identified the 10 HMTs most altered (up to 30%) in stomach adenocarcinoma samples, which are the PRDM14, PRDM9, SUV39H2, NSD2, SMYD5, SETDB1, PRDM12, SUV39H1, NSD3, and EHMT2 genes. The PRDM9 gene is among most mutated and amplified HMTs within the data set studied. PRDM14 is downregulated in 79% of the samples and the SUV39H2 gene is down expressed in patients with recurred/progressed disease. Several HMTs are altered in many cancers. It is important to generate a genetic atlas of alterations of cancer-related genes to improve the understanding of tumorigenesis events and to propose novel tools of diagnosis and prognosis for the cancer control.
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Affiliation(s)
- Dafne Alejandra Reyes
- Facultad de Ciencias Agrarias y Forestales, Universidad Católica del Maule, Talca, Chile
| | | | - Marcela Salazar-Viedma
- Laboratorio de Genética y Microevolución, Facultad de Ciencias Básicas, Universidad Católica del Maule, Talca, Chile
| | - Vívian D'Afonseca
- Centro de Investigación y Estudios Avanzados del Maule (CIEAM), Vicerrectoría de Investigación y Posgrado, Universidad Católica del Maule, Talca, Chile
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17
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Vougiouklakis T, Bernard BJ, Nigam N, Burkitt K, Nakamura Y, Saloura V. Clinicopathologic significance of protein lysine methyltransferases in cancer. Clin Epigenetics 2020; 12:146. [PMID: 33050946 PMCID: PMC7557092 DOI: 10.1186/s13148-020-00897-3] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2020] [Accepted: 07/01/2020] [Indexed: 12/26/2022] Open
Abstract
Protein lysine methyltransferases (PKMTs) constitute a large family of approximately 50 chromatin modifiers that mono-, di- and/or tri-methylate lysine residues on histone and non-histone substrates. With the advent of The Cancer Genome Atlas, it became apparent that this family of chromatin modifiers harbors frequent genetic and expression alterations in multiple types of cancer. In this regard, past and ongoing preclinical studies have provided insight into the mechanisms of action of some of these enzymes, laying the ground for the ongoing development of PKMT inhibitors as novel anticancer therapeutics. The purpose of this review is to summarize existing data obtained by different research groups through immunohistochemical analysis of the protein expression levels of PKMTs, and their respective clinicopathologic associations. We focused on studies that used immunohistochemistry to associate protein expression levels of specific PKMTs, as well as several established histone methylation marks, with clinicopathologic features and survival outcomes in various cancer types. We also review ongoing clinical trials of PKMT inhibitors in cancer treatment. This review underscores the clinical relevance and potential of targeting the family of PKMT enzymes as the next generation of cancer therapy.
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Affiliation(s)
| | - Benjamin J Bernard
- Thoracic and GI Malignancies Branch, Center for Cancer Research, National Cancer Institute, 41 Medlars Drive, National Cancer Institute, Bethesda, MD, 20892, USA
| | - Nupur Nigam
- Thoracic and GI Malignancies Branch, Center for Cancer Research, National Cancer Institute, 41 Medlars Drive, National Cancer Institute, Bethesda, MD, 20892, USA
| | - Kyunghee Burkitt
- Thoracic and GI Malignancies Branch, Center for Cancer Research, National Cancer Institute, 41 Medlars Drive, National Cancer Institute, Bethesda, MD, 20892, USA
| | - Yusuke Nakamura
- Cancer Precision Medicine Research Center, Japanese Foundation for Cancer Research, Koto, Japan
| | - Vassiliki Saloura
- Thoracic and GI Malignancies Branch, Center for Cancer Research, National Cancer Institute, 41 Medlars Drive, National Cancer Institute, Bethesda, MD, 20892, USA.
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18
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The role of the histones H3K9ac, H3K9me3, HP1γ, and H3K36me3 in oral squamous cell carcinoma loco-regional metastasis and relapse. Pathol Res Pract 2020; 216:153201. [PMID: 32971477 DOI: 10.1016/j.prp.2020.153201] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/09/2020] [Revised: 08/31/2020] [Accepted: 09/01/2020] [Indexed: 11/24/2022]
Abstract
Molecular markers with unequivocal significance in predicting cervical lymph node metastasis of oral squamous cell carcinoma (OSCC) has not yet been identified. Histones are DNA-binding proteins that can regulate gene expression, and some studies have shown that such proteins are implicated with tumor development and progression. This study aimed to investigate the expression of some histone modifications in OSCC and their roles in cervical lymph node metastasis. To address this goal, H3K9ac, H3K9me3, HP1γ, and H3K36me3 expression levels were investigated immunohistochemically in a retrospective metastatic and non-metastatic OSCC samples. We analyzed the association between these markers with clinical-pathological data and survival rates. Hyperacetylation of H3K9ac was associated with cervical lymph node metastasis and local relapse. High expression levels of H3K9m3 were related to age and symptomatology. Furthermore, it was also found a statistically significant association between high HP1γ-expressing tumors and tumor size. However, no markers were associated with reduced overall survival rate. Our results suggest that covalent histone modifications contribute to OSCC behavior, and H3K9ac may play a critical role in OSCC-derived cervical lymph node metastasis.
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19
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Canale M, Casadei-Gardini A, Ulivi P, Arechederra M, Berasain C, Lollini PL, Fernández-Barrena MG, Avila MA. Epigenetic Mechanisms in Gastric Cancer: Potential New Therapeutic Opportunities. Int J Mol Sci 2020; 21:E5500. [PMID: 32752096 PMCID: PMC7432799 DOI: 10.3390/ijms21155500] [Citation(s) in RCA: 28] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2020] [Revised: 07/27/2020] [Accepted: 07/29/2020] [Indexed: 02/07/2023] Open
Abstract
Gastric cancer (GC) is one of the deadliest malignancies worldwide. Complex disease heterogeneity, late diagnosis, and suboptimal therapies result in the poor prognosis of patients. Besides genetic alterations and environmental factors, it has been demonstrated that alterations of the epigenetic machinery guide cancer onset and progression, representing a hallmark of gastric malignancies. Moreover, epigenetic mechanisms undergo an intricate crosstalk, and distinct epigenomic profiles can be shaped under different microenvironmental contexts. In this scenario, targeting epigenetic mechanisms could be an interesting therapeutic strategy to overcome gastric cancer heterogeneity, and the efforts conducted to date are delivering promising results. In this review, we summarize the key epigenetic events involved in gastric cancer development. We conclude with a discussion of new promising epigenetic strategies for gastric cancer treatment.
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Affiliation(s)
- Matteo Canale
- Biosciences Laboratory, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, 47014 Meldola, Italy; (M.C.); (P.U.)
| | - Andrea Casadei-Gardini
- Department of Oncology and Hematology, Division of Oncology, University of Modena and Reggio Emilia, 41125 Modena, Italy
| | - Paola Ulivi
- Biosciences Laboratory, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, 47014 Meldola, Italy; (M.C.); (P.U.)
| | - Maria Arechederra
- Program of Hepatology, Center for Applied Medical Research (CIMA), University of Navarra, 31008 Pamplona, Spain; (M.A.); (C.B.); (M.G.F.-B.)
- IdiSNA, Navarra Institute for Health Research, 31008 Pamplona, Spain
| | - Carmen Berasain
- Program of Hepatology, Center for Applied Medical Research (CIMA), University of Navarra, 31008 Pamplona, Spain; (M.A.); (C.B.); (M.G.F.-B.)
- IdiSNA, Navarra Institute for Health Research, 31008 Pamplona, Spain
- National Institute for the Study of Liver and Gastrointestinal Diseases (CIBERehd, Carlos III Health Institute), 28029 Madrid, Spain
| | - Pier-Luigi Lollini
- Laboratory of Immunology and Biology of Metastasis, Department of Experimental, Diagnostic and Specialty Medicine (DIMES), University of Bologna, 40126 Bologna, Italy;
| | - Maite G. Fernández-Barrena
- Program of Hepatology, Center for Applied Medical Research (CIMA), University of Navarra, 31008 Pamplona, Spain; (M.A.); (C.B.); (M.G.F.-B.)
- IdiSNA, Navarra Institute for Health Research, 31008 Pamplona, Spain
- National Institute for the Study of Liver and Gastrointestinal Diseases (CIBERehd, Carlos III Health Institute), 28029 Madrid, Spain
| | - Matías A. Avila
- Program of Hepatology, Center for Applied Medical Research (CIMA), University of Navarra, 31008 Pamplona, Spain; (M.A.); (C.B.); (M.G.F.-B.)
- IdiSNA, Navarra Institute for Health Research, 31008 Pamplona, Spain
- National Institute for the Study of Liver and Gastrointestinal Diseases (CIBERehd, Carlos III Health Institute), 28029 Madrid, Spain
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20
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Vahidi S, Norollahi SE, Agah S, Samadani AA. DNA Methylation Profiling of hTERT Gene Alongside with the Telomere Performance in Gastric Adenocarcinoma. J Gastrointest Cancer 2020; 51:788-799. [PMID: 32617831 DOI: 10.1007/s12029-020-00427-7] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Abstract
PURPOSE Epigenetic modification including of DNA methylation, histone acetylation, histone methylation, histon phosphorylation and non-coding RNA can impress the gene expression and genomic stability and cause different types of malignancies and also main human disorder. Conspicuously, the epigenetic alteration special DNA methylation controls telomere length, telomerase activity and also function of different genes particularly hTERT expression. Telomeres are important in increasing the lifespan, health, aging, and the development and progression of some diseases like cancer. METHODS This review provides an assessment of the epigenetic alterations of telomeres, telomerase and repression of its catalytic subunit, hTERT and function of long non-coding RNAs such as telomeric-repeat containing RNA (TERRA) in carcinogenesis and tumorgenesis of gastric cancer. RESULTS hTERT expression is essential and indispensable in telomerase activation through immortality and malignancies and also plays an important role in maintaining telomere length. Telomeres and telomerase have been implicated in regulating epigenetic factors influencing certain gene expression. Correspondingly, these changes in the sub telomere and telomere regions are affected by the shortening of telomere length and increased telomerase activity and hTERT gene expression have been observed in many cancers, remarkably in gastric cancer. CONCLUSION Epigenetic alteration and regulation of hTERT gene expression are critical in controlling telomerase activity and its expression. Graphical Abstract.
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Affiliation(s)
- Sogand Vahidi
- Clinical Research Development Unit of Poursina Hospital, Guilan University of Medical Sciences, Rasht, Iran
| | - Seyedeh Elham Norollahi
- Clinical Research Development Unit of Poursina Hospital, Guilan University of Medical Sciences, Rasht, Iran.
| | - Shahram Agah
- Colorectal Research Center, Iran University of Medical Sciences, Tehran, Iran
| | - Ali Akbar Samadani
- Healthy Ageing Research Center, Neyshabur University of Medical Sciences, Neyshabur, Iran.
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21
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H3K4me3 Is a Potential Mediator for Antiproliferative Effects of Calcitriol (1α,25(OH)2D3) in Ovarian Cancer Biology. Int J Mol Sci 2020; 21:ijms21062151. [PMID: 32245092 PMCID: PMC7139961 DOI: 10.3390/ijms21062151] [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: 02/05/2020] [Revised: 03/12/2020] [Accepted: 03/18/2020] [Indexed: 12/17/2022] Open
Abstract
Posttranslational histone modification plays an important role in tumorigenesis. Histone modification is a dynamic response of chromatin to various signals, such as the exposure to calcitriol (1α,25(OH)2D3). Recent studies suggested that histone modification levels could be used to predict patient outcomes in various cancers. Our study evaluated the expression level of histone 3 lysine 4 trimethylation (H3K4me3) in a cohort of 156 epithelial ovarian cancer (EOC) cases by immunohistochemical staining and analyzed its correlation to patient prognosis. The influence of 1α,25(OH)2D3 on the proliferation of ovarian cancer cells was measured by BrdU proliferation assay in vitro. We could show that higher levels of H3K4me3 were correlated with improved overall survival (median overall survival (OS) not reached vs. 37.0 months, p = 0.047) and identified H3K4me3 as a potential prognostic factor for the present cohort. Ovarian cancer cell 1α,25(OH)2D3 treatment induced H3K4me3 protein expression and exhibited antiproliferative effects. By this, the study suggests a possible impact of H3K4me3 expression on EOC progression as well as its relation to calcitriol (1α,25(OH)2D3) treatment. These results may serve as an explanation on how 1α,25(OH)2D3 mediates its known antiproliferative effects. In addition, they further underline the potential benefit of 1α,25(OH)2D3 supplementation in context of ovarian cancer care.
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22
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Abstract
Recent advances in immunotherapy have revolutionized the treatment of certain cancers. Some patients show a durable response to these immunotherapies, while others show little benefit or develop resistance. Identification of biomarkers to predict responsiveness will be helpful for informing treatment strategies; and would furthermore lead to the identification of molecular pathways dysregulated in nonresponding patients that could be targeted for therapeutic development. Pathways of epigenetic modification, such as histone posttranslational modifications (PTMs), have been shown to be dysregulated in certain cancer and immune cells. Histones are abundant cellular proteins readily assayed with high-throughput technologies, making them attractive targets as biomarkers. We explore promising advancements for using histone PTMs as immunotherapy responsiveness biomarkers in both cancer and immune cells, and provide a methodological workflow for assaying histone PTMs in relevant samples.
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Affiliation(s)
- Erin M Taylor
- Department of Biochemistry and Molecular Biology, University of Arkansas for Medical Sciences, Little Rock, AR, USA
| | - Brian Koss
- Department of Biochemistry and Molecular Biology, University of Arkansas for Medical Sciences, Little Rock, AR, USA
| | - Lauren E Davis
- Department of Biochemistry and Molecular Biology, University of Arkansas for Medical Sciences, Little Rock, AR, USA
| | - Alan J Tackett
- Department of Biochemistry and Molecular Biology, University of Arkansas for Medical Sciences, Little Rock, AR, USA.
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23
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Okuno K, Akiyama Y, Shimada S, Nakagawa M, Tanioka T, Inokuchi M, Yamaoka S, Kojima K, Tanaka S. Asymmetric dimethylation at histone H3 arginine 2 by PRMT6 in gastric cancer progression. Carcinogenesis 2019; 40:15-26. [PMID: 30508037 DOI: 10.1093/carcin/bgy147] [Citation(s) in RCA: 25] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2018] [Revised: 09/21/2018] [Accepted: 10/19/2018] [Indexed: 12/13/2022] Open
Abstract
Histone modification plays important molecular roles in development and progression of cancers. Dysregulation of histone H3 arginine (R) methylation is still unknown in primary cancer, including gastric cancer (GC). Although PRMT6 contributes to asymmetric dimethylation at H3R2 (H3R2me2as) in cancer cells, its molecular functions are poorly understood in GC. In this study, we assessed H3R2me2as and PRMT6 expression levels in 133 primary GC tissues by immunohistochemistry. Increased H3R2me2as was found in 68 GC (51.1%) cases and independently related to poor prognosis. PRMT6 was overexpressed in 70 GC (52.6%) and strongly correlated with the global H3R2me2as levels (P < 0.001). By analyzing biological functions of PRMT6 in GC cell lines by lentivirus-based systems, PRMT6 overexpression enhanced global H3R2me2as and invasiveness in vitro, while PRMT6 knockout (PRMT6-KO) suppressed these effects and tumorigenicity in vivo. ChIP and microarray assays demonstrated that PRMT6-KO GC cells decreased the enrichments of H3R2me2as at the promoter regions of PCDH7, SCD and IGFBP5, resulting in upregulation of their gene expression. PRMT6 was recruited to the promoter regions of PCDH7 and SCD in the PRMT6-overexpressed cells. Knockdown of tumor suppressor PCDH7 in the PRMT6-KO GC cells elevated cell migration and invasion. PRMT6 expression inversely correlated with PCDH7 expression in primary GC (P = 0.021). Collectively, our findings strongly indicate that H3R2me2as is a strong prognostic indicator of GC patients, and PRMT6-overexpressing GC cells may acquire invasiveness through direct transcriptional inhibition of PCDH7 by increasing H3R2me2as level. Thus, inhibition of the PRMT6-H3R2me2as pathway could be a promising new therapeutic strategy in GC.
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Affiliation(s)
- Keisuke Okuno
- Department of Molecular Oncology, Graduate School of Medicine, Tokyo Medical and Dental University, Tokyo, Japan.,Department of Gastric Surgery, Tokyo Medical and Dental University, Tokyo, Japan.,Department of Minimally Invasive Surgery, Graduate School of Medicine, Tokyo Medical and Dental University, Tokyo, Japan
| | - Yoshimitsu Akiyama
- Department of Molecular Oncology, Graduate School of Medicine, Tokyo Medical and Dental University, Tokyo, Japan
| | - Shu Shimada
- Department of Molecular Oncology, Graduate School of Medicine, Tokyo Medical and Dental University, Tokyo, Japan
| | - Masatoshi Nakagawa
- Department of Gastric Surgery, Tokyo Medical and Dental University, Tokyo, Japan
| | - Toshiro Tanioka
- Department of Gastric Surgery, Tokyo Medical and Dental University, Tokyo, Japan
| | - Mikito Inokuchi
- Department of Gastric Surgery, Tokyo Medical and Dental University, Tokyo, Japan
| | - Shoji Yamaoka
- Department of Molecular Virology, Graduate School of Medicine, Tokyo Medical and Dental University, Tokyo, Japan
| | - Kazuyuki Kojima
- Department of Gastric Surgery, Tokyo Medical and Dental University, Tokyo, Japan.,Department of Minimally Invasive Surgery, Graduate School of Medicine, Tokyo Medical and Dental University, Tokyo, Japan
| | - Shinji Tanaka
- Department of Molecular Oncology, Graduate School of Medicine, Tokyo Medical and Dental University, Tokyo, Japan
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H3K18Ac as a Marker of Cancer Progression and Potential Target of Anti-Cancer Therapy. Cells 2019; 8:cells8050485. [PMID: 31121824 PMCID: PMC6562857 DOI: 10.3390/cells8050485] [Citation(s) in RCA: 38] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2019] [Revised: 05/13/2019] [Accepted: 05/16/2019] [Indexed: 02/07/2023] Open
Abstract
Acetylation and deacetylation are posttranslational modifications (PTMs) which affect the regulation of chromatin structure and its remodeling. Acetylation of histone 3 at lysine placed on position 18 (H3K18Ac) plays an important role in driving progression of many types of cancer, including breast, colon, lung, hepatocellular, pancreatic, prostate, and thyroid cancer. The aim of this review is to analyze and discuss the newest findings regarding the role of H3K18Ac and acetylation of other histones in carcinogenesis. We summarize the level of H3K18Ac in different cancer cell lines and analyze its association with patients’ outcomes, including overall survival (OS), progression-free survival (PFS), and disease-free survival (DFS). Finally, we describe future perspectives of cancer therapeutic strategies based on H3K18 modifications.
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25
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Li Y, Guo D, Sun R, Chen P, Qian Q, Fan H. Methylation Patterns of Lys9 and Lys27 on Histone H3 Correlate with Patient Outcome in Gastric Cancer. Dig Dis Sci 2019; 64:439-446. [PMID: 30350241 DOI: 10.1007/s10620-018-5341-8] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/13/2018] [Accepted: 10/16/2018] [Indexed: 02/06/2023]
Abstract
BACKGROUND Histone methylation has been considered as one of the epigenetic mechanisms of carcinogenesis and progression. Researches on the correlation between histone lysine methylation and gastric cancer (GC) will help in finding novel epigenetic biomarkers for monitoring cancers. AIMS The study detected the expression patterns of histone 3 lysine 9 dimethylation (H3K9me2), histone 3 lysine 9 trimethylation (H3K9me3), and histone 3 lysine 27 trimethylation (H3K27me3) in GC tissues and evaluated their clinical merit for GC patients. METHODS One hundred thirty-three paraffin-embedded GC samples were examined by immunohistochemistry for the histone markers: H3K9me2, H3K9me3, and H3K27me3. The relationship and clinicopathological significance of the three lysine methylations on histone H3 with GC were assessed by Paired t test, Chi-square test, Kaplan-Meier analysis with log-rank test, and Cox proportional hazard analyses. RESULTS Strong positive immunostaining of H3K9me2, H3K9me3, and H3K27me3 was observed in cancerous tissues than in their counterpart non-cancer tissues. Higher expression patterns of H3K9me2, H3K9me3, and H3K27me3 significantly related to differentiation degree, lymph nodes metastases, and pathological TNM staging in GC. The GC patients with low scoring of the three markers implied long survival period and best prognosis. In contrast, the patients' survival time was significantly shorter if their cancerous tissues presented high expression of the three markers. CONCLUSIONS H3K9me2, H3K9me3, and H3K27me3 expression patterns closely relate to clinicopathological features and may be the independent risk factors for the survival of GC patients. The combined pattern of the three markers rather than an individual marker is considered to more accurately evaluate the outcome of GC patients.
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Affiliation(s)
- Yiping Li
- Department of Medical Genetics and Developmental Biology, Medical School, The Key Laboratory of Developmental Genes and Human Diseases, Ministry of Education, Southeast University, Nanjing, 210009, China.,Department of Pathology, Medical School, Southeast University, Nanjing, 210009, China
| | - Didi Guo
- Institute of Life Science, The Key Laboratory of Developmental Genes and Human Diseases, Southeast University, Nanjing, 210018, China
| | - Rui Sun
- Department of Medical Genetics and Developmental Biology, Medical School, The Key Laboratory of Developmental Genes and Human Diseases, Ministry of Education, Southeast University, Nanjing, 210009, China
| | - Ping Chen
- Department of Oncology, Yancheng First People's Hospital, Yancheng, 224005, China
| | - Qi Qian
- Department of Oncology, Yancheng First People's Hospital, Yancheng, 224005, China
| | - Hong Fan
- Department of Medical Genetics and Developmental Biology, Medical School, The Key Laboratory of Developmental Genes and Human Diseases, Ministry of Education, Southeast University, Nanjing, 210009, China.
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26
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Fluctuations of epigenetic regulations in human gastric Adenocarcinoma: How does it affect? Biomed Pharmacother 2019; 109:144-156. [DOI: 10.1016/j.biopha.2018.10.094] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2018] [Revised: 10/15/2018] [Accepted: 10/15/2018] [Indexed: 12/12/2022] Open
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27
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Zhang Y, Huang J, Li Q, Chen K, Liang Y, Zhan Z, Ye F, Ni W, Chen L, Ding Y. Histone methyltransferase SETDB1 promotes cells proliferation and migration by interacting withTiam1 in hepatocellular carcinoma. BMC Cancer 2018; 18:539. [PMID: 29739365 PMCID: PMC5941371 DOI: 10.1186/s12885-018-4464-9] [Citation(s) in RCA: 30] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2017] [Accepted: 04/30/2018] [Indexed: 11/24/2022] Open
Abstract
Background SETDB1 is a histone H3K9 methyltransferase, which plays a significant role in the occurrence and progression of tumors. Previous studies have confirmed that T-lymphom invasion and metastasis gene (Tiam1) is a protein associated with the metastasis of hepatocellular carcinoma (HCC); however, we have not yet been successful in elucidating the specific mechanism of HCC. Methods Yeast two-hybrid test was conducted to screen proteins that interacted with Tiam1 gene. Glutathione-S-transferase (GST) pull-down and crosslinking-immunoprecipitation (CLIP) assays were performed to determine whether SETDB1 can interact with Tiam1 gene. A series of related experiments were performed to explore role of SETDB1 on cell proliferation, migration, and invasion in HCC. Recovery experiment was performed to investigate the effect of Tiam1 knockdown on cell proliferation and migration, which was caused by SETDB1 overexpression in HCC cells. The expression of SETDB1 was frequently upregulated in HCC tissues and positively correlated with Tiam1. Results GST pull-down and CLIP assays were performed to elucidate the interaction between SETDB1 and Tiam1. Cell proliferation, migration, and epithelial mesenchymal transformation (EMT) in HCC cells was promoted with the overexpression of SETDB1. Following the knockdown of Tiam1 gene, the effect of SETDB1 on cell proliferation and migration was reversed in HCC cells. The expression of SETDB1 was frequently up-regulated in HCC tissues, and it was positively correlated with Tiam1 gene. Conclusions Ours is the first study to prove that SETDB1 promotes the proliferation and migration of cells by forming SETDB1-Tiam1 compounds. We found that SETDB1-Tiam1 compounds were involved in a novel pathway, which regulated epigenetic modification of gene expression in HCC samples. Electronic supplementary material The online version of this article (10.1186/s12885-018-4464-9) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Yuqin Zhang
- Department of Radiation Oncology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong Province, China
| | - Jing Huang
- Department of Radiation Oncology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong Province, China
| | - Qisheng Li
- Department of Radiation Oncology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong Province, China
| | - Keli Chen
- Department of Radiation Oncology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong Province, China
| | - Yonghao Liang
- Department of Radiation Oncology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong Province, China
| | - Zetao Zhan
- Department of Radiation Oncology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong Province, China
| | - Feng Ye
- Department of Radiation Oncology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong Province, China
| | - Wen Ni
- Department of Radiation Oncology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong Province, China
| | - Longhua Chen
- Department of Radiation Oncology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong Province, China.
| | - Yi Ding
- Department of Radiation Oncology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong Province, China.
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Maia LDL, Peterle GT, dos Santos M, Trivilin LO, Mendes SO, de Oliveira MM, dos Santos JG, Stur E, Agostini LP, Couto CVMDS, Dalbó J, de Assis ALEM, Archanjo AB, Mercante AMDC, Lopez RVM, Nunes FD, de Carvalho MB, Tajara EH, Louro ID, Álvares-da-Silva AM. JMJD1A, H3K9me1, H3K9me2 and ADM expression as prognostic markers in oral and oropharyngeal squamous cell carcinoma. PLoS One 2018; 13:e0194884. [PMID: 29590186 PMCID: PMC5874045 DOI: 10.1371/journal.pone.0194884] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2017] [Accepted: 03/12/2018] [Indexed: 02/06/2023] Open
Abstract
Aims Jumonji Domain-Containing 1A (JMJD1A) protein promotes demethylation of histones, especially at lysin-9 of di-methylated histone H3 (H3K9me2) or mono-methylated (H3K9me1). Increased levels of H3 histone methylation at lysin-9 (H3K9) is related to tumor suppressor gene silencing. JMJD1A gene target Adrenomeduline (ADM) has shown to promote cell growth and tumorigenesis. JMJD1A and ADM expression, as well as H3K9 methylation level have been related with development risk and prognosis of several tumor types. Methods and results We aimed to evaluate JMJD1A, ADM, H3K9me1 and H3K9me2expression in paraffin-embedded tissue microarrays from 84 oral and oropharyngeal squamous cell carcinoma samples through immunohistochemistry analysis. Our results showed that nuclear JMJD1A expression was related to lymph node metastasis risk. In addition, JMJD1A cytoplasmic expression was an independent risk marker for advanced tumor stages. H3K9me1 cytoplasmic expression was associated with reduced disease-specific death risk. Furthermore, high H3K9me2 nuclear expression was associated with worse specific-disease and disease-free survival. Finally, high ADM cytoplasmic expression was an independent marker of lymph node metastasis risk. Conclusion JMJD1A, H3K9me1/2 and ADM expression may be predictor markers of progression and prognosis in oral and oropharynx cancer patients, as well as putative therapeutic targets.
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Affiliation(s)
- Lucas de Lima Maia
- Programa de Pós-Graduação em Biotecnologia, Universidade Federal do Espírito Santo, Vitória, Espírito Santo, Brazil
- * E-mail:
| | - Gabriela Tonini Peterle
- Programa de Pós-Graduação em Biotecnologia, Universidade Federal do Espírito Santo, Vitória, Espírito Santo, Brazil
| | - Marcelo dos Santos
- Escola Multicampi de Ciências Médicas do Rio Grande do Norte, Universidade Federal do Rio Grande do Norte, Caicó, Rio Grande do Norte, Brazil
| | - Leonardo Oliveira Trivilin
- Programa de Pós-Graduação em Biotecnologia, Universidade Federal do Espírito Santo, Vitória, Espírito Santo, Brazil
| | - Suzanny Oliveira Mendes
- Programa de Pós-Graduação em Biotecnologia, Universidade Federal do Espírito Santo, Vitória, Espírito Santo, Brazil
| | - Mayara Mota de Oliveira
- Programa de Pós-Graduação em Biotecnologia, Universidade Federal do Espírito Santo, Vitória, Espírito Santo, Brazil
| | - Joaquim Gasparini dos Santos
- Programa de Pós-Graduação em Biotecnologia, Universidade Federal do Espírito Santo, Vitória, Espírito Santo, Brazil
| | - Elaine Stur
- Programa de Pós-Graduação em Biotecnologia, Universidade Federal do Espírito Santo, Vitória, Espírito Santo, Brazil
| | - Lidiane Pignaton Agostini
- Programa de Pós-Graduação em Biotecnologia, Universidade Federal do Espírito Santo, Vitória, Espírito Santo, Brazil
| | | | - Juliana Dalbó
- Programa de Pós-Graduação em Biotecnologia, Universidade Federal do Espírito Santo, Vitória, Espírito Santo, Brazil
| | | | - Anderson Barros Archanjo
- Programa de Pós-Graduação em Biotecnologia, Universidade Federal do Espírito Santo, Vitória, Espírito Santo, Brazil
| | | | | | - Fábio Daumas Nunes
- Departamento de Patologia Bucal, Faculdade de Odontologia, Universidade de São Paulo, São Paulo, São Paulo, Brazil
| | | | - Eloiza Helena Tajara
- Departamento de Biologia Molecular, Faculdade de Medicina, São José do Rio Preto, São Paulo, Brazil
| | - Iúri Drumond Louro
- Programa de Pós-Graduação em Biotecnologia, Universidade Federal do Espírito Santo, Vitória, Espírito Santo, Brazil
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29
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Puneet, Kazmi HR, Kumari S, Tiwari S, Khanna A, Narayan G. Epigenetic Mechanisms and Events in Gastric Cancer-Emerging Novel Biomarkers. Pathol Oncol Res 2018; 24:757-770. [PMID: 29552712 DOI: 10.1007/s12253-018-0410-z] [Citation(s) in RCA: 38] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/19/2017] [Accepted: 03/07/2018] [Indexed: 12/12/2022]
Abstract
Gastric cancer is one of the most common malignancy worldwide. The various genetic and epigenetic events have been found to be associated with its carcinogenesis. The epigenetic is a heritable and transient/reversible change in the gene expression that is not accompanied by modification in the DNA sequence. This event is characterized by the alteration in the promoter CpG island of the gene or histone modification. These events are associated with silencing of critical tumor suppressor gene and activation of oncogenes leading to carcinogenesis. The DNA methylation is a chemical change in the DNA sequence that most commonly occurs at cytosine moiety of CpG dinucleotide and histone, primarily on N- terminal tail that ultimately effect the interaction of DNA with chromatin modifying protein.Hypermethylation of tumor suppressor genes and global hypomethylation of oncogenes are widely studied epigenetic modifications. There are large number of publish reports regarding epigenetic events involving gastric cancer. These changes are potentially useful in identifying markers for early diagnosis and management of this lethal malignancy. Also, role of specific miRNAs and long non coding RNAs in regulation of gene expression is gaining interest and is a matter of further investigation. In this review, we aimed to summarize major epigenetic events (DNA methylation) in gastric cancer along with alteration in miRNAs and long non coding RNAs which plays an important role in pathology of this poorly understood malignancy.
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Affiliation(s)
- Puneet
- Department of Surgery, Institute of Medical Science, Banaras Hindu University, Varanasi, 221005, India.
| | - Hasan Raza Kazmi
- Cancer Genetics Laboratory, Department of Molecular and Human Genetics, Institute of Science, Banaras Hindu University, Varanasi, 221005, India
| | - Soni Kumari
- Cancer Genetics Laboratory, Department of Molecular and Human Genetics, Institute of Science, Banaras Hindu University, Varanasi, 221005, India
| | - Satendra Tiwari
- Department of Surgery, Institute of Medical Science, Banaras Hindu University, Varanasi, 221005, India
| | - A Khanna
- Department of Surgery, Institute of Medical Science, Banaras Hindu University, Varanasi, 221005, India
| | - Gopeshwar Narayan
- Cancer Genetics Laboratory, Department of Molecular and Human Genetics, Institute of Science, Banaras Hindu University, Varanasi, 221005, India
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Nishikawaji T, Akiyama Y, Shimada S, Kojima K, Kawano T, Eishi Y, Yuasa Y, Tanaka S. Oncogenic roles of the SETDB2 histone methyltransferase in gastric cancer. Oncotarget 2018; 7:67251-67265. [PMID: 27572307 PMCID: PMC5341872 DOI: 10.18632/oncotarget.11625] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2016] [Accepted: 08/11/2016] [Indexed: 12/13/2022] Open
Abstract
SETDB2 is a histone H3 lysine 9 (H3K9) tri-methyltransferase that is involved in transcriptional gene silencing. Since it is still unknown whether SETDB2 is linked to carcinogenesis, we studied alterations and functions of SETDB2 in human gastric cancers (GCs). SETDB2 protein was highly expressed in 30 of 72 (41.7%) primary GC tissues compared with their normal counterparts by immunohistochemistry. SETDB2 overexpression was significantly associated with the late stage of GCs (P<0.05) and poor prognosis of GC patients (P<0.05). The GC cell lines with SETDB2 knockdown and overexpression significantly decreased and increased cell proliferation, migration and invasion, respectively (P<0.05). Knockdown of SETDB2 in MKN74 and MKN45 cells reduced global H3K9 tri-methylation (me3) levels. Microarray analysis indicated that expression of WWOX and CADM1, tumor suppressor genes, was significantly enhanced in MKN74 cells after SETDB2 knockdown. Chromatin immunoprecipitation assays showed that the H3K9me3 levels at the promoter regions of these two genes corresponded to the SETDB2 expression levels in GC cells. Moreover, ectopic SETDB2 protein was recruited to their promoter regions. Our data suggest that SETDB2 is associated with transcriptional repression of WWOX and CADM1, and hence overexpression of SETDB2 may contribute to GC progression.
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Affiliation(s)
- Taketo Nishikawaji
- Department of Molecular Oncology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan
| | - Yoshimitsu Akiyama
- Department of Molecular Oncology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan
| | - Shu Shimada
- Department of Molecular Oncology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan
| | - Kazuyuki Kojima
- Department of Surgical Oncology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan
| | - Tatsuyuki Kawano
- Department of Surgery, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan
| | - Yoshinobu Eishi
- Department of Human Pathology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan
| | - Yasuhito Yuasa
- Department of Molecular Oncology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan
| | - Shinji Tanaka
- Department of Molecular Oncology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan
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Fu LN, Tan J, Chen YX, Fang JY. Genetic variants in the histone methylation and acetylation pathway and their risks in eight types of cancers. J Dig Dis 2018; 19:102-111. [PMID: 29292860 DOI: 10.1111/1751-2980.12574] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/27/2017] [Revised: 05/16/2017] [Accepted: 12/29/2017] [Indexed: 12/11/2022]
Abstract
OBJECTIVES The histone methylation and acetylation pathway genes regulate cell growth and survival. Aberrations in this pathway are implicated in a variety of cancers. This study aimed to identify germline genetic variants in histone methylation and acetylation pathway genes that may contribute to risk in eight types of cancers and to explore the relation between the whole pathway and their risks in these types of cancers. METHODS Germline genetic variants in 89 genes in the histone methylation and acetylation pathway were explored. Gene-based and pathway-based associations with eight types of cancers were analyzed using logistic regression models and the permutation-based adaptive rank-truncated product method, respectively. RESULTS Gene-level associations revealed that genetic variants in 45 genes were significantly associated with the risk of cancer. The total histone methylation and acetylation pathway was significantly associated with the risk of esophageal squamous cell carcinoma (P = 0.0492) and prostate (P = 0.0038), lung (P = 0.00015), and bladder cancer (P = 0.00135), but not with breast (P = 0.182), pancreatic (P = 0.336) and gastric cancer (P = 0.347) and renal cell carcinoma (P =0.828). CONCLUSIONS Our study suggested there is an association between germline genetic variation at the overall histone methylation and acetylation pathway level and some individual genes with cancer risk. Further studies are needed to validate these relations and to explore relative mechanisms.
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Affiliation(s)
- Lin Na Fu
- Division of Gastroenterology and Hepatology, Key Laboratory of Gastroenterology and Hepatology, Ministry of Health, State Key Laboratory for Oncogenes and Related Genes, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai Institute of Digestive Disease, Shanghai, China
| | - Juan Tan
- Division of Gastroenterology and Hepatology, Key Laboratory of Gastroenterology and Hepatology, Ministry of Health, State Key Laboratory for Oncogenes and Related Genes, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai Institute of Digestive Disease, Shanghai, China
| | - Ying Xuan Chen
- Division of Gastroenterology and Hepatology, Key Laboratory of Gastroenterology and Hepatology, Ministry of Health, State Key Laboratory for Oncogenes and Related Genes, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai Institute of Digestive Disease, Shanghai, China
| | - Jing-Yuan Fang
- Division of Gastroenterology and Hepatology, Key Laboratory of Gastroenterology and Hepatology, Ministry of Health, State Key Laboratory for Oncogenes and Related Genes, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai Institute of Digestive Disease, Shanghai, China
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Assenov Y, Brocks D, Gerhäuser C. Intratumor heterogeneity in epigenetic patterns. Semin Cancer Biol 2018; 51:12-21. [PMID: 29366906 DOI: 10.1016/j.semcancer.2018.01.010] [Citation(s) in RCA: 42] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2017] [Revised: 11/24/2017] [Accepted: 01/17/2018] [Indexed: 02/08/2023]
Abstract
Analogous to life on earth, tumor cells evolve through space and time and adapt to different micro-environmental conditions. As a result, tumors are composed of millions of genetically diversified cells at the time of diagnosis. Profiling these variants contributes to understanding tumors' clonal origins and might help to better understand response to therapy. However, even genetically homogenous cell populations show remarkable diversity in their response to different environmental stimuli, suggesting that genetic heterogeneity does not explain the full spectrum of tumor plasticity. Understanding epigenetic diversity across cancer cells provides important additional information about the functional state of subclones and therefore allows better understanding of tumor evolution and resistance to current therapies.
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Affiliation(s)
- Yassen Assenov
- Epigenomics and Cancer Risk Factors, German Cancer Research Center, Im Neuenheimer Feld 280, 69120 Heidelberg, Germany
| | - David Brocks
- Epigenomics and Cancer Risk Factors, German Cancer Research Center, Im Neuenheimer Feld 280, 69120 Heidelberg, Germany
| | - Clarissa Gerhäuser
- Epigenomics and Cancer Risk Factors, German Cancer Research Center, Im Neuenheimer Feld 280, 69120 Heidelberg, Germany.
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Hosseini A, Minucci S. Alterations of Histone Modifications in Cancer. EPIGENETICS IN HUMAN DISEASE 2018:141-217. [DOI: 10.1016/b978-0-12-812215-0.00006-6] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/04/2025]
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Park T, Lee YJ, Jeong SH, Choi SK, Jung EJ, Ju YT, Jeong CY, Park M, Hah YS, Yoo J, Ha WS, Hong SC, Ko GH. Overexpression of Neuron-Specific Enolase as a Prognostic Factor in Patients with Gastric Cancer. J Gastric Cancer 2017; 17:228-236. [PMID: 28970953 PMCID: PMC5620092 DOI: 10.5230/jgc.2017.17.e28] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/08/2017] [Revised: 07/02/2017] [Accepted: 07/27/2017] [Indexed: 11/20/2022] Open
Abstract
PURPOSE Enolase is a cytoplasmic enzyme that catalyzes the conversion of 2-phosphoglycerate to phosphoenolpyruvate in the glycolytic pathway. The aim of this study was to investigate whether the overexpression of neuron-specific enolase (NSE) can serve as a prognostic factor in patients with gastric cancer (GC). MATERIALS AND METHODS To assess its prognostic value in GC, NSE expression was measured by immunohistochemistry in a clinically annotated tissue microarray comprising of 327 human GC specimens. Cytoplasmic NSE expression was scored from 0 to 4, reflecting the percentage of NSE-positive cells. RESULTS In terms of histology as per the World Health Organization criteria (P=0.340), there were no differences between the NSE overexpression (NSE-OE) and NSE underexpression (NSE-UE) groups. The NSE-OE group showed a significantly lower rate of advanced GC (P<0.010), lymph node metastasis (P=0.010), advanced stage group (P<0.010), cancer-related death (P<0.010), and cancer recurrence (P<0.010). Additionally, a Kaplan-Meier survival analysis revealed that the NSE-OE group had longer cumulative survival times than the NSE-UE group (log-rank test, P<0.010). However, there were no significant differences in the serum levels of NSE expression in patients with GC and healthy volunteers (P=0.280). CONCLUSIONS Patients with NSE overexpressing GC tissues showed better prognostic results, implying that NSE could be a candidate biomarker of GC.
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Affiliation(s)
- Taejin Park
- Department of Surgery, Gyeongsang National University School of Medicine, Jinju, Korea.,Gyeongnam Regional Cancer Center, Gyeongsang National University School of Medicine, Jinju, Korea.,Institue of Health Sciences, Gyeongsang National University School of Medicine, Jinju, Korea
| | - Young-Joon Lee
- Department of Surgery, Gyeongsang National University School of Medicine, Jinju, Korea.,Gyeongnam Regional Cancer Center, Gyeongsang National University School of Medicine, Jinju, Korea.,Institue of Health Sciences, Gyeongsang National University School of Medicine, Jinju, Korea
| | - Sang-Ho Jeong
- Department of Surgery, Gyeongsang National University School of Medicine, Jinju, Korea.,Gyeongnam Regional Cancer Center, Gyeongsang National University School of Medicine, Jinju, Korea.,Institue of Health Sciences, Gyeongsang National University School of Medicine, Jinju, Korea
| | - Sang-Kyung Choi
- Department of Surgery, Gyeongsang National University School of Medicine, Jinju, Korea.,Gyeongnam Regional Cancer Center, Gyeongsang National University School of Medicine, Jinju, Korea.,Institue of Health Sciences, Gyeongsang National University School of Medicine, Jinju, Korea
| | - Eun-Jung Jung
- Department of Surgery, Gyeongsang National University School of Medicine, Jinju, Korea.,Gyeongnam Regional Cancer Center, Gyeongsang National University School of Medicine, Jinju, Korea.,Institue of Health Sciences, Gyeongsang National University School of Medicine, Jinju, Korea
| | - Young-Tae Ju
- Department of Surgery, Gyeongsang National University School of Medicine, Jinju, Korea.,Gyeongnam Regional Cancer Center, Gyeongsang National University School of Medicine, Jinju, Korea.,Institue of Health Sciences, Gyeongsang National University School of Medicine, Jinju, Korea
| | - Chi-Young Jeong
- Department of Surgery, Gyeongsang National University School of Medicine, Jinju, Korea.,Gyeongnam Regional Cancer Center, Gyeongsang National University School of Medicine, Jinju, Korea.,Institue of Health Sciences, Gyeongsang National University School of Medicine, Jinju, Korea
| | - Miyeong Park
- Department of Anesthesiology, Gyeongsang National University School of Medicine, Jinju, Korea
| | - Young-Sool Hah
- Gyeongnam Regional Cancer Center, Gyeongsang National University School of Medicine, Jinju, Korea.,Institue of Health Sciences, Gyeongsang National University School of Medicine, Jinju, Korea.,Biomedical Research Institute, Gyeongsang National University Hospital, Jinju, Korea
| | - Jiyun Yoo
- Department of Microbiology/Research Institute of Life Science, Gyeongsang National University College of Natural Sciences, Jinju, Korea
| | - Woo-Song Ha
- Department of Surgery, Gyeongsang National University School of Medicine, Jinju, Korea.,Gyeongnam Regional Cancer Center, Gyeongsang National University School of Medicine, Jinju, Korea.,Institue of Health Sciences, Gyeongsang National University School of Medicine, Jinju, Korea
| | - Soon-Chan Hong
- Department of Surgery, Gyeongsang National University School of Medicine, Jinju, Korea.,Gyeongnam Regional Cancer Center, Gyeongsang National University School of Medicine, Jinju, Korea.,Institue of Health Sciences, Gyeongsang National University School of Medicine, Jinju, Korea
| | - Gyung Hyuck Ko
- Gyeongnam Regional Cancer Center, Gyeongsang National University School of Medicine, Jinju, Korea.,Institue of Health Sciences, Gyeongsang National University School of Medicine, Jinju, Korea.,Department of Pathology, Gyeongsang National University School of Medicine, Jinju, Korea
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Abstract
Gastric cancer is a deadly malignancy afflicting close to a million people worldwide. Patient survival is poor and largely due to late diagnosis and suboptimal therapies. Disease heterogeneity is a substantial obstacle, underscoring the need for precision treatment strategies. Studies have identified different subgroups of gastric cancer displaying not just genetic, but also distinct epigenetic hallmarks. Accumulating evidence suggests that epigenetic abnormalities in gastric cancer are not mere bystander events, but rather promote carcinogenesis through active mechanisms. Epigenetic aberrations, induced by pathogens such as Helicobacter pylori, are an early component of gastric carcinogenesis, probably preceding genetic abnormalities. This Review summarizes our current understanding of the gastric cancer epigenome, highlighting key advances in recent years in both tumours and pre-malignant lesions, made possible through targeted and genome-wide technologies. We focus on studies related to DNA methylation and histone modifications, linking these findings to potential therapeutic opportunities. Lessons learned from the gastric cancer epigenome might also prove relevant for other gastrointestinal cancers.
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Yu C, Yao X, Zhao L, Wang P, Zhang Q, Zhao C, Yao S, Wei Y. Wolf-Hirschhorn Syndrome Candidate 1 (whsc1) Functions as a Tumor Suppressor by Governing Cell Differentiation. Neoplasia 2017; 19:606-616. [PMID: 28654864 PMCID: PMC5487304 DOI: 10.1016/j.neo.2017.05.001] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2017] [Revised: 03/25/2017] [Accepted: 05/02/2017] [Indexed: 02/07/2023]
Abstract
Wolf–Hirschhorn syndrome candidate 1 (WHSC1) is a histone 3 lysine 36 (H3K36) specific methyltransferase that is frequently deleted in Wolf–Hirschhorn syndrome (WHS). Whsc1 is also found mutated in a subgroup of B-cell derived malignant diseases by genomic translocation or point mutation, both of which resulted in hyperactivity of WHSC1 mediated H3K36 methylation and uncontrolled cell proliferation, suggesting that whsc1 functions as an oncogene. However, here we provided evidences to show that whsc1 also has tumor suppressor functions. We used zebrafish as an in vivo model and generated homozygous whsc1 mutant lines via clustered regularly interspaced short palindromic repeats-associated protein Cas9 (CRISPR/Cas9) technology. Then western-blot (WB) and immunofluorescence (IF) were performed to analysis the expression level of H3K36Me2 and H3K36Me3, and we identified the diseased tissue via hematoxylin–eosin (HE) staining, IF staining or immunohistochemistry (IHC). Whsc1 lose-of-function led to significant decrease in di- and tri-methylation of H3K36. A series of WHS related phenotypes were found in whsc1−/− zebrafish, including growth retardation, neural development defects and heart failure. In addition, loss of function of whsc1 led to defects in the development of swim bladder, possibly through the dis-regulation of key genes in swim bladder organogenesis and inhibition of progenitor cell differentiation, which was correlated with its expression in this organ during embryonic development. At later stage, these whsc1−/− zebrafishes are inclined to grow tumors in the swim bladder. Our work suggested that whsc1 may function as a tumor suppressor by governing progenitor cell differentiation.
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Affiliation(s)
- Chuan Yu
- State Key Laboratory of Biotherapy/Collaborative Innovation Center of Biotherapy, West China Hospital, College of Life Science, Sichuan University, Chengdu, 610041, People's Republic of China
| | - Xiaomin Yao
- State Key Laboratory of Biotherapy/Collaborative Innovation Center of Biotherapy, West China Hospital, College of Life Science, Sichuan University, Chengdu, 610041, People's Republic of China
| | - Linjie Zhao
- State Key Laboratory of Biotherapy/Collaborative Innovation Center of Biotherapy, West China Hospital, College of Life Science, Sichuan University, Chengdu, 610041, People's Republic of China
| | - Ping Wang
- State Key Laboratory of Biotherapy/Collaborative Innovation Center of Biotherapy, West China Hospital, College of Life Science, Sichuan University, Chengdu, 610041, People's Republic of China
| | - Qian Zhang
- State Key Laboratory of Biotherapy/Collaborative Innovation Center of Biotherapy, West China Hospital, College of Life Science, Sichuan University, Chengdu, 610041, People's Republic of China
| | - Chengjian Zhao
- State Key Laboratory of Biotherapy/Collaborative Innovation Center of Biotherapy, West China Hospital, College of Life Science, Sichuan University, Chengdu, 610041, People's Republic of China
| | - Shaohua Yao
- State Key Laboratory of Biotherapy/Collaborative Innovation Center of Biotherapy, West China Hospital, College of Life Science, Sichuan University, Chengdu, 610041, People's Republic of China.
| | - Yuquan Wei
- State Key Laboratory of Biotherapy/Collaborative Innovation Center of Biotherapy, West China Hospital, College of Life Science, Sichuan University, Chengdu, 610041, People's Republic of China.
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Maizels Y, Elbaz A, Hernandez-Vicens R, Sandrusy O, Rosenberg A, Gerlitz G. Increased chromatin plasticity supports enhanced metastatic potential of mouse melanoma cells. Exp Cell Res 2017; 357:282-290. [PMID: 28551377 DOI: 10.1016/j.yexcr.2017.05.025] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2017] [Revised: 05/23/2017] [Accepted: 05/24/2017] [Indexed: 12/17/2022]
Abstract
Metastasis formation is strongly dependent on the migration capabilities of tumor cells. Recently it has become apparent that nuclear structure and morphology affect the cellular ability to migrate. Previously we found that migration of melanoma cells is both associated with and dependent on global chromatin condensation. Therefore, we anticipated that tumor progression would be associated with increased chromatin condensation. Interestingly, the opposite has been reported for melanoma. In trying to resolve this contradiction, we show that during growth conditions, tumor progression is associated with global chromatin de-condensation that is beneficial for faster proliferation. However, upon induction of migration, in both low- and high-metastatic mouse melanoma cells chromatin undergoes condensation to support cell migration. Our results reveal that throughout tumor progression induction of chromatin condensation by migration signals is maintained, whereas the organization of chromatin during growth conditions is altered. Thus, tumor progression is associated with an increase in chromatin dynamics.
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Affiliation(s)
- Yael Maizels
- Department of Molecular Biology, Faculty of Life Sciences, Ariel University, Israel
| | - Adi Elbaz
- Department of Molecular Biology, Faculty of Life Sciences, Ariel University, Israel
| | | | - Oshrat Sandrusy
- Department of Molecular Biology, Faculty of Life Sciences, Ariel University, Israel
| | - Anna Rosenberg
- Department of Molecular Biology, Faculty of Life Sciences, Ariel University, Israel
| | - Gabi Gerlitz
- Department of Molecular Biology, Faculty of Life Sciences, Ariel University, Israel.
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Zeng XQ, Wang J, Chen SY. Methylation modification in gastric cancer and approaches to targeted epigenetic therapy (Review). Int J Oncol 2017; 50:1921-1933. [DOI: 10.3892/ijo.2017.3981] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2017] [Accepted: 03/22/2017] [Indexed: 11/06/2022] Open
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Altieri F, Di Stadio CS, Federico A, Miselli G, De Palma M, Rippa E, Arcari P. Epigenetic alterations of gastrokine 1 gene expression in gastric cancer. Oncotarget 2017; 8:16899-16911. [PMID: 28129645 PMCID: PMC5370009 DOI: 10.18632/oncotarget.14817] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2016] [Accepted: 11/05/2016] [Indexed: 12/12/2022] Open
Abstract
The gastrokine 1 (GKN1) protein is important for maintaining the physiological function of the gastric mucosa. GKN1 is down-regulated in gastric tumor tissues and derived cell lines and its over-expression in gastric cancer cells induces apoptosis, suggesting a possible role for the protein as a tumor suppressor. However, the mechanism by which GKN1 is inactivated in gastric cancer remains unknown. Here, we investigated the causes of GKN1 silencing to determine if epigenetic mechanisms such as histonic modification could contribute to its down-regulation. To this end, chromatin immunoprecipitation assays for the trimethylation of histone 3 at lysine 9 (H3K9triMe) and its specific histone-lysine N-methyltransferase (SUV39H1) were performed on biopsies of normal and cancerous human gastric tissues. GKN1 down-regulation in gastric cancer tissues was shown to be associated with high levels of H3K9triMe and with the recruitment of SUV39H1 to the GKN1 promoter, suggesting the presence of an epigenetic transcriptional complex that negatively regulates GKN1 expression in gastric tumors. The inhibition of histone deacetylases with trichostatin A was also shown to increase GKN1 mRNA levels. Collectively, our results indicate that complex epigenetic machinery regulates GKN1 expression at the transcriptional level, and likely at the translational level.
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Affiliation(s)
- Filomena Altieri
- Department of Molecular Medicine and Medical Biotechnology, University of Naples Federico II, Naples, Italy
| | - Chiara Stella Di Stadio
- Department of Molecular Medicine and Medical Biotechnology, University of Naples Federico II, Naples, Italy
| | - Antonella Federico
- Department of Molecular Medicine and Medical Biotechnology, University of Naples Federico II, Naples, Italy
| | - Giuseppina Miselli
- Department of Molecular Medicine and Medical Biotechnology, University of Naples Federico II, Naples, Italy
| | | | - Emilia Rippa
- Department of Molecular Medicine and Medical Biotechnology, University of Naples Federico II, Naples, Italy
| | - Paolo Arcari
- Department of Molecular Medicine and Medical Biotechnology, University of Naples Federico II, Naples, Italy
- CEINGE, Advanced Biotechnology Scarl, Naples, Italy
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40
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Liu X, Meltzer SJ. Gastric Cancer in the Era of Precision Medicine. Cell Mol Gastroenterol Hepatol 2017; 3:348-358. [PMID: 28462377 PMCID: PMC5404028 DOI: 10.1016/j.jcmgh.2017.02.003] [Citation(s) in RCA: 81] [Impact Index Per Article: 10.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/10/2017] [Accepted: 02/13/2017] [Indexed: 12/14/2022]
Abstract
Gastric cancer (GC) remains the third most common cause of cancer death worldwide, with limited therapeutic strategies available. With the advent of next-generation sequencing and new preclinical model technologies, our understanding of its pathogenesis and molecular alterations continues to be revolutionized. Recently, the genomic landscape of GC has been delineated. Molecular characterization and novel therapeutic targets of each molecular subtype have been identified. At the same time, patient-derived tumor xenografts and organoids now comprise effective tools for genetic evolution studies, biomarker identification, drug screening, and preclinical evaluation of personalized medicine strategies for GC patients. These advances are making it feasible to integrate clinical, genome-based and phenotype-based diagnostic and therapeutic methods and apply them to individual GC patients in the era of precision medicine.
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Key Words
- CIMP, CpG island methylator phenotype
- CIN, chromosomally unstable/chromosomal instability
- Cancer Genomics
- EBV, Epstein-Barr virus
- GAPPS, gastric adenocarcinoma and proximal polyposis of the stomach
- GC, gastric cancer
- GTPase, guanosine triphosphatase
- Gastric Cancer
- HDGC, hereditary diffuse gastric cancer
- LOH, loss of heterozygosity
- MSI, microsatellite unstable/instability
- MSI-H, high microsatellite instability
- MSS/EMT, microsatellite stable with epithelial-to-mesenchymal transition features
- Molecular Classification
- NGS, next-generation sequencing
- PDX, patient-derived tumor xenografts
- Preclinical Models
- TCGA, The Cancer Genome Atlas
- TGF, transforming growth factor
- hPSC, human pluripotent stem cell
- lncRNA, long noncoding RNA
- miRNA, microRNA
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Affiliation(s)
- Xi Liu
- Department of Pathology, First Affiliated Hospital of Xi’ an Jiaotong University, Xi’ an, Shaanxi, China,Division of Gastroenterology, Department of Medicine, and Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, School of Medicine, Baltimore, Maryland
| | - Stephen J. Meltzer
- Division of Gastroenterology, Department of Medicine, and Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, School of Medicine, Baltimore, Maryland,Correspondence Address correspondence to: Stephen J. Meltzer, MD, Johns Hopkins University School of Medicine, 1503 East Jefferson Street, Room 112, Baltimore, Maryland 21287. fax: (410) 502-1329.Johns Hopkins University School of Medicine1503 East Jefferson Street, Room 112BaltimoreMaryland21287
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41
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Circulating Nucleosomes and Nucleosome Modifications as Biomarkers in Cancer. Cancers (Basel) 2017; 9:cancers9010005. [PMID: 28075351 PMCID: PMC5295776 DOI: 10.3390/cancers9010005] [Citation(s) in RCA: 76] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2016] [Revised: 12/31/2016] [Accepted: 01/01/2017] [Indexed: 12/17/2022] Open
Abstract
Traditionally the stratification of many cancers involves combining tumour and clinicopathological features (e.g., patient age; tumour size, grade, receptor status and location) to inform treatment options and predict recurrence risk and survival. However, current biomarkers often require invasive excision of the tumour for profiling, do not allow monitoring of the response to treatment and stratify patients into broad heterogeneous groups leading to inconsistent treatment responses. Here we explore and describe the benefits of using circulating biomarkers (nucleosomes and/or modifications to nucleosomes) as a non-invasive method for detecting cancer and monitoring response to treatment. Nucleosomes (DNA wound around eight core histone proteins) are responsible for compacting our genome and their composition and post-translational modifications are responsible for regulating gene expression. Here, we focus on breast and colorectal cancer as examples where utilizing circulating nucleosomes as biomarkers hold real potential as liquid biopsies. Utilizing circulating nucleosomes as biomarkers is an exciting new area of research that promises to allow both the early detection of cancer and monitoring of treatment response. Nucleosome-based biomarkers combine with current biomarkers, increasing both specificity and sensitivity of current tests and have the potential to provide individualised precision-medicine based treatments for patients.
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Moosavi A, Ardekani AM. Role of Epigenetics in Biology and Human Diseases. IRANIAN BIOMEDICAL JOURNAL 2016; 20:246-58. [PMID: 27377127 PMCID: PMC5075137 DOI: 10.22045/ibj.2016.01] [Citation(s) in RCA: 97] [Impact Index Per Article: 10.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/16/2016] [Revised: 02/22/2016] [Accepted: 03/08/2016] [Indexed: 12/11/2022]
Abstract
For a long time, scientists have tried to describe disorders just by genetic or environmental factors. However, the role of epigenetics in human diseases has been considered from a half of century ago. In the last decade, this subject has attracted many interests, especially in complicated disorders such as behavior plasticity, memory, cancer, autoimmune disease, and addiction as well as neurodegenerative and psychological disorders. This review first explains the history and classification of epigenetic modifications, and then the role of epigenetic in biology and connection between the epigenetics and environment are explained. Furthermore, the role of epigenetics in human diseases is considered by focusing on some diseases with some complicated features, and at the end, we have given the future perspective of this field. The present review article provides concepts with some examples to reveal a broad view of different aspects of epigenetics in biology and human diseases.
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Affiliation(s)
- Azam Moosavi
- Department of Biochemistry, School of Medicine, Alborz University of Medical Sciences, Alborz, Iran
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Khan SA, Amnekar R, Khade B, Barreto SG, Ramadwar M, Shrikhande SV, Gupta S. p38-MAPK/MSK1-mediated overexpression of histone H3 serine 10 phosphorylation defines distance-dependent prognostic value of negative resection margin in gastric cancer. Clin Epigenetics 2016; 8:88. [PMID: 27588146 PMCID: PMC5007744 DOI: 10.1186/s13148-016-0255-9] [Citation(s) in RCA: 28] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2016] [Accepted: 08/21/2016] [Indexed: 01/09/2023] Open
Abstract
Background Alterations in histone modifications are now well known to result in epigenetic heterogeneity in tumor tissues; however, their prognostic value and association with resection margins still remain poorly understood and controversial. Further, histopathologically negative resection margins in several cancers have been associated with better prognosis of the disease. However, in gastric cancer, despite a high rate of R0 resection, a considerably high incidence of loco-regional recurrence is observed. We believe alterations of global histone post-translational modifications could help in identifying molecular signatures for defining the true negative surgical resection margins and also the prognosis of gastric cancer patients. Results The present study compares the level of H3S10ph among paired tumor and histopathologically confirmed disease-free (R0) proximal and distal surgical resection margin (PRM and DRM) tissue samples of GC patients (n = 101). Immunoblotting and immune-histochemical analysis showed a significantly (p < 0.01) higher level of H3S10ph in tumor compared to R0 surgical resection margins. Along with tumor, high H3S10ph levels in both PRM and DRM correlated with clinical parameters and poor survival. Interestingly, in the case of PRM and DRM, the association of H3S10ph with poor survival was only found in a patient group with the resection margin distance <4 cm. Further investigations revealed that the increase of H3S10ph in tumor tissues is not due to the change in cell cycle profile but rather an interphase-associated phenomenon. Moreover, an increase in ph-MSK1 and ph-p38 levels in tumor tissues and the decrease in ph-MSK1 and H3S10ph on p38 inhibition in gastric cancer cells confirmed p38-MAPK/MSK1 pathway-mediated regulation of H3S10ph in gastric cancer. Conclusions Our study provides the first evidence that p38-MAPK/MSK1-regulated increase of H3S10ph in GC is predictive of a more aggressive cancer phenotype and could help in defining true negative surgical resection margin. Importantly, our data also gave a new rationale for exploration of the use of MSK1 inhibitor in gastric cancer therapy and the combination of histone post-translational modifications, H4K16ac and H4K20me3 along with H3S10ph as epigenetic prognostic markers. Electronic supplementary material The online version of this article (doi:10.1186/s13148-016-0255-9) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Shafqat Ali Khan
- Epigenetics and Chromatin Biology Group, Gupta Laboratory, Cancer Research Centre, Advanced Centre for Treatment Research and Education in Cancer, Tata Memorial Centre, Kharghar, Navi Mumbai, MH 410210 India ; Homi Bhabha National Institute, Training School Complex, Anushakti Nagar, Mumbai, MH 400085 India
| | - Ramchandra Amnekar
- Epigenetics and Chromatin Biology Group, Gupta Laboratory, Cancer Research Centre, Advanced Centre for Treatment Research and Education in Cancer, Tata Memorial Centre, Kharghar, Navi Mumbai, MH 410210 India ; Homi Bhabha National Institute, Training School Complex, Anushakti Nagar, Mumbai, MH 400085 India
| | - Bharat Khade
- Epigenetics and Chromatin Biology Group, Gupta Laboratory, Cancer Research Centre, Advanced Centre for Treatment Research and Education in Cancer, Tata Memorial Centre, Kharghar, Navi Mumbai, MH 410210 India
| | | | - Mukta Ramadwar
- Department of Pathology, Tata Memorial Hospital, Mumbai, MH 400012 India
| | - Shailesh V Shrikhande
- Department of Surgical Oncology, Gastrointestinal and Hepato-Pancreato-Biliary Service, Tata Memorial Hospital, Mumbai, MH 400012 India
| | - Sanjay Gupta
- Epigenetics and Chromatin Biology Group, Gupta Laboratory, Cancer Research Centre, Advanced Centre for Treatment Research and Education in Cancer, Tata Memorial Centre, Kharghar, Navi Mumbai, MH 410210 India ; Homi Bhabha National Institute, Training School Complex, Anushakti Nagar, Mumbai, MH 400085 India
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Vorinostat in combination with capecitabine plus cisplatin as a first-line chemotherapy for patients with metastatic or unresectable gastric cancer: phase II study and biomarker analysis. Br J Cancer 2016; 114:1185-90. [PMID: 27172248 PMCID: PMC4891506 DOI: 10.1038/bjc.2016.125] [Citation(s) in RCA: 36] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2016] [Revised: 03/10/2016] [Accepted: 04/18/2016] [Indexed: 12/20/2022] Open
Abstract
BACKGROUND Vorinostat, a histone deacetylase (HDAC) inhibitor, was investigated in combination with capecitabine plus cisplatin (XP) as a first-line chemotherapy for patients with unresectable or metastatic gastric cancer (GC). METHODS Eligible patients received 400 mg vorinostat once daily on days 1-14, 1000 mg m(-2) capecitabine twice daily on days 1-14, and 60 mg m(-2) cisplatin on day 1 every 3 weeks. Plasma levels of acetyl-H3, HDAC2, and p21 were measured for correlative analysis. The primary end point was the 6-month progression-free survival (PFS) rate. Secondary end points included the response rate, PFS, overall survival (OS), and safety profile. RESULTS A total of 45 patients with HER2-negative GC were included in this study. The objective response rate was 42%. The median PFS was 5.9 months, and the 6-month PFS rate was 44.4%. The median OS was 12.7 months. Most common grade 3-4 toxicities were neutropenia (41%), fatigue (34%), anorexia (32%), thromboembolism (27%), stomatitis (14%), and thrombocytopenia (11%). High plasma acetyl-H3 and p21 levels were significantly associated with a poor OS (P=0.02 and P=0.03, respectively). CONCLUSIONS Vorinostat-XP is a feasible first-line chemotherapy for patients with advanced GC. However, this trial did not meet its primary end point, and more adverse events were observed in comparison with the historical data of flouropyrimidine-platinium doublet regimens.
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Altered primary chromatin structures and their implications in cancer development. Cell Oncol (Dordr) 2016; 39:195-210. [PMID: 27007278 DOI: 10.1007/s13402-016-0276-6] [Citation(s) in RCA: 32] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 03/02/2016] [Indexed: 12/11/2022] Open
Abstract
BACKGROUND Cancer development is a complex process involving both genetic and epigenetic changes. Genetic changes in oncogenes and tumor-suppressor genes are generally considered as primary causes, since these genes may directly regulate cellular growth. In addition, it has been found that changes in epigenetic factors, through mutation or altered gene expression, may contribute to cancer development. In the nucleus of eukaryotic cells DNA and histone proteins form a structure called chromatin which consists of nucleosomes that, like beads on a string, are aligned along the DNA strand. Modifications in chromatin structure are essential for cell type-specific activation or repression of gene transcription, as well as other processes such as DNA repair, DNA replication and chromosome segregation. Alterations in epigenetic factors involved in chromatin dynamics may accelerate cell cycle progression and, ultimately, result in malignant transformation. Abnormal expression of remodeler and modifier enzymes, as well as histone variants, may confer to cancer cells the ability to reprogram their genomes and to yield, maintain or exacerbate malignant hallmarks. At the end, genetic and epigenetic alterations that are encountered in cancer cells may culminate in chromatin changes that may, by altering the quantity and quality of gene expression, promote cancer development. METHODS During the last decade a vast number of studies has uncovered epigenetic abnormalities that are associated with the (anomalous) packaging and remodeling of chromatin in cancer genomes. In this review I will focus on recently published work dealing with alterations in the primary structure of chromatin resulting from imprecise arrangements of nucleosomes along DNA, and its functional implications for cancer development. CONCLUSIONS The primary chromatin structure is regulated by a variety of epigenetic mechanisms that may be deregulated through gene mutations and/or gene expression alterations. In recent years, it has become evident that changes in chromatin structure may coincide with the occurrence of cancer hallmarks. The functional interrelationships between such epigenetic alterations and cancer development are just becoming manifest and, therefore, the oncology community should continue to explore the molecular mechanisms governing the primary chromatin structure, both in normal and in cancer cells, in order to improve future approaches for cancer detection, prevention and therapy, as also for circumventing drug resistance.
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Lin X, Huang Y, Zou Y, Chen X, Ma X. Depletion of G9a gene induces cell apoptosis in human gastric carcinoma. Oncol Rep 2016; 35:3041-9. [PMID: 27081761 DOI: 10.3892/or.2016.4692] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2015] [Accepted: 01/12/2016] [Indexed: 11/06/2022] Open
Abstract
G9a is a mammalian histone methyltransferase that contributes to the epigenetic silencing of tumor suppressor genes. Evidence suggests that G9a is required to maintain the malignant phenotype, but little documentation show the role of G9a function in mediating tumor growth. We retrospectively analyzed the protein of G9a and monomethylated histone H3 lysine 9 (H3K9 me1), and dimethylated histone H3 lysine 9 (H3K9 me2) in 175 cases of gastric carcinoma by immunohistochemistry. RNAi-based inhibition of G9a in MGC803 cancer cell line was studied. G9a depletion was done by transient transfection using Lipofectamine 2000. Depletion efficiency of G9a was tested using real-time PCR and western blot analysis. Cell apoptosis and proliferation were detected by TUNEL assay and MTT, respectively. The proteins of H3K9 me1, me2, trimethylation of H3K9 (H3K9 me3), monomethylated histone H3 lysine 27 (H3K27 me1), dimethylated histone H3 lysine 27 (H3K27 me2) and histone acetylated H3, apoptotic proteins were studied by western blot analysis. G9a and H3K9 me2 expression was higher in gastric cancer cells compared to the control (p<0.05). Both G9a and H3K9 me2 were positively correlated with the degree of differentiation, depth of infiltration, lymphatic invasions and tumor-node-metastasis stage in gastric carcinoma, (p<0.05). RNAi-mediated knockdown of G9a induced cell apoptosis and inhibited cell proliferation. Depletion of G9a reduced the levels of H3K9 me1 and me2, H3K27 me1 and me2. Nonetheless, it did not activate acetylation of H3 and H3K9 me3. These data suggest that G9a is required in tumorigenesis, and correlated with prognosis. Furthermore, G9a plays a critical role in regulating epigenetics. Depletion of G9a inhibits cell growth and induces cells apoptosis in gastric cancer. It might be of therapeutic benefit in gastric cancers.
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Affiliation(s)
- Xiaolei Lin
- Zhangzhou Affiliated Hospital of Fujian Medical University, Zhangzhou, Fujian 363000, P.R. China
| | - Yiqun Huang
- Zhangzhou Affiliated Hospital of Fujian Medical University, Zhangzhou, Fujian 363000, P.R. China
| | - Yong Zou
- Zhangzhou Affiliated Hospital of Fujian Medical University, Zhangzhou, Fujian 363000, P.R. China
| | - Xingsheng Chen
- United Hospital of Fujian Medical University, Fuzhou, Fujian 350001, P.R. China
| | - Xudong Ma
- Zhangzhou Affiliated Hospital of Fujian Medical University, Zhangzhou, Fujian 363000, P.R. China
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Verma M. The Role of Epigenomics in the Study of Cancer Biomarkers and in the Development of Diagnostic Tools. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2016; 867:59-80. [PMID: 26530360 DOI: 10.1007/978-94-017-7215-0_5] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Epigenetics plays a key role in cancer development. Genetics alone cannot explain sporadic cancer and cancer development in individuals with no family history or a weak family history of cancer. Epigenetics provides a mechanism to explain the development of cancer in such situations. Alterations in epigenetic profiling may provide important insights into the etiology and natural history of cancer. Because several epigenetic changes occur before histopathological changes, they can serve as biomarkers for cancer diagnosis and risk assessment. Many cancers may remain asymptomatic until relatively late stages; in managing the disease, efforts should be focused on early detection, accurate prediction of disease progression, and frequent monitoring. This chapter describes epigenetic biomarkers as they are expressed during cancer development and their potential use in cancer diagnosis and prognosis. Based on epigenomic information, biomarkers have been identified that may serve as diagnostic tools; some such biomarkers also may be useful in identifying individuals who will respond to therapy and survive longer. The importance of analytical and clinical validation of biomarkers is discussed, along with challenges and opportunities in this field.
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Affiliation(s)
- Mukesh Verma
- Epidemiology and Genomics Research Program, Division of Cancer Control and Population Sciences, National Cancer Institute (NCI), National Institutes of Health (NIH), Suite# 4E102. 9609 Medical Center Drive, MSC 9763, Bethesda, MD, 20892-9726, USA.
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Hollar D. Epigenetic Significance of Chromatin Organization During Cellular Aging and Organismal Lifespan. EPIGENETICS, THE ENVIRONMENT, AND CHILDREN’S HEALTH ACROSS LIFESPANS 2016. [PMCID: PMC7153164 DOI: 10.1007/978-3-319-25325-1_2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
Affiliation(s)
- David Hollar
- Pfeiffer University, Morrisville, North Carolina USA
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Khan SA, Reddy D, Gupta S. Global histone post-translational modifications and cancer: Biomarkers for diagnosis, prognosis and treatment? World J Biol Chem 2015; 6:333-345. [PMID: 26629316 PMCID: PMC4657128 DOI: 10.4331/wjbc.v6.i4.333] [Citation(s) in RCA: 76] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/01/2015] [Revised: 07/10/2015] [Accepted: 10/08/2015] [Indexed: 02/05/2023] Open
Abstract
Global alterations in epigenetic landscape are now recognized as a hallmark of cancer. Epigenetic mechanisms such as DNA methylation, histone modifications, nucleosome positioning and non-coding RNAs are proven to have strong association with cancer. In particular, covalent post-translational modifications of histone proteins are known to play an important role in chromatin remodeling and thereby in regulation of gene expression. Further, histone modifications have also been associated with different aspects of carcinogenesis and have been studied for their role in the better management of cancer patients. In this review, we will explore and discuss how histone modifications are involved in cancer diagnosis, prognosis and treatment.
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Nawrocki M, Strugała A, Piotrowski P, Wudarski M, Olesińska M, Jagodziński P. JHDM1D and HDAC1–3 mRNA expression levels in peripheral blood mononuclear cells of patients with systemic lupus erythematosus. Z Rheumatol 2015; 74:902-10. [DOI: 10.1007/s00393-015-1619-9] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
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