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Atterton C, Trew I, Cale JM, Aung-Htut MT, Grens K, Kiernan J, Delagrammatikas CG, Piper M. Overgrowth-intellectual disability disorders: progress in biology, patient advocacy and innovative therapies. Dis Model Mech 2025; 18:dmm052300. [PMID: 40353642 DOI: 10.1242/dmm.052300] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/14/2025] Open
Abstract
Overgrowth-intellectual disability (OGID) syndromes encompass a group of rare neurodevelopmental disorders that frequently share common clinical presentations. Although the genetic causes of many OGID syndromes are now known, we lack a clear mechanistic understanding of how such variants disrupt developmental processes and ultimately culminate in overgrowth and neurological symptoms. Patient advocacy groups, such as the Overgrowth Syndromes Alliance (OSA), are mobilising patients, families, clinicians and researchers to work together towards a deeper understanding of the clinical needs of patients with OGID, as well as to understand the fundamental biology of the relevant genes, with the goal of developing treatments. In this Review, we summarise three OGID syndromes encompassed by the OSA, namely Sotos syndrome, Malan syndrome and Tatton-Brown-Rahman syndrome. We discuss similarities and differences in the biology behind each disorder and explore future approaches that could potentially provide a way to ameliorate some of the unmet clinical needs of patients with OGID.
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Affiliation(s)
- Cooper Atterton
- The School of Biomedical Sciences, The University of Queensland, Brisbane, QLD 4072, Australia
| | - Isabella Trew
- Personalised Medicine Centre, Health Futures Institute, Murdoch University, Murdoch, WA 6150, Australia
- Centre for Neuromuscular and Neurological Disorders, Perron Institute for Neurological and Translational Science, Nedlands, WA 6009, Australia
| | - Jessica M Cale
- Personalised Medicine Centre, Health Futures Institute, Murdoch University, Murdoch, WA 6150, Australia
- Centre for Neuromuscular and Neurological Disorders, Perron Institute for Neurological and Translational Science, Nedlands, WA 6009, Australia
| | - May T Aung-Htut
- Personalised Medicine Centre, Health Futures Institute, Murdoch University, Murdoch, WA 6150, Australia
- Centre for Neuromuscular and Neurological Disorders, Perron Institute for Neurological and Translational Science, Nedlands, WA 6009, Australia
| | - Kerry Grens
- TBRS Community, Stanfordville, NY 12581, USA
| | | | | | - Michael Piper
- The School of Biomedical Sciences, The University of Queensland, Brisbane, QLD 4072, Australia
- The Queensland Brain Institute, The University of Queensland, Brisbane, QLD 4072, Australia
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2
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Zhu W. Magnetic resonance imaging evaluation and nuclear receptor binding SET domain protein 1 mutation in the Sotos syndrome with attention-deficit/hyperactivity disorder. World J Clin Cases 2025; 13:98319. [PMID: 39823103 PMCID: PMC11577501 DOI: 10.12998/wjcc.v13.i2.98319] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/24/2024] [Revised: 09/25/2024] [Accepted: 10/16/2024] [Indexed: 11/08/2024] Open
Abstract
Sotos syndrome is characterized by overgrowth features and is caused by alterations in the nuclear receptor binding SET domain protein 1 gene. Attention-deficit/hyperactivity disorder (ADHD) is considered a neurodevelopment and psychiatric disorder in childhood. Genetic characteristics and clinical presentation could play an important role in the diagnosis of Sotos syndrome and ADHD. Magnetic resonance imaging (MRI) has been used to assess medical images in Sotos syndrome and ADHD. The images process is considered to display in MRI while wavelet fusion has been used to integrate distinct images for achieving more complete information in single image in this editorial. In the future, genetic mechanisms and artificial intelligence related to medical images could be used in the clinical diagnosis of Sotos syndrome and ADHD.
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Affiliation(s)
- Wei Zhu
- Shanghai XiRong Information Science and Technology Co., Ltd, National Science and Technology Park, School of Life Sciences and Technology, Tongji University, Shanghai 200092, China
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3
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Liapodimitri A, Tetens AR, Craig-Schwartz J, Lunsford K, Skalitzky KO, Koldobskiy MA. Progress Toward Epigenetic Targeted Therapies for Childhood Cancer. Cancers (Basel) 2024; 16:4149. [PMID: 39766049 PMCID: PMC11674401 DOI: 10.3390/cancers16244149] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2024] [Revised: 12/09/2024] [Accepted: 12/10/2024] [Indexed: 01/11/2025] Open
Abstract
Among the most significant discoveries from cancer genomics efforts has been the critical role of epigenetic dysregulation in cancer development and progression. Studies across diverse cancer types have revealed frequent mutations in genes encoding epigenetic regulators, alterations in DNA methylation and histone modifications, and a dramatic reorganization of chromatin structure. Epigenetic changes are especially relevant to pediatric cancers, which are often characterized by a low rate of genetic mutations. The inherent reversibility of epigenetic lesions has led to an intense interest in the development of epigenetic targeted therapies. Additionally, the recent appreciation of the interplay between the epigenome and immune regulation has sparked interest in combination therapies and synergistic immunotherapy approaches. Further, the recent appreciation of epigenetic variability as a driving force in cancer evolution has suggested new roles for epigenetic therapies in limiting plasticity and resistance. Here, we review recent progress and emerging directions in the development of epigenetic targeted therapeutics and their promise across the landscape of childhood cancers.
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Affiliation(s)
- Athanasia Liapodimitri
- Division of Pediatric Oncology, Department of Oncology, School of Medicine, Johns Hopkins University, Baltimore, MD 21287, USA; (A.L.); (A.R.T.); (J.C.-S.); (K.L.); (K.O.S.)
| | - Ashley R. Tetens
- Division of Pediatric Oncology, Department of Oncology, School of Medicine, Johns Hopkins University, Baltimore, MD 21287, USA; (A.L.); (A.R.T.); (J.C.-S.); (K.L.); (K.O.S.)
| | - Jordyn Craig-Schwartz
- Division of Pediatric Oncology, Department of Oncology, School of Medicine, Johns Hopkins University, Baltimore, MD 21287, USA; (A.L.); (A.R.T.); (J.C.-S.); (K.L.); (K.O.S.)
| | - Kayleigh Lunsford
- Division of Pediatric Oncology, Department of Oncology, School of Medicine, Johns Hopkins University, Baltimore, MD 21287, USA; (A.L.); (A.R.T.); (J.C.-S.); (K.L.); (K.O.S.)
| | - Kegan O. Skalitzky
- Division of Pediatric Oncology, Department of Oncology, School of Medicine, Johns Hopkins University, Baltimore, MD 21287, USA; (A.L.); (A.R.T.); (J.C.-S.); (K.L.); (K.O.S.)
| | - Michael A. Koldobskiy
- Division of Pediatric Oncology, Department of Oncology, School of Medicine, Johns Hopkins University, Baltimore, MD 21287, USA; (A.L.); (A.R.T.); (J.C.-S.); (K.L.); (K.O.S.)
- Sidney Kimmel Comprehensive Cancer Center, School of Medicine, Johns Hopkins University, Baltimore, MD 21287, USA
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Kang B, Song B, Shin H, Lee IS. Downregulation of nuclear receptor-binding SET domain protein 1 induces proinflammatory cytokine expression via mitogen-activated protein kinase pathways in U87MG cells. Biochem Biophys Res Commun 2024; 734:150638. [PMID: 39236589 DOI: 10.1016/j.bbrc.2024.150638] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2024] [Accepted: 08/30/2024] [Indexed: 09/07/2024]
Abstract
Haploinsufficiency of the nuclear receptor binding SET domain-containing protein 1 gene (NSD1) leads to a neurodevelopmental disorder known as Sotos syndrome (SOTOS). This study investigated the effects of NSD1 knockdown in glial cells. U87MG glioma cells were transfected with siRNA targeting NSD1, which resulted in morphological changes characteristic of activated astrocytes. These activated phenotypes were accompanied by specific activation of mitogen-activated protein kinase (MAPK) signaling pathways, particularly those mediated by p38 MAPK and c-Jun N-terminal kinase (JNK). Transcriptome analysis showed increased expression of proinflammatory cytokine genes, particularly interleukin (IL)-1α, IL-1β, and IL-6, following NSD1 knockdown. Treatment with MAPK inhibitors significantly reduced the cytokine induction caused by NSD1 knockdown, with the p38 MAPK inhibitor being more effective than the JNK inhibitor. These findings provide new insights into the role of NSD1 loss in neurological dysfunctions associated with SOTOS.
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Affiliation(s)
- Byungjun Kang
- Department of Biological Sciences, Konkuk University, 120 Neungdong-ro, Gwangjin-gu, Seoul, 05029, Republic of Korea
| | - Bokyeong Song
- Department of Biological Sciences, Konkuk University, 120 Neungdong-ro, Gwangjin-gu, Seoul, 05029, Republic of Korea
| | - Hyewon Shin
- Department of Biological Sciences, Konkuk University, 120 Neungdong-ro, Gwangjin-gu, Seoul, 05029, Republic of Korea
| | - Im-Soon Lee
- Department of Biological Sciences, Konkuk University, 120 Neungdong-ro, Gwangjin-gu, Seoul, 05029, Republic of Korea.
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Esteller M, Dawson MA, Kadoch C, Rassool FV, Jones PA, Baylin SB. The Epigenetic Hallmarks of Cancer. Cancer Discov 2024; 14:1783-1809. [PMID: 39363741 DOI: 10.1158/2159-8290.cd-24-0296] [Citation(s) in RCA: 18] [Impact Index Per Article: 18.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/29/2024] [Revised: 05/08/2024] [Accepted: 06/24/2024] [Indexed: 10/05/2024]
Abstract
Cancer is a complex disease in which several molecular and cellular pathways converge to foster the tumoral phenotype. Notably, in the latest iteration of the cancer hallmarks, "nonmutational epigenetic reprogramming" was newly added. However, epigenetics, much like genetics, is a broad scientific area that deserves further attention due to its multiple roles in cancer initiation, progression, and adaptive nature. Herein, we present a detailed examination of the epigenetic hallmarks affected in human cancer, elucidating the pathways and genes involved, and dissecting the disrupted landscapes for DNA methylation, histone modifications, and chromatin architecture that define the disease. Significance: Cancer is a disease characterized by constant evolution, spanning from its initial premalignant stages to the advanced invasive and disseminated stages. It is a pathology that is able to adapt and survive amidst hostile cellular microenvironments and diverse treatments implemented by medical professionals. The more fixed setup of the genetic structure cannot fully provide transformed cells with the tools to survive but the rapid and plastic nature of epigenetic changes is ready for the task. This review summarizes the epigenetic hallmarks that define the ecological success of cancer cells in our bodies.
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Affiliation(s)
- Manel Esteller
- Cancer Epigenetics Group, Josep Carreras Leukaemia Research Institute (IJC), Barcelona, Spain
- Centro de Investigacion Biomedica en Red Cancer (CIBERONC), Madrid, Spain
- Institucio Catalana de Recerca i Estudis Avançats (ICREA), Barcelona, Spain
- Physiological Sciences Department, School of Medicine and Health Sciences, University of Barcelona (UB), Barcelona, Spain
| | - Mark A Dawson
- Peter MacCallum Cancer Centre, Melbourne, Australia
- Sir Peter MacCallum Department of Oncology, University of Melbourne, Melbourne, Australia
- Centre for Cancer Research, University of Melbourne, Melbourne, Australia
| | - Cigall Kadoch
- Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts
- Broad Institute of MIT and Harvard, Cambridge, Massachusetts
- Howard Hughes Medical Institute, Chevy Chase, Maryland
| | - Feyruz V Rassool
- Marlene and Stewart Greenebaum Comprehensive Cancer Center, University of Maryland School of Medicine, Baltimore, Maryland
- Department of Radiation Oncology, University of Maryland School of Medicine, Baltimore, Maryland
| | - Peter A Jones
- Department of Epigenetics, Van Andel Institute, Grand Rapids, Michigan
| | - Stephen B Baylin
- Department of Epigenetics, Van Andel Institute, Grand Rapids, Michigan
- Department of Oncology, The Johns Hopkins School of Medicine, The Sidney Kimmel Comprehensive Cancer Center, Baltimore, Maryland
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6
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Ma S, Long G, Jiang Z, Zhang Y, Sun L, Pan Y, You Q, Guo X. Recent advances in targeting histone H3 lysine 36 methyltransferases for cancer therapy. Eur J Med Chem 2024; 274:116532. [PMID: 38805937 DOI: 10.1016/j.ejmech.2024.116532] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2024] [Revised: 05/14/2024] [Accepted: 05/22/2024] [Indexed: 05/30/2024]
Abstract
Histone H3 lysine 36 (H3K36) methylation is a typical epigenetic histone modification that is involved in various biological processes such as DNA transcription, repair and recombination in vivo. Mutations, translocations, and aberrant gene expression associated with H3K36 methyltransferases have been implicated in different malignancies such as acute myeloid leukemia, lung cancer, multiple myeloma, and others. Herein, we provided a comprehensive overview of the latest advances in small molecule inhibitors targeting H3K36 methyltransferases. We analyzed the structures and biological functions of the H3K36 methyltransferases family members. Additionally, we discussed the potential directions for future development of inhibitors targeting H3K36 methyltransferases.
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Affiliation(s)
- Sai Ma
- Jiangsu Key Laboratory of Drug Design and Optimization and State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, 210009, China
| | - Guanlu Long
- Jiangsu Key Laboratory of Drug Design and Optimization and State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, 210009, China
| | - Zheng Jiang
- Jiangsu Key Laboratory of Drug Design and Optimization and State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, 210009, China
| | - Yan Zhang
- Jiangsu Key Laboratory of Drug Design and Optimization and State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, 210009, China
| | - Liangkui Sun
- Jiangsu Key Laboratory of Drug Design and Optimization and State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, 210009, China
| | - Yun Pan
- Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing, 210009, China
| | - Qidong You
- Jiangsu Key Laboratory of Drug Design and Optimization and State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, 210009, China; Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing, 210009, China.
| | - Xiaoke Guo
- Jiangsu Key Laboratory of Drug Design and Optimization and State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, 210009, China; Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing, 210009, China.
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Huang X, Chen Y, Xiao Q, Shang X, Liu Y. Chemical inhibitors targeting histone methylation readers. Pharmacol Ther 2024; 256:108614. [PMID: 38401773 DOI: 10.1016/j.pharmthera.2024.108614] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2023] [Revised: 02/01/2024] [Accepted: 02/15/2024] [Indexed: 02/26/2024]
Abstract
Histone methylation reader domains are protein modules that recognize specific histone methylation marks, such as methylated or unmethylated lysine or arginine residues on histones. These reader proteins play crucial roles in the epigenetic regulation of gene expression, chromatin structure, and DNA damage repair. Dysregulation of these proteins has been linked to various diseases, including cancer, neurodegenerative diseases, and developmental disorders. Therefore, targeting these proteins with chemical inhibitors has emerged as an attractive approach for therapeutic intervention, and significant progress has been made in this area. In this review, we will summarize the development of inhibitors targeting histone methylation readers, including MBT domains, chromodomains, Tudor domains, PWWP domains, PHD fingers, and WD40 repeat domains. For each domain, we will briefly discuss its identification and biological/biochemical functions, and then focus on the discovery of inhibitors tailored to target this domain, summarizing the property and potential application of most inhibitors. We will also discuss the structural basis for the potency and selectivity of these inhibitors, which will aid in further lead generation and optimization. Finally, we will also address the challenges and strategies involved in the development of these inhibitors. It should facilitate the rational design and development of novel chemical scaffolds and new targeting strategies for histone methylation reader domains with the help of this body of data.
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Affiliation(s)
- Xiaolei Huang
- Jiangsu Key Laboratory of Neuropsychiatric Diseases, Jiangsu Province Engineering Research Center of Precision Diagnostics and Therapeutics Development, College of Pharmaceutical Sciences, Soochow University, Suzhou, Jiangsu 215123, PR China
| | - Yichang Chen
- Jiangsu Key Laboratory of Neuropsychiatric Diseases, Jiangsu Province Engineering Research Center of Precision Diagnostics and Therapeutics Development, College of Pharmaceutical Sciences, Soochow University, Suzhou, Jiangsu 215123, PR China
| | - Qin Xiao
- Jiangsu Key Laboratory of Neuropsychiatric Diseases, Jiangsu Province Engineering Research Center of Precision Diagnostics and Therapeutics Development, College of Pharmaceutical Sciences, Soochow University, Suzhou, Jiangsu 215123, PR China
| | - Xinci Shang
- Jiangsu Key Laboratory of Neuropsychiatric Diseases, Jiangsu Province Engineering Research Center of Precision Diagnostics and Therapeutics Development, College of Pharmaceutical Sciences, Soochow University, Suzhou, Jiangsu 215123, PR China
| | - Yanli Liu
- Jiangsu Key Laboratory of Neuropsychiatric Diseases, Jiangsu Province Engineering Research Center of Precision Diagnostics and Therapeutics Development, College of Pharmaceutical Sciences, Soochow University, Suzhou, Jiangsu 215123, PR China.
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8
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Kim HJ, Batara DC, Jeon YJ, Lee S, Beck S, Kim SH. The impact of MEIS1 TALE homeodomain transcription factor knockdown on glioma stem cell growth. Anim Cells Syst (Seoul) 2024; 28:93-109. [PMID: 38487309 PMCID: PMC10939110 DOI: 10.1080/19768354.2024.2327340] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2024] [Accepted: 02/28/2024] [Indexed: 03/17/2024] Open
Abstract
Myeloid ecotropic virus insertion site 1 (MEIS1) is a HOX co-factor necessary for organ development and normal hematopoiesis. Recently, MEIS1 has been linked to the development and progression of various cancers. However, its role in gliomagenesis particularly on glioma stem cells (GSCs) remains unclear. Here, we demonstrate that MEIS1 is highly upregulated in GSCs compared to normal, and glioma cells and to its differentiated counterparts. Inhibition of MEIS1 expression by shRNA significantly reduced GSC growth in both in vitro and in vivo experiments. On the other hand, integrated transcriptomics analyses of glioma datasets revealed that MEIS1 expression is correlated to cell cycle-related genes. Clinical data analysis revealed that MEIS1 expression is elevated in high-grade gliomas, and patients with high MEIS1 levels have poorer overall survival outcomes. The findings suggest that MEIS1 is a prognostic biomarker for glioma patients and a possible target for developing novel therapeutic strategies against GBM.
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Affiliation(s)
- Hyun-Jin Kim
- Animal Molecular Biochemistry Laboratory, Department of Animal Science, College of Agriculture and Life Sciences, Chonnam National University, Gwangju, Republic of Korea
| | - Don Carlo Batara
- Animal Molecular Biochemistry Laboratory, Department of Animal Science, College of Agriculture and Life Sciences, Chonnam National University, Gwangju, Republic of Korea
| | - Young-Jun Jeon
- Department of Integrative Biotechnology, Sungkyunkwan University, Suwon-si, Gyeonggi-do, Republic of Korea
| | - Seongsoo Lee
- Gwangju Center, Korea Basic Science Institute (KBSI), Gwangju, Republic of Korea
- Department of Systems Biotechnology, Chung-Ang University, Anseong-si, Gyeonggi-do, Republic of Korea
| | - Samuel Beck
- Department of Dermatology, Center for Aging Research, Chobanian & Avedisian School of Medicine, Boston University, Boston, USA
| | - Sung-Hak Kim
- Animal Molecular Biochemistry Laboratory, Department of Animal Science, College of Agriculture and Life Sciences, Chonnam National University, Gwangju, Republic of Korea
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Aziz N, Hong YH, Kim HG, Kim JH, Cho JY. Tumor-suppressive functions of protein lysine methyltransferases. Exp Mol Med 2023; 55:2475-2497. [PMID: 38036730 PMCID: PMC10766653 DOI: 10.1038/s12276-023-01117-7] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2023] [Revised: 08/30/2023] [Accepted: 09/05/2023] [Indexed: 12/02/2023] Open
Abstract
Protein lysine methyltransferases (PKMTs) play crucial roles in histone and nonhistone modifications, and their dysregulation has been linked to the development and progression of cancer. While the majority of studies have focused on the oncogenic functions of PKMTs, extensive evidence has indicated that these enzymes also play roles in tumor suppression by regulating the stability of p53 and β-catenin, promoting α-tubulin-mediated genomic stability, and regulating the transcription of oncogenes and tumor suppressors. Despite their contradictory roles in tumorigenesis, many PKMTs have been identified as potential therapeutic targets for cancer treatment. However, PKMT inhibitors may have unintended negative effects depending on the specific cancer type and target enzyme. Therefore, this review aims to comprehensively summarize the tumor-suppressive effects of PKMTs and to provide new insights into the development of anticancer drugs targeting PKMTs.
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Affiliation(s)
- Nur Aziz
- Department of Integrative Biotechnology, Sungkyunkwan University, Suwon, 16419, Republic of Korea
| | - Yo Han Hong
- Department of Integrative Biotechnology, Sungkyunkwan University, Suwon, 16419, Republic of Korea
| | - Han Gyung Kim
- Department of Integrative Biotechnology, Sungkyunkwan University, Suwon, 16419, Republic of Korea.
| | - Ji Hye Kim
- Department of Integrative Biotechnology, Sungkyunkwan University, Suwon, 16419, Republic of Korea.
| | - Jae Youl Cho
- Department of Integrative Biotechnology, Sungkyunkwan University, Suwon, 16419, Republic of Korea.
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Ma Z, Bolinger AA, Chen H, Zhou J. Drug Discovery Targeting Nuclear Receptor Binding SET Domain Protein 2 (NSD2). J Med Chem 2023; 66:10991-11026. [PMID: 37578463 PMCID: PMC11092389 DOI: 10.1021/acs.jmedchem.3c00948] [Citation(s) in RCA: 18] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 08/15/2023]
Abstract
Nuclear receptor binding SET domain proteins (NSDs) catalyze the mono- or dimethylation of histone 3 lysine 36 (H3K36me1 and H3K36me2), using S-adenosyl-l-methionine (SAM) as a methyl donor. As a key member of the NSD family of proteins, NSD2 plays an important role in the pathogenesis and progression of various diseases such as cancers, inflammations, and infectious diseases, serving as a promising drug target. Developing potent and specific NSD2 inhibitors may provide potential novel therapeutics. Several NSD2 inhibitors and degraders have been discovered while remaining in the early stage of drug development. Excitingly, KTX-1001, a selective NSD2 inhibitor, has entered clinical trials. In this Perspective, the structures and functions of NSD2, its roles in various human diseases, and the recent advances in drug discovery strategies targeting NSD2 have been summarized. The challenges, opportunities, and future directions for developing NSD2 inhibitors and degraders are also discussed.
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Affiliation(s)
- Zonghui Ma
- Chemical Biology Program, Department of Pharmacology and Toxicology, University of Texas Medical Branch (UTMB), Galveston, Texas 77555, United States
| | - Andrew A Bolinger
- Chemical Biology Program, Department of Pharmacology and Toxicology, University of Texas Medical Branch (UTMB), Galveston, Texas 77555, United States
| | - Haiying Chen
- Chemical Biology Program, Department of Pharmacology and Toxicology, University of Texas Medical Branch (UTMB), Galveston, Texas 77555, United States
| | - Jia Zhou
- Chemical Biology Program, Department of Pharmacology and Toxicology, University of Texas Medical Branch (UTMB), Galveston, Texas 77555, United States
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11
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Agredo A, Kasinski AL. Histone 4 lysine 20 tri-methylation: a key epigenetic regulator in chromatin structure and disease. Front Genet 2023; 14:1243395. [PMID: 37671044 PMCID: PMC10475950 DOI: 10.3389/fgene.2023.1243395] [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: 06/20/2023] [Accepted: 08/07/2023] [Indexed: 09/07/2023] Open
Abstract
Chromatin is a vital and dynamic structure that is carefully regulated to maintain proper cell homeostasis. A great deal of this regulation is dependent on histone proteins which have the ability to be dynamically modified on their tails via various post-translational modifications (PTMs). While multiple histone PTMs are studied and often work in concert to facilitate gene expression, here we focus on the tri-methylation of histone H4 on lysine 20 (H4K20me3) and its function in chromatin structure, cell cycle, DNA repair, and development. The recent studies evaluated in this review have shed light on how H4K20me3 is established and regulated by various interacting partners and how H4K20me3 and the proteins that interact with this PTM are involved in various diseases. Through analyzing the current literature on H4K20me3 function and regulation, we aim to summarize this knowledge and highlights gaps that remain in the field.
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Affiliation(s)
- Alejandra Agredo
- Department of Biological Sciences, Purdue University, West Lafayette, IN, United States
- Purdue Life Sciences Interdisciplinary Program (PULSe), Purdue University, West Lafayette, IN, United States
| | - Andrea L. Kasinski
- Department of Biological Sciences, Purdue University, West Lafayette, IN, United States
- Purdue Institute for Cancer Research, Purdue University, West Lafayette, IN, United States
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12
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Khella MS, Schnee P, Weirich S, Bui T, Bröhm A, Bashtrykov P, Pleiss J, Jeltsch A. The T1150A cancer mutant of the protein lysine dimethyltransferase NSD2 can introduce H3K36 trimethylation. J Biol Chem 2023:104796. [PMID: 37150325 DOI: 10.1016/j.jbc.2023.104796] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2023] [Revised: 04/20/2023] [Accepted: 04/29/2023] [Indexed: 05/09/2023] Open
Abstract
Protein lysine methyltransferases (PKMTs) play essential roles in gene expression regulation and cancer development. Somatic mutations in PKMTs are frequently observed in cancer cells. In biochemical experiments, we show here that the NSD1 mutations Y1971C, R2017Q and R2017L observed mostly in solid cancers are catalytically inactive suggesting that NSD1 acts as tumor suppressor gene in these tumors. In contrast, the frequently observed T1150A in NSD2 and its T2029A counterpart in NSD1, both observed in leukemia, are hyperactive and introduce up to thee methyl groups in H3K36 in biochemical and cellular assays, while wildtype NSD2 and NSD1 only introduce up to two methyl groups. In molecular dynamics simulations, we determine key mechanistic and structural features controlling the product specificity of this class of enzymes. Simulations with NSD2 revealed that H3K36me3 formation is possible due to an enlarged active site pocket of T1150A and loss of direct contacts of T1150 to critical residues which regulate the product specificity of NSD2. Bioinformatic analyses of published data suggested that the generation of H3K36me3 by NSD2 T1150A could alter gene regulation by antagonizing H3K27me3 finally leading to the upregulation of oncogenes.
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Affiliation(s)
- Mina S Khella
- Institute of Biochemistry and Technical Biochemistry, University of Stuttgart, Allmandring 31, 70569, Stuttgart, Germany; Biochemistry Department, Faculty of Pharmacy, Ain Shams University, African Union Organization Street, Abbassia, Cairo, 11566, Egypt
| | - Philipp Schnee
- Institute of Biochemistry and Technical Biochemistry, University of Stuttgart, Allmandring 31, 70569, Stuttgart, Germany
| | - Sara Weirich
- Institute of Biochemistry and Technical Biochemistry, University of Stuttgart, Allmandring 31, 70569, Stuttgart, Germany
| | - Tan Bui
- Institute of Biochemistry and Technical Biochemistry, University of Stuttgart, Allmandring 31, 70569, Stuttgart, Germany
| | - Alexander Bröhm
- Institute of Biochemistry and Technical Biochemistry, University of Stuttgart, Allmandring 31, 70569, Stuttgart, Germany
| | - Pavel Bashtrykov
- Institute of Biochemistry and Technical Biochemistry, University of Stuttgart, Allmandring 31, 70569, Stuttgart, Germany
| | - Jürgen Pleiss
- Institute of Biochemistry and Technical Biochemistry, University of Stuttgart, Allmandring 31, 70569, Stuttgart, Germany
| | - Albert Jeltsch
- Institute of Biochemistry and Technical Biochemistry, University of Stuttgart, Allmandring 31, 70569, Stuttgart, Germany.
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Chu DT, Ngo AD, Wu CC. Epigenetics in cancer development, diagnosis and therapy. PROGRESS IN MOLECULAR BIOLOGY AND TRANSLATIONAL SCIENCE 2023; 198:73-92. [PMID: 37225325 DOI: 10.1016/bs.pmbts.2023.01.009] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 03/08/2023]
Abstract
Cancer is a dangerous disease and one of the leading causes of death in the world. In 2020, there were nearly 10 million cancer deaths and approximately 20 million new cases. New cases and deaths from cancer are expected to increase further in the coming years. To have a deeper insight into the mechanism of carcinogenesis, epigenetics studies have been published and received much attention from scientists, doctors, and patients. Among alterations in epigenetics, DNA methylation and histone modification are studied by many scientists. They have been reported to be a major contributor in tumor formation and are involved in metastasis. From the understanding of DNA methylation and histone modification, effective, accurate and cost-effective methods for diagnosis and screening of cancer patients have been introduced. Furthermore, therapeutic approaches and drugs targeting altered epigenetics have also been clinically studied and have shown positive results in combating tumor progression. Several cancer drugs that rely on DNA methylation inactivation or histone modification have been approved by the FDA for the treatment of cancer patients. In summary, epigenetics changes such as DNA methylation or histone modification are take part in tumor growth, and they also have great prospect to study diagnostic and therapeutic methods of this dangerous disease.
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Affiliation(s)
- Dinh-Toi Chu
- Center for Biomedicine and Community Health, International School, Vietnam National University, Hanoi, Vietnam; Faculty of Applied Sciences, International School, Vietnam National University, Hanoi, Vietnam.
| | - Anh-Dao Ngo
- Center for Biomedicine and Community Health, International School, Vietnam National University, Hanoi, Vietnam
| | - Chia-Ching Wu
- Department of Cell Biology and Anatomy, College of Medicine, National Cheng Kung University, Tainan, Taiwan; International Center for Wound Repair and Regeneration, National Cheng Kung University, Tainan, Taiwan; Department of Biomedical Engineering, National Cheng Kung University, Tainan, Taiwan
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14
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Splicing-Disrupting Mutations in Inherited Predisposition to Solid Pediatric Cancer. Cancers (Basel) 2022; 14:cancers14235967. [PMID: 36497448 PMCID: PMC9739414 DOI: 10.3390/cancers14235967] [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: 10/17/2022] [Revised: 11/25/2022] [Accepted: 11/28/2022] [Indexed: 12/09/2022] Open
Abstract
The prevalence of hereditary cancer in children was estimated to be very low until recent studies suggested that at least 10% of pediatric cancer patients carry a germline mutation in a cancer predisposition gene. A significant proportion of pathogenic variants associated with an increased risk of hereditary cancer are variants affecting splicing. RNA splicing is an essential process involved in different cellular processes such as proliferation, survival, and differentiation, and alterations in this pathway have been implicated in many human cancers. Hereditary cancer genes are highly susceptible to splicing mutations, and among them there are several genes that may contribute to pediatric solid tumors when mutated in the germline. In this review, we have focused on the analysis of germline splicing-disrupting mutations found in pediatric solid tumors, as the discovery of pathogenic splice variants in pediatric cancer is a growing field for the development of personalized therapies. Therapies developed to correct aberrant splicing in cancer are also discussed as well as the options to improve the diagnostic yield based on the increase in the knowledge in splicing.
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15
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Shah A, Sharma A, Katiyar S, Gupta A, Chaturvedi CP. Upfront Screening by Quantitative Real-Time PCR Assay Identifies NUP98::NSD1 Fusion Transcript in Indian AML Patients. Diagnostics (Basel) 2022; 12:diagnostics12123001. [PMID: 36553008 PMCID: PMC9777445 DOI: 10.3390/diagnostics12123001] [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: 10/12/2022] [Revised: 11/08/2022] [Accepted: 11/15/2022] [Indexed: 12/03/2022] Open
Abstract
NUP98::NSD1 fusion, a cryptic translocation of t(5;11)(q35;p15.5), occurs predominantly in pediatric AML, having a poor prognostic outcome. There are limited studies on the diagnosis of NUP98::NSD1 fusion in a clinical setting, and most of the data are from Western countries. No study on the detection of this translocation has been reported from the Indian subcontinent to date. One possible reason could be the lack of availability of a potential tool to detect the fusion transcript. We have developed a real-time quantitative PCR (qRT-PCR)-based assay to detect NUP98::NSD1 fusion transcript with high sensitivity and specificity. Screening 150 AML patients (38 pediatric and 112 adults) using the assay showed the presence of fusion transcript in six patients including 03 pediatric, and 03 adult patients. We observed a prevalence rate of 7.89% (3/38) and 2.67% (3/112) fusion transcript in pediatric and adult patients, respectively. Sanger sequencing further validated the occurrence of NUP98::NSD1 fusion in all six patients. Molecular characterization of these patients revealed a co-occurrence of FLT3-ITD mutation, accompanied by altered expression of the HOX and other genes associated with AML. All six patients responded poorly to induction therapy. Overall, this is the first study to show the presence of the NUP98::NSD1 fusion transcript in Indian AML patients. Further, we demonstrate that our in-house developed qRT-PCR assay can be used to screen NUP98::NSD1 fusion in clinical settings.
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Affiliation(s)
- Arunim Shah
- Stem Cell Research Center, Department of Hematology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Raebareli Road, Lucknow 226014, India
| | - Akhilesh Sharma
- Department of Hematology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Raebareli Road, Lucknow 226014, India
| | - Shobhita Katiyar
- Stem Cell Research Center, Department of Hematology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Raebareli Road, Lucknow 226014, India
| | - Anshul Gupta
- Department of Hematology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Raebareli Road, Lucknow 226014, India
| | - Chandra Prakash Chaturvedi
- Stem Cell Research Center, Department of Hematology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Raebareli Road, Lucknow 226014, India
- Correspondence: ; Tel.: +91-522-2495891; Fax: +91-522-2668017
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16
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Zhai S, Cao M, Zhou H, Zhu H, Xu T, Wang Y, Wang X, Cai Z. H3K36 methyltransferase NSD1 is essential for normal B1 and B2 cell development and germinal center formation. Front Immunol 2022; 13:959021. [PMID: 36532012 PMCID: PMC9750791 DOI: 10.3389/fimmu.2022.959021] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2022] [Accepted: 11/14/2022] [Indexed: 12/03/2022] Open
Abstract
B cells, which consist of two well-defined populations: B1 and B2 cells, which can produce antibodies that are essential for host protection against infections, through virus neutralization, opsonization and antibody-dependent cellular cytotoxicity. Epigenetic modifications, such as DNA methylation and histone modification could regulate immune cell differentiation and functions. In this study, we found a significant reduction of GC response in the B cell specific knockout of H3K36 methyltransferase NSD1 (Mb1-Cre+ NSD1fl/fl, NSD1B KO) mice compared with the wildtype control (Mb1-Cre+ NSD1+/+, NSD1B WT). We also demonstrated reduced production of high-affinity antibody, but increased production of low-affinity antibody in the NSD1B KO mice. Further analysis revealed that loss of NSD1 promoted the development of B1 cells by increasing the expression of Rap1b and Arid3a. In conclusion, our data suggest that NSD1 plays an important role in regulation the development of B1 and B2 cells, and the process of germinal center formation and high-affinity antibody production.
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Affiliation(s)
- Sulan Zhai
- Department of Immunology, Key Laboratory of Immune Microenvironment and Diseases, Nanjing Medical University, Nanjing, China
| | - Min Cao
- Department of Immunology, Key Laboratory of Immune Microenvironment and Diseases, Nanjing Medical University, Nanjing, China
| | - Han Zhou
- Department of Immunology, Key Laboratory of Immune Microenvironment and Diseases, Nanjing Medical University, Nanjing, China,Reproductive Medicine Centre, Changzhou No. 2 People’s Hospital, The Affiliated Hospital of Nanjing Medical University, Changzhou, China
| | - Huamin Zhu
- Department of Immunology, Key Laboratory of Immune Microenvironment and Diseases, Nanjing Medical University, Nanjing, China
| | - Tongchang Xu
- Department of Immunology, Key Laboratory of Immune Microenvironment and Diseases, Nanjing Medical University, Nanjing, China
| | - Yuliang Wang
- Department of Immunology, Key Laboratory of Immune Microenvironment and Diseases, Nanjing Medical University, Nanjing, China
| | - Xiaoming Wang
- Department of Immunology, Key Laboratory of Immune Microenvironment and Diseases, Nanjing Medical University, Nanjing, China,State Key Laboratory of Reproductive Medicine, Nanjing Medical University, Nanjing, China,National Health Commission (NHC) Key Laboratory of Antibody Technique, Nanjing Medical University, Nanjing, China,*Correspondence: Xiaoming Wang, ; Zhenming Cai,
| | - Zhenming Cai
- Department of Immunology, Key Laboratory of Immune Microenvironment and Diseases, Nanjing Medical University, Nanjing, China,*Correspondence: Xiaoming Wang, ; Zhenming Cai,
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17
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Berardi A, Botrugno OA, Quilici G, Manteiga JMG, Bachi A, Tonon G, Musco G. Nizp1 is a specific
NUP98
‐
NSD1
functional interactor that regulates
NUP98
‐
NSD1
‐dependent oncogenic programs. FEBS J 2022; 290:1782-1797. [PMID: 36271682 DOI: 10.1111/febs.16664] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2022] [Revised: 09/27/2022] [Accepted: 10/21/2022] [Indexed: 11/05/2022]
Abstract
NSD1, NSD2 and NSD3 proteins constitute a family of histone 3 lysine 36 (H3K36) methyltransferases with similar domain architecture, but diversified activities, in part, dependent on their non-enzymatic domains. These domains, despite their high sequence identity, recruit the hosting proteins to different chromatin regions through the recognition of diverse epigenetic marks and/or associations to distinct interactors. In this sense, the PHDvC5HCH finger tandem domain represents a paradigmatic example of functional divergence within the NSD family. In this work, we prove and give a structural rationale for the uniqueness of the PHDvC5HCH domain of NSD1 in recognizing the C2HR Zinc finger domain of Nizp1 (NSD1 interacting Zn finger protein). Importantly, we show that, in a leukaemogenic context, Nizp1 is pivotal in driving the unscheduled expression of HoxA genes and of genes involved in the type I IFN pathway, triggered by the expression of the fusion protein NUP98-NSD1. These data provide the first insight into the pathophysiological relevance of the Nizp1-NSD1 functional association. Targeting of this interaction might open new therapeutic windows to inhibit the NUP98-NSD1 oncogenic properties.
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Affiliation(s)
- Andrea Berardi
- Biomolecular NMR, Division of Genetics and Cell Biology IRCCS Ospedale San Raffaele Milan Italy
| | - Oronza A. Botrugno
- Functional Genomics of Cancer, Division of Experimental Oncology IRCCS Ospedale San Raffaele Milan Italy
| | - Giacomo Quilici
- Biomolecular NMR, Division of Genetics and Cell Biology IRCCS Ospedale San Raffaele Milan Italy
| | | | - Angela Bachi
- Functional Proteomics Group IFOM‐FIRC Institute of Molecular Oncology Milan Italy
| | - Giovanni Tonon
- Functional Genomics of Cancer, Division of Experimental Oncology IRCCS Ospedale San Raffaele Milan Italy
| | - Giovanna Musco
- Biomolecular NMR, Division of Genetics and Cell Biology IRCCS Ospedale San Raffaele Milan Italy
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18
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Krossa I, Strub T, Aplin AE, Ballotti R, Bertolotto C. Lysine Methyltransferase NSD1 and Cancers: Any Role in Melanoma? Cancers (Basel) 2022; 14:cancers14194865. [PMID: 36230787 PMCID: PMC9563040 DOI: 10.3390/cancers14194865] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2022] [Revised: 09/27/2022] [Accepted: 09/29/2022] [Indexed: 11/23/2022] Open
Abstract
Simple Summary Epigenetic events, which comprise post-translational modifications of histone tails or DNA methylation, control gene expression by altering chromatin structure without change in the DNA sequence. Histone tails modifications are driven by specific cellular enzymes such as histone methyltransferases or histone acetylases, which play a key role in regulating diverse biological processes. Their alteration may have consequences on growth and tumorigenesis. Abstract Epigenetic regulations, that comprise histone modifications and DNA methylation, are essential to processes as diverse as development and cancer. Among the histone post-translational modifications, lysine methylation represents one of the most important dynamic marks. Here, we focused on methyltransferases of the nuclear binding SET domain 1 (NSD) family, that catalyze the mono- and di-methylation of histone H3 lysine 36. We review the loss of function mutations of NSD1 in humans that are the main cause of SOTOS syndrome, a disease associated with an increased risk of developing cancer. We then report the role of NSD1 in triggering tumor suppressive or promoter functions according to the tissue context and we discuss the role of NSD1 in melanoma. Finally, we examine the ongoing efforts to target NSD1 signaling in cancers.
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Affiliation(s)
- Imène Krossa
- Université Côte d’Azur, 06100 Nice, France
- Team 1, Biology and Pathologies of melanocytes, Inserm, Equipe labellisée Ligue 2020 and Equipe labellisée ARC 2022, Centre Méditerranéen de Médecine Moléculaire, 06200 Nice, France
- Correspondence: (I.K.); (C.B.)
| | - Thomas Strub
- Université Côte d’Azur, 06100 Nice, France
- Team 1, Biology and Pathologies of melanocytes, Inserm, Equipe labellisée Ligue 2020 and Equipe labellisée ARC 2022, Centre Méditerranéen de Médecine Moléculaire, 06200 Nice, France
| | - Andrew E. Aplin
- Department of Pharmacology, Physiology, and Cancer Biology, Thomas Jefferson University, Philadelphia, PA 19107, USA
| | - Robert Ballotti
- Université Côte d’Azur, 06100 Nice, France
- Team 1, Biology and Pathologies of melanocytes, Inserm, Equipe labellisée Ligue 2020 and Equipe labellisée ARC 2022, Centre Méditerranéen de Médecine Moléculaire, 06200 Nice, France
| | - Corine Bertolotto
- Université Côte d’Azur, 06100 Nice, France
- Team 1, Biology and Pathologies of melanocytes, Inserm, Equipe labellisée Ligue 2020 and Equipe labellisée ARC 2022, Centre Méditerranéen de Médecine Moléculaire, 06200 Nice, France
- Correspondence: (I.K.); (C.B.)
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19
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Conteduca G, Cangelosi D, Coco S, Malacarne M, Baldo C, Arado A, Pinto R, Testa B, Coviello DA. NSD1 Mutations in Sotos Syndrome Induce Differential Expression of Long Noncoding RNAs, miR646 and Genes Controlling the G2/M Checkpoint. Life (Basel) 2022; 12:life12070988. [PMID: 35888078 PMCID: PMC9324496 DOI: 10.3390/life12070988] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2022] [Revised: 06/28/2022] [Accepted: 07/01/2022] [Indexed: 12/16/2022] Open
Abstract
An increasing amount of evidence indicates the critical role of the NSD1 gene in Sotos syndrome (SoS), a rare genetic disease, and in tumors. Molecular mechanisms affected by NSD1 mutations are largely uncharacterized. In order to assess the impact of NSD1 haploinsufficiency in the pathogenesis of SoS, we analyzed the gene expression profile of fibroblasts isolated from the skin samples of 15 SoS patients and of 5 healthy parents. We identified seven differentially expressed genes and five differentially expressed noncoding RNAs. The most upregulated mRNA was stratifin (SFN) (fold change, 3.9, Benjamini−Hochberg corrected p < 0.05), and the most downregulated mRNA was goosecoid homeobox (GSC) (fold change, 3.9, Benjamini−Hochberg corrected p < 0.05). The most upregulated lncRNA was lnc-C2orf84-1 (fold change, 4.28, Benjamini−Hochberg corrected p < 0.001), and the most downregulated lncRNA was Inc-C15orf57 (fold change, −0.7, Benjamini−Hochberg corrected p < 0.05). A gene set enrichment analysis reported the enrichment of genes involved in the KRAS and E2F signaling pathways, splicing regulation and cell cycle G2/M checkpoints. Our results suggest that NSD1 is involved in cell cycle regulation and that its mutation can induce the down-expression of genes involved in tumoral and neoplastic differentiation. The results contribute to defining the role of NSD1 in fibroblasts for the prevention, diagnosis and control of SoS.
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Affiliation(s)
- Giuseppina Conteduca
- Laboratory of Human Genetics, IRCCS Istituto Giannina Gaslini, 16147 Genoa, Italy; (G.C.); (M.M.); (C.B.); (A.A.); (R.P.); (B.T.)
| | - Davide Cangelosi
- Clinical Bioinformatics Unit, IRCCS Istituto Giannina Gaslini, 16147 Genoa, Italy;
| | - Simona Coco
- Lung Cancer Unit, IRCCS Ospedale Policlinico San Martino, 16132 Genoa, Italy;
| | - Michela Malacarne
- Laboratory of Human Genetics, IRCCS Istituto Giannina Gaslini, 16147 Genoa, Italy; (G.C.); (M.M.); (C.B.); (A.A.); (R.P.); (B.T.)
| | - Chiara Baldo
- Laboratory of Human Genetics, IRCCS Istituto Giannina Gaslini, 16147 Genoa, Italy; (G.C.); (M.M.); (C.B.); (A.A.); (R.P.); (B.T.)
| | - Alessia Arado
- Laboratory of Human Genetics, IRCCS Istituto Giannina Gaslini, 16147 Genoa, Italy; (G.C.); (M.M.); (C.B.); (A.A.); (R.P.); (B.T.)
| | - Rute Pinto
- Laboratory of Human Genetics, IRCCS Istituto Giannina Gaslini, 16147 Genoa, Italy; (G.C.); (M.M.); (C.B.); (A.A.); (R.P.); (B.T.)
| | - Barbara Testa
- Laboratory of Human Genetics, IRCCS Istituto Giannina Gaslini, 16147 Genoa, Italy; (G.C.); (M.M.); (C.B.); (A.A.); (R.P.); (B.T.)
| | - Domenico A. Coviello
- Laboratory of Human Genetics, IRCCS Istituto Giannina Gaslini, 16147 Genoa, Italy; (G.C.); (M.M.); (C.B.); (A.A.); (R.P.); (B.T.)
- Correspondence: ; Tel.: +39-010-5636-3977
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20
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Lam UTF, Tan BKY, Poh JJX, Chen ES. Structural and functional specificity of H3K36 methylation. Epigenetics Chromatin 2022; 15:17. [PMID: 35581654 PMCID: PMC9116022 DOI: 10.1186/s13072-022-00446-7] [Citation(s) in RCA: 32] [Impact Index Per Article: 10.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2021] [Accepted: 04/04/2022] [Indexed: 12/20/2022] Open
Abstract
The methylation of histone H3 at lysine 36 (H3K36me) is essential for maintaining genomic stability. Indeed, this methylation mark is essential for proper transcription, recombination, and DNA damage response. Loss- and gain-of-function mutations in H3K36 methyltransferases are closely linked to human developmental disorders and various cancers. Structural analyses suggest that nucleosomal components such as the linker DNA and a hydrophobic patch constituted by histone H2A and H3 are likely determinants of H3K36 methylation in addition to the histone H3 tail, which encompasses H3K36 and the catalytic SET domain. Interaction of H3K36 methyltransferases with the nucleosome collaborates with regulation of their auto-inhibitory changes fine-tunes the precision of H3K36me in mediating dimethylation by NSD2 and NSD3 as well as trimethylation by Set2/SETD2. The identification of specific structural features and various cis-acting factors that bind to different forms of H3K36me, particularly the di-(H3K36me2) and tri-(H3K36me3) methylated forms of H3K36, have highlighted the intricacy of H3K36me functional significance. Here, we consolidate these findings and offer structural insight to the regulation of H3K36me2 to H3K36me3 conversion. We also discuss the mechanisms that underlie the cooperation between H3K36me and other chromatin modifications (in particular, H3K27me3, H3 acetylation, DNA methylation and N6-methyladenosine in RNAs) in the physiological regulation of the epigenomic functions of chromatin.
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Affiliation(s)
- Ulysses Tsz Fung Lam
- Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
| | - Bryan Kok Yan Tan
- Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
| | - John Jia Xin Poh
- Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
| | - Ee Sin Chen
- Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore.
- National University Health System (NUHS), Singapore, Singapore.
- NUS Center for Cancer Research, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore.
- Integrative Sciences & Engineering Programme, National University of Singapore, Singapore, Singapore.
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21
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Topchu I, Pangeni RP, Bychkov I, Miller SA, Izumchenko E, Yu J, Golemis E, Karanicolas J, Boumber Y. The role of NSD1, NSD2, and NSD3 histone methyltransferases in solid tumors. Cell Mol Life Sci 2022; 79:285. [PMID: 35532818 PMCID: PMC9520630 DOI: 10.1007/s00018-022-04321-2] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2022] [Revised: 04/19/2022] [Accepted: 04/20/2022] [Indexed: 11/03/2022]
Abstract
NSD1, NSD2, and NSD3 constitute the nuclear receptor-binding SET Domain (NSD) family of histone 3 lysine 36 (H3K36) methyltransferases. These structurally similar enzymes mono- and di-methylate H3K36, which contribute to the maintenance of chromatin integrity and regulate the expression of genes that control cell division, apoptosis, DNA repair, and epithelial-mesenchymal transition (EMT). Aberrant expression or mutation of members of the NSD family is associated with developmental defects and the occurrence of some types of cancer. In this review, we discuss the effect of alterations in NSDs on cancer patient's prognosis and response to treatment. We summarize the current understanding of the biological functions of NSD proteins, focusing on their activities and the role in the formation and progression in solid tumors biology, as well as how it depends on tumor etiologies. This review also discusses ongoing efforts to develop NSD inhibitors as a promising new class of cancer therapeutic agents.
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Affiliation(s)
- Iuliia Topchu
- Division of Hematology/Oncology, Department of Medicine, Robert H. Lurie Comprehensive Cancer Center, Feinberg School of Medicine, Northwestern University, 303 E. Superior Street, Chicago, IL, 60611, USA
| | - Rajendra P Pangeni
- Division of Hematology/Oncology, Department of Medicine, Robert H. Lurie Comprehensive Cancer Center, Feinberg School of Medicine, Northwestern University, 303 E. Superior Street, Chicago, IL, 60611, USA
- Department of Natural and Applied Sciences, Nexus Institute of Research and Innovation (NIRI), Sitapakha, Mahalaxmi-4, Lalitpur, Bagmati, 44700, Nepal
| | - Igor Bychkov
- Division of Hematology/Oncology, Department of Medicine, Robert H. Lurie Comprehensive Cancer Center, Feinberg School of Medicine, Northwestern University, 303 E. Superior Street, Chicago, IL, 60611, USA
| | - Sven A Miller
- Molecular Therapeutics Program, Fox Chase Cancer Center, 333 Cottman Avenue, Philadelphia, PA, 19111, USA
| | - Evgeny Izumchenko
- Department of Medicine, Section of Hematology and Oncology, University of Chicago, Chicago, IL, 60637, USA
| | - Jindan Yu
- Department of Medicine-Hematology/Oncology and Biochemistry and Molecular Genetics, Northwestern University Feinberg School of Medicine, 303 E. Superior Street, Chicago, IL, 60611, USA
| | - Erica Golemis
- Molecular Therapeutics Program, Fox Chase Cancer Center, 333 Cottman Avenue, Philadelphia, PA, 19111, USA
- Department of Cancer and Cellular Biology, Lewis Katz School of Medicine at Temple University, 3500 North Broad St, Philadelphia, PA, 19140, USA
| | - John Karanicolas
- Molecular Therapeutics Program, Fox Chase Cancer Center, 333 Cottman Avenue, Philadelphia, PA, 19111, USA
- Moulder Center for Drug Discovery Research, Temple University School of Pharmacy, Philadelphia, PA, 19140, USA
| | - Yanis Boumber
- Division of Hematology/Oncology, Department of Medicine, Robert H. Lurie Comprehensive Cancer Center, Feinberg School of Medicine, Northwestern University, 303 E. Superior Street, Chicago, IL, 60611, USA.
- Institute of Fundamental Medicine and Biology, Kazan (Volga Region) Federal University, ul. 74 Karl Marks, Kazan, 420012, Russia.
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22
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Downregulation of MEIS1 mediated by ELFN1-AS1/EZH2/DNMT3a axis promotes tumorigenesis and oxaliplatin resistance in colorectal cancer. Signal Transduct Target Ther 2022; 7:87. [PMID: 35351858 PMCID: PMC8964798 DOI: 10.1038/s41392-022-00902-6] [Citation(s) in RCA: 98] [Impact Index Per Article: 32.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2021] [Revised: 01/17/2022] [Accepted: 01/19/2022] [Indexed: 02/07/2023] Open
Abstract
Oxaliplatin is widely used in the frontline treatment of colorectal cancer (CRC), but an estimated 50% of patients will eventually stop responding to treatment due to acquired resistance. This study revealed that diminished MEIS1 expression was detected in CRC and harmed the survival of CRC patients. MEIS1 impaired CRC cell viabilities and tumor growth in mice and enhanced CRC cell sensitivity to oxaliplatin by preventing DNA damage repair. Mechanistically, oxaliplatin resistance following MEIS1 suppression was critically dependent on enhanced FEN1 expression. Subsequently, we confirmed that EZH2-DNMT3a was assisted by lncRNA ELFN1-AS1 in locating the promoter of MEIS1 to suppress MEIS1 transcription epigenetically. Based on the above, therapeutics targeting the role of MEIS1 in oxaliplatin resistance were developed and our results suggested that the combination of oxaliplatin with either ELFN1-AS1 ASO or EZH2 inhibitor GSK126 could largely suppress tumor growth and reverse oxaliplatin resistance. This study highlights the potential of therapeutics targeting ELFN1-AS1 and EZH2 in cell survival and oxaliplatin resistance, based on their controlling of MEIS1 expression, which deserve further verification as a prospective therapeutic strategy.
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23
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Bröhm A, Schoch T, Grünberger D, Khella MS, Schuhmacher MK, Weirich S, Jeltsch A. The H3.3 G34W oncohistone mutation increases K36 methylation by the protein lysine methyltransferase NSD1. Biochimie 2022; 198:86-91. [PMID: 35341929 DOI: 10.1016/j.biochi.2022.03.007] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2022] [Revised: 03/14/2022] [Accepted: 03/22/2022] [Indexed: 11/20/2022]
Abstract
The H3.3 G34W mutation has been observed in 90% of the patients affected by giant cell tumor of bone (GCTB). It had been shown to reduce the activity of the SETD2 H3K36 protein lysine methyltransferase (PKMT) and lead to genome wide changes in epigenome modifications including a global reduction in DNA methylation. Here, we investigated the effect of the H3.3 G34W mutation on the activity of the H3K36me2 methyltransferase NSD1, because NSD1 is known to play an important role in the differentiation of chondrocytes and osteoblasts. Unexpectedly, we observed that H3.3 G34W has a gain-of-function effect and it stimulates K36 methylation by NSD1 by about 2.3-fold with peptide substrates and 6.3-fold with recombinant nucleosomal substrates. This effect is specific for NSD1, as NSD2 and SETD2 show only a very mild stimulation and even reduced activity on G34W substrates. The potential downstream effects of the G34W induced hyperactivity of NSD1 on DNA methylation, H3K27me3, histone acetylation and splicing are discussed.
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Affiliation(s)
- Alexander Bröhm
- Department of Biochemistry, Institute of Biochemistry and Technical Biochemistry, University of Stuttgart, Allmandring 31, 70569, Stuttgart, Germany
| | - Tabea Schoch
- Department of Biochemistry, Institute of Biochemistry and Technical Biochemistry, University of Stuttgart, Allmandring 31, 70569, Stuttgart, Germany
| | - David Grünberger
- Department of Biochemistry, Institute of Biochemistry and Technical Biochemistry, University of Stuttgart, Allmandring 31, 70569, Stuttgart, Germany
| | - Mina S Khella
- Department of Biochemistry, Institute of Biochemistry and Technical Biochemistry, University of Stuttgart, Allmandring 31, 70569, Stuttgart, Germany; Biochemistry Department, Faculty of Pharmacy, Ain Shams University, African Union Organization Street, Abbassia, Cairo, 11566, Egypt
| | - Maren Kirstin Schuhmacher
- Department of Biochemistry, Institute of Biochemistry and Technical Biochemistry, University of Stuttgart, Allmandring 31, 70569, Stuttgart, Germany
| | - Sara Weirich
- Department of Biochemistry, Institute of Biochemistry and Technical Biochemistry, University of Stuttgart, Allmandring 31, 70569, Stuttgart, Germany
| | - Albert Jeltsch
- Department of Biochemistry, Institute of Biochemistry and Technical Biochemistry, University of Stuttgart, Allmandring 31, 70569, Stuttgart, Germany.
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Chen Y, Li X, Xu J, Xiao H, Tang C, Liang W, Zhu X, Fang Y, Wang H, Shi J. Knockdown of nuclear receptor binding SET domain-containing protein 1 (NSD1) inhibits proliferation and facilitates apoptosis in paclitaxel-resistant breast cancer cells via inactivating the Wnt/β-catenin signaling pathway. Bioengineered 2022; 13:3526-3536. [PMID: 35200072 PMCID: PMC8973718 DOI: 10.1080/21655979.2021.2018973] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
The burden of breast cancer (BC) has exacerbated over decades. Paclitaxel resistance is responsible for increasing BC treatment burden. Nuclear receptor binding SET domain-containing protein 1 (NSD1) is positively correlated with a poor prognosis in patients with BC. This study investigates the function of NSD1 in paclitaxel-resistant (PR) BC cells. The high levels of NSD1 and Wnt10b in PR BC cell lines (MCF-7/PR) or MCF-7 parental cells were determined by RT-qPCR. Western blotting was conducted to measure the levels of NSD1 protein, apoptosis-associated proteins, Wnt10b protein, H3K36me2 protein, H3K27me3 protein, and signal pathway-associated proteins in MCF-7/PR cells or MCF-7 cells or in vivo subcutaneous xenografted tumor model, and the results demonstrated that NSD1 inhibited cell apoptosis and promoted cell proliferation and tumor growth via activating Wnt/β-catenin pathway. Cell apoptosis and viability were estimated using cell counting kit-8 assays and flow cytometry. Positive correlation between NSD1 and Wnt10b was identified by chromatin immunoprecipitation assay. The distribution of β-catenin was determined by immunofluorescence assays. We conclude that NSD1 knockdown inhibits the viability and promotes the apoptosis of paclitaxel-resistant BC cells by inactivating the NSD1/H3K27me3/Wnt10b/β-catenin signaling pathway.
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Affiliation(s)
- Yi Chen
- Department of Oncology, Nanjing Pukou Central Hospital, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, China
| | - Xiao Li
- Department of Thyroid and Mammary Gland Surgery, Nanjing First Hospital, Nanjing Medical University, Nanjing, Jiangsu, China
| | - Jin Xu
- Department of Thyroid and Mammary Gland Surgery, Nanjing First Hospital, Nanjing Medical University, Nanjing, Jiangsu, China
| | - Hua Xiao
- Department of General Surgery, Nanjing First Hospital, Nanjing Medical University, Nanjing, Jiangsu, China
| | - Cuiju Tang
- Department of Oncology, Nanjing First Hospital, Nanjing Medical University, Nanjing, Jiangsu, China
| | - Wei Liang
- Department of Oncology, Nanjing First Hospital, Nanjing Medical University, Nanjing, Jiangsu, China
| | - Xuedan Zhu
- Department of Oncology, Nanjing First Hospital, Nanjing Medical University, Nanjing, Jiangsu, China
| | - Yueyu Fang
- Department of Oncology, Nanjing Pukou Central Hospital, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, China
| | - Hanjin Wang
- Department of Thyroid and Mammary Gland Surgery, Nanjing First Hospital, Nanjing Medical University, Nanjing, Jiangsu, China
| | - Junfeng Shi
- Department of Oncology, Nanjing First Hospital, Nanjing Medical University, Nanjing, Jiangsu, China
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25
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Wilson KD, Porter EG, Garcia BA. Reprogramming of the epigenome in neurodevelopmental disorders. Crit Rev Biochem Mol Biol 2022; 57:73-112. [PMID: 34601997 PMCID: PMC9462920 DOI: 10.1080/10409238.2021.1979457] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2021] [Revised: 07/23/2021] [Accepted: 09/08/2021] [Indexed: 02/03/2023]
Abstract
The etiology of neurodevelopmental disorders (NDDs) remains a challenge for researchers. Human brain development is tightly regulated and sensitive to cellular alterations caused by endogenous or exogenous factors. Intriguingly, the surge of clinical sequencing studies has revealed that many of these disorders are monogenic and monoallelic. Notably, chromatin regulation has emerged as highly dysregulated in NDDs, with many syndromes demonstrating phenotypic overlap, such as intellectual disabilities, with one another. Here we discuss epigenetic writers, erasers, readers, remodelers, and even histones mutated in NDD patients, predicted to affect gene regulation. Moreover, this review focuses on disorders associated with mutations in enzymes involved in histone acetylation and methylation, and it highlights syndromes involving chromatin remodeling complexes. Finally, we explore recently discovered histone germline mutations and their pathogenic outcome on neurological function. Epigenetic regulators are mutated at every level of chromatin organization. Throughout this review, we discuss mechanistic investigations, as well as various animal and iPSC models of these disorders and their usefulness in determining pathomechanism and potential therapeutics. Understanding the mechanism of these mutations will illuminate common pathways between disorders. Ultimately, classifying these disorders based on their effects on the epigenome will not only aid in prognosis in patients but will aid in understanding the role of epigenetic machinery throughout neurodevelopment.
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Affiliation(s)
- Khadija D Wilson
- Department of Pharmacology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
| | - Elizabeth G Porter
- Department of Biochemistry and Molecular Biophysics, University of Washington School of Medicine, St. Louis, MO, USA
| | - Benjamin A Garcia
- Department of Biochemistry and Molecular Biophysics, University of Washington School of Medicine, St. Louis, MO, USA
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26
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Shrestha A, Kim N, Lee SJ, Jeon YH, Song JJ, An H, Cho SJ, Kadayat TM, Chin J. Targeting the Nuclear Receptor-Binding SET Domain Family of Histone Lysine Methyltransferases for Cancer Therapy: Recent Progress and Perspectives. J Med Chem 2021; 64:14913-14929. [PMID: 34488340 DOI: 10.1021/acs.jmedchem.1c01116] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]
Abstract
Nuclear receptor-binding SET domain (NSD) proteins are a class of histone lysine methyltransferases (HKMTases) that are amplified, mutated, translocated, or overexpressed in various types of cancers. Several campaigns to develop NSD inhibitors for cancer treatment have begun following recent advances in knowledge of NSD1, NSD2, and NSD3 structures and functions as well as the U.S. FDA approval of the first HKMTase inhibitor (tazemetostat, an EZH2 inhibitor) to treat follicular lymphoma and epithelioid sarcoma. This perspective highlights recent findings on the structures of catalytic su(var), enhancer-of-zeste, trithorax (SET) domains and other functional domains of NSD methyltransferases. In addition, recent progress and efforts to discover NSD-specific small molecule inhibitors against cancer-targeting catalytic SET domains, plant homeodomains, and proline-tryptophan-tryptophan-proline domains are summarized.
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Affiliation(s)
- Aarajana Shrestha
- New Drug Development Center, Daegu-Gyeongbuk Medical Innovation Foundation (DGMIF), Daegu 41061, Republic of Korea
| | - Nayeon Kim
- New Drug Development Center, Daegu-Gyeongbuk Medical Innovation Foundation (DGMIF), Daegu 41061, Republic of Korea
| | - Su-Jeong Lee
- New Drug Development Center, Daegu-Gyeongbuk Medical Innovation Foundation (DGMIF), Daegu 41061, Republic of Korea
| | - Yong Hyun Jeon
- Laboratory Animal Center, Daegu-Gyeongbuk Medical Innovation Foundation (DGMIF), Daegu 41061, Republic of Korea
| | - Ji-Joon Song
- Department of Biological Sciences, Korea Advanced Institute of Science and Technology (KAIST), Daejeon 34141, Republic of Korea
| | - Hongchan An
- New Drug Development Center, Daegu-Gyeongbuk Medical Innovation Foundation (DGMIF), Daegu 41061, Republic of Korea
| | - Sung Jin Cho
- Convergence Research Center for Diagnosis, Treatment and Care System of Dementia, Korea Institute of Science and Technology, Seoul 02792, Republic of Korea
| | - Tara Man Kadayat
- New Drug Development Center, Daegu-Gyeongbuk Medical Innovation Foundation (DGMIF), Daegu 41061, Republic of Korea
| | - Jungwook Chin
- New Drug Development Center, Daegu-Gyeongbuk Medical Innovation Foundation (DGMIF), Daegu 41061, Republic of Korea
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27
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Yang C, Wang K, Liang Q, Tian TT, Zhong Z. Role of NSD1 as potential therapeutic target in tumor. Pharmacol Res 2021; 173:105888. [PMID: 34536546 DOI: 10.1016/j.phrs.2021.105888] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/03/2021] [Revised: 09/10/2021] [Accepted: 09/12/2021] [Indexed: 12/29/2022]
Abstract
Nuclear receptor binding SET Domain Protein 1 (NSD1) is a bifunctional transcriptional regulatory protein that encodes histone methyltransferase. Mono- and di-methylation of H3K36 by NSD1 is mainly primarily involved in the regulation of gene expression, DNA repair, alternative splicing, and other important biological processes. Many types of cancers, including acute myelogenous leukemia (AML), liver cancer, lung cancer, endometrial carcinoma, colorectal cancer, and pancreatic cancer, are associated with NSD1 fusion, missense mutation, nonsense mutation, silent mutation, deletion, and insertion of frameshift, and deletion in a frame. Therefore, targeting NSD1 may be a potential strategy for tumor therapy. An in-depth study of the structure and biological activities of NSD1 sets the groundwork for improving tumor therapy and creating NSD1 inhibitors. This article emphasizes the role of NSD1 in tumorigenesis and the development of NSD1 targeted small-molecule inhibitors.
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Affiliation(s)
- Chao Yang
- National Engineering Research Center for Marine Aquaculture, Institute of Innovation & Application, Zhejiang Ocean University, Zhoushan, Zhejiang Province 316022, China
| | - Kai Wang
- Key Laboratory of Epigenetics and Oncology, The Research Center for Preclinical Medicine, Southwest Medical University, Luzhou, Sichuan Province 646000, China
| | - Qilian Liang
- Oncology Center, Affiliated Hospital of Guangdong Medical University, Zhanjiang, Guangdong Province 524001, China
| | - Tian-Tian Tian
- Center for Biological Science and Technology, Beijing Normal University, Zhuhai, Guangdong Province 519087, China.
| | - Zhangfeng Zhong
- Macau Centre for Research and Development in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macao SAR 999078, China.
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28
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López V, Tejedor JR, Carella A, García MG, Santamarina-Ojeda P, Pérez RF, Mangas C, Urdinguio RG, Aranburu A, de la Nava D, Corte-Torres MD, Astudillo A, Mollejo M, Meléndez B, Fernández AF, Fraga MF. Epigenetic Deregulation of the Histone Methyltransferase KMT5B Contributes to Malignant Transformation in Glioblastoma. Front Cell Dev Biol 2021; 9:671838. [PMID: 34447744 PMCID: PMC8383299 DOI: 10.3389/fcell.2021.671838] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2021] [Accepted: 07/15/2021] [Indexed: 01/18/2023] Open
Abstract
Glioblastoma multiforme (GBM) is the most common and aggressive type of brain tumor in adulthood. Epigenetic mechanisms are known to play a key role in GBM although the involvement of histone methyltransferase KMT5B and its mark H4K20me2 has remained largely unexplored. The present study shows that DNA hypermethylation and loss of DNA hydroxymethylation is associated with KMT5B downregulation and genome-wide reduction of H4K20me2 levels in a set of human GBM samples and cell lines as compared with non-tumoral specimens. Ectopic overexpression of KMT5B induced tumor suppressor-like features in vitro and in a mouse tumor xenograft model, as well as changes in the expression of several glioblastoma-related genes. H4K20me2 enrichment was found immediately upstream of the promoter regions of a subset of deregulated genes, thus suggesting a possible role for KMT5B in GBM through the epigenetic modulation of key target cancer genes.
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Affiliation(s)
- Virginia López
- Cancer Epigenetics and Nanomedicine Laboratory, Department of Organisms and Systems Biology, Nanomaterials and Nanotechnology Research Center (CINN-CSIC), Health Research Institute of Asturias (ISPA), Institute of Oncology of Asturias (IUOPA), Rare Diseases CIBER (CIBERER) of the Carlos III Health Institute (ISCIII), University of Oviedo, Oviedo, Spain
| | - Juan Ramón Tejedor
- Cancer Epigenetics and Nanomedicine Laboratory, Department of Organisms and Systems Biology, Nanomaterials and Nanotechnology Research Center (CINN-CSIC), Health Research Institute of Asturias (ISPA), Institute of Oncology of Asturias (IUOPA), Rare Diseases CIBER (CIBERER) of the Carlos III Health Institute (ISCIII), University of Oviedo, Oviedo, Spain
| | - Antonella Carella
- Cancer Epigenetics and Nanomedicine Laboratory, Department of Organisms and Systems Biology, Nanomaterials and Nanotechnology Research Center (CINN-CSIC), Health Research Institute of Asturias (ISPA), Institute of Oncology of Asturias (IUOPA), Rare Diseases CIBER (CIBERER) of the Carlos III Health Institute (ISCIII), University of Oviedo, Oviedo, Spain
| | - María G García
- Cancer Epigenetics and Nanomedicine Laboratory, Department of Organisms and Systems Biology, Nanomaterials and Nanotechnology Research Center (CINN-CSIC), Health Research Institute of Asturias (ISPA), Institute of Oncology of Asturias (IUOPA), Rare Diseases CIBER (CIBERER) of the Carlos III Health Institute (ISCIII), University of Oviedo, Oviedo, Spain
| | - Pablo Santamarina-Ojeda
- Cancer Epigenetics and Nanomedicine Laboratory, Department of Organisms and Systems Biology, Nanomaterials and Nanotechnology Research Center (CINN-CSIC), Health Research Institute of Asturias (ISPA), Institute of Oncology of Asturias (IUOPA), Rare Diseases CIBER (CIBERER) of the Carlos III Health Institute (ISCIII), University of Oviedo, Oviedo, Spain
| | - Raúl F Pérez
- Cancer Epigenetics and Nanomedicine Laboratory, Department of Organisms and Systems Biology, Nanomaterials and Nanotechnology Research Center (CINN-CSIC), Health Research Institute of Asturias (ISPA), Institute of Oncology of Asturias (IUOPA), Rare Diseases CIBER (CIBERER) of the Carlos III Health Institute (ISCIII), University of Oviedo, Oviedo, Spain
| | - Cristina Mangas
- Cancer Epigenetics and Nanomedicine Laboratory, Department of Organisms and Systems Biology, Nanomaterials and Nanotechnology Research Center (CINN-CSIC), Health Research Institute of Asturias (ISPA), Institute of Oncology of Asturias (IUOPA), Rare Diseases CIBER (CIBERER) of the Carlos III Health Institute (ISCIII), University of Oviedo, Oviedo, Spain
| | - Rocío G Urdinguio
- Cancer Epigenetics and Nanomedicine Laboratory, Department of Organisms and Systems Biology, Nanomaterials and Nanotechnology Research Center (CINN-CSIC), Health Research Institute of Asturias (ISPA), Institute of Oncology of Asturias (IUOPA), Rare Diseases CIBER (CIBERER) of the Carlos III Health Institute (ISCIII), University of Oviedo, Oviedo, Spain
| | - Aitziber Aranburu
- Cancer Epigenetics and Nanomedicine Laboratory, Department of Organisms and Systems Biology, Nanomaterials and Nanotechnology Research Center (CINN-CSIC), Health Research Institute of Asturias (ISPA), Institute of Oncology of Asturias (IUOPA), Rare Diseases CIBER (CIBERER) of the Carlos III Health Institute (ISCIII), University of Oviedo, Oviedo, Spain
| | - Daniel de la Nava
- Cancer Epigenetics and Nanomedicine Laboratory, Department of Organisms and Systems Biology, Nanomaterials and Nanotechnology Research Center (CINN-CSIC), Health Research Institute of Asturias (ISPA), Institute of Oncology of Asturias (IUOPA), Rare Diseases CIBER (CIBERER) of the Carlos III Health Institute (ISCIII), University of Oviedo, Oviedo, Spain
| | - María D Corte-Torres
- Biobanco del Principado de Asturias, Hospital Universitario Central de Asturias (HUCA), Oviedo, Spain
| | - Aurora Astudillo
- Departamento de Anatomía Patológica, Hospital Universitario Central de Asturias (HUCA), Oviedo, Spain
| | - Manuela Mollejo
- Departamento de Patología, Hospital Virgen de la Salud (CHT), Toledo, Spain
| | - Bárbara Meléndez
- Departamento de Patología, Hospital Virgen de la Salud (CHT), Toledo, Spain
| | - Agustín F Fernández
- Cancer Epigenetics and Nanomedicine Laboratory, Department of Organisms and Systems Biology, Nanomaterials and Nanotechnology Research Center (CINN-CSIC), Health Research Institute of Asturias (ISPA), Institute of Oncology of Asturias (IUOPA), Rare Diseases CIBER (CIBERER) of the Carlos III Health Institute (ISCIII), University of Oviedo, Oviedo, Spain
| | - Mario F Fraga
- Cancer Epigenetics and Nanomedicine Laboratory, Department of Organisms and Systems Biology, Nanomaterials and Nanotechnology Research Center (CINN-CSIC), Health Research Institute of Asturias (ISPA), Institute of Oncology of Asturias (IUOPA), Rare Diseases CIBER (CIBERER) of the Carlos III Health Institute (ISCIII), University of Oviedo, Oviedo, Spain
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29
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Tauchmann S, Schwaller J. NSD1: A Lysine Methyltransferase between Developmental Disorders and Cancer. Life (Basel) 2021; 11:life11090877. [PMID: 34575025 PMCID: PMC8465848 DOI: 10.3390/life11090877] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2021] [Revised: 08/16/2021] [Accepted: 08/23/2021] [Indexed: 01/25/2023] Open
Abstract
Recurrent epigenomic alterations associated with multiple human pathologies have increased the interest in the nuclear receptor binding SET domain protein 1 (NSD1) lysine methyltransferase. Here, we review the current knowledge about the biochemistry, cellular function and role of NSD1 in human diseases. Several studies have shown that NSD1 controls gene expression by methylation of lysine 36 of histone 3 (H3K36me1/2) in a complex crosstalk with de novo DNA methylation. Inactivation in flies and mice revealed that NSD1 is essential for normal development and that it regulates multiple cell type-specific functions by interfering with transcriptional master regulators. In humans, putative loss of function NSD1 mutations characterize developmental syndromes, such as SOTOS, as well as cancer from different organs. In pediatric hematological malignancies, a recurrent chromosomal translocation forms a NUP98-NSD1 fusion with SET-dependent leukemogenic activity, which seems targetable by small molecule inhibitors. To treat or prevent diseases driven by aberrant NSD1 activity, future research will need to pinpoint the mechanistic correlation between the NSD1 gene dosage and/or mutational status with development, homeostasis, and malignant transformation.
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30
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Chromatin insulation dynamics in glioblastoma: challenges and future perspectives of precision oncology. Clin Epigenetics 2021; 13:150. [PMID: 34332627 PMCID: PMC8325855 DOI: 10.1186/s13148-021-01139-w] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2021] [Accepted: 07/23/2021] [Indexed: 12/13/2022] Open
Abstract
Glioblastoma (GBM) is the most aggressive primary brain tumor, having a poor prognosis and a median overall survival of less than two years. Over the last decade, numerous findings regarding the distinct molecular and genetic profiles of GBM have led to the emergence of several therapeutic approaches. Unfortunately, none of them has proven to be effective against GBM progression and recurrence. Epigenetic mechanisms underlying GBM tumor biology, including histone modifications, DNA methylation, and chromatin architecture, have become an attractive target for novel drug discovery strategies. Alterations on chromatin insulator elements (IEs) might lead to aberrant chromatin remodeling via DNA loop formation, causing oncogene reactivation in several types of cancer, including GBM. Importantly, it is shown that mutations affecting the isocitrate dehydrogenase (IDH) 1 and 2 genes, one of the most frequent genetic alterations in gliomas, lead to genome-wide DNA hypermethylation and the consequent IE dysfunction. The relevance of IEs has also been observed in a small population of cancer stem cells known as glioma stem cells (GSCs), which are thought to participate in GBM tumor initiation and drug resistance. Recent studies revealed that epigenomic alterations, specifically chromatin insulation and DNA loop formation, play a crucial role in establishing and maintaining the GSC transcriptional program. This review focuses on the relevance of IEs in GBM biology and their implementation as a potential theranostic target to stratify GBM patients and develop novel therapeutic approaches. We will also discuss the state-of-the-art emerging technologies using big data analysis and how they will settle the bases on future diagnosis and treatment strategies in GBM patients.
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31
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Laliotis GI, Chavdoula E, Paraskevopoulou MD, Kaba A, La Ferlita A, Singh S, Anastas V, Nair KA, Orlacchio A, Taraslia V, Vlachos I, Capece M, Hatzigeorgiou A, Palmieri D, Tsatsanis C, Alaimo S, Sehgal L, Carbone DP, Coppola V, Tsichlis PN. AKT3-mediated IWS1 phosphorylation promotes the proliferation of EGFR-mutant lung adenocarcinomas through cell cycle-regulated U2AF2 RNA splicing. Nat Commun 2021; 12:4624. [PMID: 34330897 PMCID: PMC8324843 DOI: 10.1038/s41467-021-24795-1] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2020] [Accepted: 03/05/2021] [Indexed: 02/06/2023] Open
Abstract
AKT-phosphorylated IWS1 regulates alternative RNA splicing via a pathway that is active in lung cancer. RNA-seq studies in lung adenocarcinoma cells lacking phosphorylated IWS1, identified a exon 2-deficient U2AF2 splice variant. Here, we show that exon 2 inclusion in the U2AF2 mRNA is a cell cycle-dependent process that is regulated by LEDGF/SRSF1 splicing complexes, whose assembly is controlled by the IWS1 phosphorylation-dependent deposition of histone H3K36me3 marks in the body of target genes. The exon 2-deficient U2AF2 mRNA encodes a Serine-Arginine-Rich (RS) domain-deficient U2AF65, which is defective in CDCA5 pre-mRNA processing. This results in downregulation of the CDCA5-encoded protein Sororin, a phosphorylation target and regulator of ERK, G2/M arrest and impaired cell proliferation and tumor growth. Analysis of human lung adenocarcinomas, confirmed activation of the pathway in EGFR-mutant tumors and showed that pathway activity correlates with tumor stage, histologic grade, metastasis, relapse after treatment, and poor prognosis.
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Affiliation(s)
- Georgios I Laliotis
- Department of Cancer Biology and Genetics, The Ohio State University, Columbus, OH, USA.
- The Ohio State University Comprehensive Cancer Center-Arthur G. James Cancer Hospital and Richard J. Solove Research Institute, Columbus, OH, USA.
- School of Medicine, University of Crete, Heraklion, Crete, Greece.
- Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins School of Medicine, Baltimore, MD, USA.
| | - Evangelia Chavdoula
- Department of Cancer Biology and Genetics, The Ohio State University, Columbus, OH, USA
- The Ohio State University Comprehensive Cancer Center-Arthur G. James Cancer Hospital and Richard J. Solove Research Institute, Columbus, OH, USA
| | | | - Abdul Kaba
- Department of Cancer Biology and Genetics, The Ohio State University, Columbus, OH, USA
- The Ohio State University Comprehensive Cancer Center-Arthur G. James Cancer Hospital and Richard J. Solove Research Institute, Columbus, OH, USA
| | - Alessandro La Ferlita
- Department of Cancer Biology and Genetics, The Ohio State University, Columbus, OH, USA
- The Ohio State University Comprehensive Cancer Center-Arthur G. James Cancer Hospital and Richard J. Solove Research Institute, Columbus, OH, USA
- Department of Clinical and Experimental Medicine, Bioinformatics Unit, University of Catania, Catania, Italy
| | - Satishkumar Singh
- The Ohio State University Comprehensive Cancer Center-Arthur G. James Cancer Hospital and Richard J. Solove Research Institute, Columbus, OH, USA
- Department of Medicine, Division of Hematology, The Ohio State University, Columbus, OH, USA
| | - Vollter Anastas
- Department of Cancer Biology and Genetics, The Ohio State University, Columbus, OH, USA
- The Ohio State University Comprehensive Cancer Center-Arthur G. James Cancer Hospital and Richard J. Solove Research Institute, Columbus, OH, USA
- Tufts Graduate School of Biomedical Sciences, Program in Genetics, Boston, MA, USA
| | - Keith A Nair
- Department of Cancer Biology and Genetics, The Ohio State University, Columbus, OH, USA
- The Ohio State University Comprehensive Cancer Center-Arthur G. James Cancer Hospital and Richard J. Solove Research Institute, Columbus, OH, USA
| | - Arturo Orlacchio
- Department of Cancer Biology and Genetics, The Ohio State University, Columbus, OH, USA
- The Ohio State University Comprehensive Cancer Center-Arthur G. James Cancer Hospital and Richard J. Solove Research Institute, Columbus, OH, USA
| | - Vasiliki Taraslia
- Molecular Oncology Research Institute, Tufts Medical Center, Boston, MA, USA
- Center of Basic Research, Biomedical Research Foundation of the Academy of Athens, Athens, Greece
| | - Ioannis Vlachos
- DIANA-Lab, Hellenic Pasteur Institute, Athens, Greece
- Department Of Pathology, Beth Israel-Deaconess Medical Center, Harvard Medical School, Boston, MA, USA
| | - Marina Capece
- Department of Cancer Biology and Genetics, The Ohio State University, Columbus, OH, USA
- The Ohio State University Comprehensive Cancer Center-Arthur G. James Cancer Hospital and Richard J. Solove Research Institute, Columbus, OH, USA
| | | | - Dario Palmieri
- Department of Cancer Biology and Genetics, The Ohio State University, Columbus, OH, USA
- The Ohio State University Comprehensive Cancer Center-Arthur G. James Cancer Hospital and Richard J. Solove Research Institute, Columbus, OH, USA
| | - Christos Tsatsanis
- School of Medicine, University of Crete, Heraklion, Crete, Greece
- Institute of Molecular Biology and Biotechnology, Foundation for Research and Technology Hellas, Heraklion, Crete, Greece
| | - Salvatore Alaimo
- Department of Clinical and Experimental Medicine, Bioinformatics Unit, University of Catania, Catania, Italy
| | - Lalit Sehgal
- The Ohio State University Comprehensive Cancer Center-Arthur G. James Cancer Hospital and Richard J. Solove Research Institute, Columbus, OH, USA
- Department of Medicine, Division of Hematology, The Ohio State University, Columbus, OH, USA
| | - David P Carbone
- The Ohio State University Comprehensive Cancer Center-Arthur G. James Cancer Hospital and Richard J. Solove Research Institute, Columbus, OH, USA
- Department of Internal Medicine, Division of Medical Oncology, The Ohio State University Medical Center, Columbus, OH, USA
| | - Vincenzo Coppola
- Department of Cancer Biology and Genetics, The Ohio State University, Columbus, OH, USA
- The Ohio State University Comprehensive Cancer Center-Arthur G. James Cancer Hospital and Richard J. Solove Research Institute, Columbus, OH, USA
| | - Philip N Tsichlis
- Department of Cancer Biology and Genetics, The Ohio State University, Columbus, OH, USA.
- The Ohio State University Comprehensive Cancer Center-Arthur G. James Cancer Hospital and Richard J. Solove Research Institute, Columbus, OH, USA.
- Tufts Graduate School of Biomedical Sciences, Program in Genetics, Boston, MA, USA.
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32
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Zhang M, Yang Y, Zhou M, Dong A, Yan X, Loppnau P, Min J, Liu Y. Histone and DNA binding ability studies of the NSD subfamily of PWWP domains. Biochem Biophys Res Commun 2021; 569:199-206. [PMID: 34271259 DOI: 10.1016/j.bbrc.2021.07.017] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2021] [Accepted: 07/06/2021] [Indexed: 10/20/2022]
Abstract
The NSD proteins, namely NSD1, NSD2 and NSD3, are lysine methyltransferases, which catalyze mono- and di-methylation of histone H3K36. They are multi-domain proteins, including two PWWP domains (PWWP1 and PWWP2) separated by some other domains. These proteins act as potent oncoproteins and are implicated in various cancers. However the biological functions of these PWWP domains are still largely unknown. To better understand the functions of these proteins' PWWP domains, we cloned, expressed and purified all the PWWP domains of these NSD proteins to characterize their interactions with methylated histone peptides and dsDNA by quantitative binding assays and crystallographic analysis. Our studies indicate that all these PWWP domains except NSD1_PWWP1 bind to trimethylated H3K36, H3K79 peptides and dsDNA weakly. Our crystal structures uncover that the NDS3_PWWP2 and NSD2_PWWP1 domains, which hold an extremely long α-helix and α-helix bundle, respectively, need a conformation adjustment to interact with nucleosome.
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Affiliation(s)
- Mengmeng Zhang
- College of Pharmaceutical Sciences, Soochow University, Suzhou, Jiangsu, China
| | - Yinxue Yang
- College of Pharmaceutical Sciences, Soochow University, Suzhou, Jiangsu, China
| | - Mengqi Zhou
- Hubei Key Laboratory of Genetic Regulation and Integrative Biology, School of Life Sciences, Central China Normal University, Wuhan, Hubei, China; Structural Genomics Consortium, University of Toronto, Toronto, Ontario, Canada
| | - Aiping Dong
- Structural Genomics Consortium, University of Toronto, Toronto, Ontario, Canada
| | - Xuemei Yan
- College of Pharmaceutical Sciences, Soochow University, Suzhou, Jiangsu, China
| | - Peter Loppnau
- Hubei Key Laboratory of Genetic Regulation and Integrative Biology, School of Life Sciences, Central China Normal University, Wuhan, Hubei, China
| | - Jinrong Min
- Hubei Key Laboratory of Genetic Regulation and Integrative Biology, School of Life Sciences, Central China Normal University, Wuhan, Hubei, China; Structural Genomics Consortium, University of Toronto, Toronto, Ontario, Canada; Department of Physiology, University of Toronto, Toronto, Ontario, Canada.
| | - Yanli Liu
- College of Pharmaceutical Sciences, Soochow University, Suzhou, Jiangsu, China.
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33
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Velasco G, Ulveling D, Rondeau S, Marzin P, Unoki M, Cormier-Daire V, Francastel C. Interplay between Histone and DNA Methylation Seen through Comparative Methylomes in Rare Mendelian Disorders. Int J Mol Sci 2021; 22:3735. [PMID: 33916664 PMCID: PMC8038329 DOI: 10.3390/ijms22073735] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2021] [Revised: 03/30/2021] [Accepted: 04/01/2021] [Indexed: 12/13/2022] Open
Abstract
DNA methylation (DNAme) profiling is used to establish specific biomarkers to improve the diagnosis of patients with inherited neurodevelopmental disorders and to guide mutation screening. In the specific case of mendelian disorders of the epigenetic machinery, it also provides the basis to infer mechanistic aspects with regard to DNAme determinants and interplay between histone and DNAme that apply to humans. Here, we present comparative methylomes from patients with mutations in the de novo DNA methyltransferases DNMT3A and DNMT3B, in their catalytic domain or their N-terminal parts involved in reading histone methylation, or in histone H3 lysine (K) methylases NSD1 or SETD2 (H3 K36) or KMT2D/MLL2 (H3 K4). We provide disease-specific DNAme signatures and document the distinct consequences of mutations in enzymes with very similar or intertwined functions, including at repeated sequences and imprinted loci. We found that KMT2D and SETD2 germline mutations have little impact on DNAme profiles. In contrast, the overlapping DNAme alterations downstream of NSD1 or DNMT3 mutations underlines functional links, more specifically between NSD1 and DNMT3B at heterochromatin regions or DNMT3A at regulatory elements. Together, these data indicate certain discrepancy with the mechanisms described in animal models or the existence of redundant or complementary functions unforeseen in humans.
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Affiliation(s)
- Guillaume Velasco
- Université de Paris, Epigenetics and Cell Fate, CNRS UMR7216, 75013 Paris, France; (G.V.); (D.U.)
| | - Damien Ulveling
- Université de Paris, Epigenetics and Cell Fate, CNRS UMR7216, 75013 Paris, France; (G.V.); (D.U.)
| | - Sophie Rondeau
- Imagine Institute, Université de Paris, Clinical Genetics, INSERM UMR 1163, Necker Enfants Malades Hospital, 75015 Paris, France; (S.R.); (P.M.); (V.C.-D.)
| | - Pauline Marzin
- Imagine Institute, Université de Paris, Clinical Genetics, INSERM UMR 1163, Necker Enfants Malades Hospital, 75015 Paris, France; (S.R.); (P.M.); (V.C.-D.)
| | - Motoko Unoki
- Division of Epigenomics and Development, Medical Institute of Bioregulation, Kyushu University, Fukuoka 812-8582, Japan;
| | - Valérie Cormier-Daire
- Imagine Institute, Université de Paris, Clinical Genetics, INSERM UMR 1163, Necker Enfants Malades Hospital, 75015 Paris, France; (S.R.); (P.M.); (V.C.-D.)
| | - Claire Francastel
- Université de Paris, Epigenetics and Cell Fate, CNRS UMR7216, 75013 Paris, France; (G.V.); (D.U.)
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34
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Yamaguchi M, Lee IS, Jantrapirom S, Suda K, Yoshida H. Drosophila models to study causative genes for human rare intractable neurological diseases. Exp Cell Res 2021; 403:112584. [PMID: 33812867 DOI: 10.1016/j.yexcr.2021.112584] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2021] [Revised: 03/25/2021] [Accepted: 03/27/2021] [Indexed: 12/11/2022]
Abstract
Drosophila is emerging as a convenient model for investigating human diseases. Functional homologues of almost 75% of human disease-related genes are found in Drosophila. Amyotrophic lateral sclerosis (ALS) is a severe neurodegenerative disease that causes defects in motoneurons. Charcot-Marie-Tooth disease (CMT) is one of the most commonly found inherited neuropathies affecting both motor and sensory neurons. No effective therapy has been established for either of these diseases. In this review, after overviewing ALS, Drosophila models targeting several ALS-causing genes, including TDP-43, FUS and Ubiquilin2, are described with their genetic interactants. Then, after overviewing CMT, examples of Drosophila models targeting several CMT-causing genes, including mitochondria-related genes and FIG 4, are also described with their genetic interactants. In addition, we introduce Sotos syndrome caused by mutations in the epigenetic regulator gene NSD1. Lastly, several genes and pathways that commonly interact with ALS- and/or CMT-causing genes are described. In the case of ALS and CMT that have many causative genes, it may be not practical to perform gene therapy for each of the many disease-causing genes. The possible uses of the common genes and pathways as novel diagnosis markers and effective therapeutic targets are discussed.
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Affiliation(s)
- Masamitsu Yamaguchi
- Department of Applied Biology, Kyoto Institute of Technology, Matsugasaki, Sakyo-ku, Kyoto, 606-8585, Japan; Kansai Gakken Laboratory, Kankyo Eisei Yakuhin Co. Ltd., Seika-cho, Kyoto, 619-0237, Japan
| | - Im-Soon Lee
- Department of Biological Sciences, Konkuk University, Seoul, Republic of Korea
| | - Salinee Jantrapirom
- Department of Pharmacology, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand
| | - Kojiro Suda
- Department of Applied Biology, Kyoto Institute of Technology, Matsugasaki, Sakyo-ku, Kyoto, 606-8585, Japan
| | - Hideki Yoshida
- Department of Applied Biology, Kyoto Institute of Technology, Matsugasaki, Sakyo-ku, Kyoto, 606-8585, Japan.
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35
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Gİrgİn B, KaradaĞ-Alpaslan M, KocabaŞ F. Oncogenic and tumor suppressor function of MEIS and associated factors. ACTA ACUST UNITED AC 2021; 44:328-355. [PMID: 33402862 PMCID: PMC7759197 DOI: 10.3906/biy-2006-25] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2020] [Accepted: 08/13/2020] [Indexed: 12/14/2022]
Abstract
MEIS proteins are historically associated with tumorigenesis, metastasis, and invasion in cancer. MEIS and associated PBX-HOX proteins may act as tumor suppressors or oncogenes in different cellular settings. Their expressions tend to be misregulated in various cancers. Bioinformatic analyses have suggested their upregulation in leukemia/lymphoma, thymoma, pancreas, glioma, and glioblastoma, and downregulation in cervical, uterine, rectum, and colon cancers. However, every cancer type includes, at least, a subtype with high MEIS expression. In addition, studies have highlighted that MEIS proteins and associated factors may function as diagnostic or therapeutic biomarkers for various diseases. Herein, MEIS proteins and associated factors in tumorigenesis are discussed with recent discoveries in addition to how they could be modulated by noncoding RNAs or newly developed small-molecule MEIS inhibitors.
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Affiliation(s)
- Birkan Gİrgİn
- Regenerative Biology Research Laboratory, Department of Genetics and Bioengineering, Faculty of Engineering, Yeditepe University, İstanbul Turkey.,Graduate School of Natural and Applied Sciences, Yeditepe University, İstanbul Turkey.,Meinox Pharma Technologies, İstanbul Turkey
| | - Medine KaradaĞ-Alpaslan
- Department of Medical Genetics, Faculty of Medicine, Ondokuz Mayıs University, Samsun Turkey
| | - Fatih KocabaŞ
- Regenerative Biology Research Laboratory, Department of Genetics and Bioengineering, Faculty of Engineering, Yeditepe University, İstanbul Turkey.,Graduate School of Natural and Applied Sciences, Yeditepe University, İstanbul Turkey.,Meinox Pharma Technologies, İstanbul Turkey
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36
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Uddin MS, Mamun AA, Alghamdi BS, Tewari D, Jeandet P, Sarwar MS, Ashraf GM. Epigenetics of glioblastoma multiforme: From molecular mechanisms to therapeutic approaches. Semin Cancer Biol 2020; 83:100-120. [PMID: 33370605 DOI: 10.1016/j.semcancer.2020.12.015] [Citation(s) in RCA: 111] [Impact Index Per Article: 22.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2020] [Revised: 12/21/2020] [Accepted: 12/22/2020] [Indexed: 02/07/2023]
Abstract
Glioblastoma multiforme (GBM) is the most common form of brain cancer and one of the most aggressive cancers found in humans. Most of the signs and symptoms of GBM can be mild and slowly aggravated, although other symptoms might demonstrate it as an acute ailment. However, the precise mechanisms of the development of GBM remain unknown. Due to the improvement of molecular pathology, current researches have reported that glioma progression is strongly connected with different types of epigenetic phenomena, such as histone modifications, DNA methylation, chromatin remodeling, and aberrant microRNA. Furthermore, the genes and the proteins that control these alterations have become novel targets for treating glioma because of the reversibility of epigenetic modifications. In some cases, gene mutations including P16, TP53, and EGFR, have been observed in GBM. In contrast, monosomies, including removals of chromosome 10, particularly q23 and q25-26, are considered the standard markers for determining the development and aggressiveness of GBM. Recently, amid the epigenetic therapies, histone deacetylase inhibitors (HDACIs) and DNA methyltransferase inhibitors have been used for treating tumors, either single or combined. Specifically, HDACIs are served as a good choice and deliver a novel pathway to treat GBM. In this review, we focus on the epigenetics of GBM and the consequence of its mutations. We also highlight various treatment approaches, namely gene editing, epigenetic drugs, and microRNAs to combat GBM.
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Affiliation(s)
- Md Sahab Uddin
- Department of Pharmacy, Southeast University, Dhaka, Bangladesh; Pharmakon Neuroscience Research Network, Dhaka, Bangladesh
| | - Abdullah Al Mamun
- Teaching and Research Division, School of Chinese Medicine, Hong Kong Baptist University, 7 Baptist University Road, Kowloon Tong, Kowloon, Hong Kong Special Administrative Region
| | - Badrah S Alghamdi
- Department of Physiology, Neuroscience Unit, Faculty of Medicine, King Abdulaziz University, Jeddah, Saudi Arabia; Pre-Clinical Research Unit, King Fahd Medical Research Center, King Abdulaziz University, Jeddah, Saudi Arabia
| | - Devesh Tewari
- Department of Pharmacognosy, School of Pharmaceutical Sciences, Lovely Professional University, Phagwara, Punjab, India
| | - Philippe Jeandet
- Research Unit, Induced Resistance and Plant Bioprotection, EA 4707, SFR Condorcet FR CNRS 3417, Faculty of Sciences, University of Reims Champagne-Ardenne, PO Box 1039, 51687, Reims Cedex 2, France
| | - Md Shahid Sarwar
- Department of Pharmacy, Noakhali Science and Technology University, Noakhali-3814, Bangladesh
| | - Ghulam Md Ashraf
- Pre-Clinical Research Unit, King Fahd Medical Research Center, King Abdulaziz University, Jeddah, Saudi Arabia; Department of Medical Laboratory Technology, Faculty of Applied Medical Sciences, King Abdulaziz University, Jeddah, Saudi Arabia.
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37
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Use of DNA methylation profiling in translational oncology. Semin Cancer Biol 2020; 83:523-535. [PMID: 33352265 DOI: 10.1016/j.semcancer.2020.12.011] [Citation(s) in RCA: 32] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2020] [Revised: 12/09/2020] [Accepted: 12/10/2020] [Indexed: 02/06/2023]
Abstract
DNA methylation is a highly regulated process that has a critical role in human development and homeostatic control of the cell. The number of genes affected by anomalous DNA methylation in cancer-associated pathways is swiftly accelerating and with the advancement of molecular technologies, new layers of complexity are opening up and refining our strategies to combat cancer. DNA methylation profiling is an essential facet to understanding malignant transformation and is becoming an increasingly important tool for cancer diagnosis, prognosis and therapy monitoring. In this review, the role of DNA methylation in normal cellular function is discussed, as well as how epigenetic aberrations override normal cellular cues that lead to tumor initiation and propagation. The review also focuses on the latest advancements in DNA methylation profiling as a biomarker for early cancer detection, predicting patient clinical outcomes and responses to treatment and provides new insights into epigenetic-based therapy in clinical oncology.
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38
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Long non-coding RNAs MACC1-AS1 and FOXD2-AS1 mediate NSD2-induced cisplatin resistance in esophageal squamous cell carcinoma. MOLECULAR THERAPY. NUCLEIC ACIDS 2020; 23:592-602. [PMID: 33552680 PMCID: PMC7819824 DOI: 10.1016/j.omtn.2020.12.007] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/23/2020] [Accepted: 12/06/2020] [Indexed: 11/23/2022]
Abstract
The nuclear receptor-binding SET domain (NSD) protein family encoding histone lysine methyltransferases is involved in cancer progression. However, the role of NSDs in esophageal squamous cell carcinoma (ESCC) remains unclear. Here we examined the expression of NSDs in cisplatin-resistant and parental ESCC cells and revealed the upregulation of NSD2 in cisplatin-resistant cells. Ectopic expression of NSD2 increased cisplatin resistance and attenuated cisplatin-induced apoptosis. Colony formation assay indicated that NSD2 overexpression enhanced long-term survival of ESCC cells after treatment with cisplatin. In contrast, knockdown of NSD2 inhibited ESCC cell proliferation and sensitized ESCC cells to cisplatin. Depletion of NSD2 augmented the cytotoxic effect of cisplatin on EC109 xenograft tumors. NSD2 stimulated long non-coding RNA MACC1-AS1 in ESCC cells. Knockdown of MACC1-AS1 impaired NSD2-induced cisplatin resistance. Moreover, MACC1-AS1 overexpression promoted ESCC cell proliferation and cisplatin resistance. Clinically, MACC1-AS1 was upregulated in ESCC relative to adjacent noncancerous tissues. High MACC1-AS1 levels were significantly associated with reduced overall survival of ESCC patients. There was a positive correlation between MACC1-AS1 and NSD2 expression in ESCC specimens. Taken together, MACC1-AS1 induced by NSD2 mediates resistance to cisplatin in ESCC and may represent a novel target to improve cisplatin-based chemotherapy.
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39
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Gomes TM, Dias da Silva D, Carmo H, Carvalho F, Silva JP. Epigenetics and the endocannabinoid system signaling: An intricate interplay modulating neurodevelopment. Pharmacol Res 2020; 162:105237. [PMID: 33053442 DOI: 10.1016/j.phrs.2020.105237] [Citation(s) in RCA: 27] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/24/2020] [Revised: 09/16/2020] [Accepted: 10/02/2020] [Indexed: 01/08/2023]
Abstract
The endocannabinoid (eCB) system is a complex system comprising endogenous cannabinoids (eCBs), their synthesis and degradation enzymes, and cannabinoid receptors. These elements crucially regulate several biological processes during neurodevelopment, such as proliferation, differentiation, and migration. Recently, eCBs were also reported to have an epigenetic action on genes that play key functions in the neurotransmitter signaling, consequently regulating their expression. In turn, epigenetic modifications (e.g. DNA methylation, histone modifications) may also modulate the function of eCB system's elements. For example, the expression of the cnr gene in the central nervous system may be epigenetically regulated (e.g. DNA methylation, histone modifications), thus altering the function of the cannabinoid receptor type-1 (CB1R). Considering the importance of the eCB system during neurodevelopment, it is thus reasonable to expect that alterations in this interaction between the eCB system and epigenetic modifications may give rise to neurodevelopmental disorders. Here, we review key concepts related to the regulation of neuronal function by the eCB system and the different types of epigenetic modifications. In particular, we focus on the mechanisms involved in the intricate interplay between both signaling systems and how they control cell fate during neurodevelopment. Noteworthy, such mechanistic understanding assumes high relevance considering the implications of the dysregulation of key neurogenic processes towards the onset of neurodevelopment-related disorders. Moreover, considering the increasing popularity of cannabis and its synthetic derivatives among young adults, it becomes of utmost importance to understand how exogenous cannabinoids may epigenetically impact neurodevelopment.
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Affiliation(s)
- Telma Marisa Gomes
- UCIBIO, REQUIMTE, Laboratory of Toxicology, Department of Biological Sciences, Faculty of Pharmacy, University of Porto, 4050-313, Porto, Portugal
| | - Diana Dias da Silva
- UCIBIO, REQUIMTE, Laboratory of Toxicology, Department of Biological Sciences, Faculty of Pharmacy, University of Porto, 4050-313, Porto, Portugal
| | - Helena Carmo
- UCIBIO, REQUIMTE, Laboratory of Toxicology, Department of Biological Sciences, Faculty of Pharmacy, University of Porto, 4050-313, Porto, Portugal
| | - Félix Carvalho
- UCIBIO, REQUIMTE, Laboratory of Toxicology, Department of Biological Sciences, Faculty of Pharmacy, University of Porto, 4050-313, Porto, Portugal.
| | - João Pedro Silva
- UCIBIO, REQUIMTE, Laboratory of Toxicology, Department of Biological Sciences, Faculty of Pharmacy, University of Porto, 4050-313, Porto, Portugal.
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40
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Capasso M, Montella A, Tirelli M, Maiorino T, Cantalupo S, Iolascon A. Genetic Predisposition to Solid Pediatric Cancers. Front Oncol 2020; 10:590033. [PMID: 33194750 PMCID: PMC7656777 DOI: 10.3389/fonc.2020.590033] [Citation(s) in RCA: 32] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2020] [Accepted: 09/08/2020] [Indexed: 12/15/2022] Open
Abstract
Progresses over the past years have extensively improved our capacity to use genome-scale analyses—including high-density genotyping and exome and genome sequencing—to identify the genetic basis of pediatric tumors. In particular, exome sequencing has contributed to the evidence that about 10% of children and adolescents with tumors have germline genetic variants associated with cancer predisposition. In this review, we provide an overview of genetic variations predisposing to solid pediatric tumors (medulloblastoma, ependymoma, astrocytoma, neuroblastoma, retinoblastoma, Wilms tumor, osteosarcoma, rhabdomyosarcoma, and Ewing sarcoma) and outline the biological processes affected by the involved mutated genes. A careful description of the genetic basis underlying a large number of syndromes associated with an increased risk of pediatric cancer is also reported. We place particular emphasis on the emerging view that interactions between germline and somatic alterations are a key determinant of cancer development. We propose future research directions, which focus on the biological function of pediatric risk alleles and on the potential links between the germline genome and somatic changes. Finally, the importance of developing new molecular diagnostic tests including all the identified risk germline mutations and of considering the genetic predisposition in screening tests and novel therapies is emphasized.
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Affiliation(s)
- Mario Capasso
- Dipartimento di Medicina Molecolare e Biotecnologie Mediche, Università degli Studi di Napoli Federico II, Naples, Italy.,CEINGE Biotecnologie Avanzate, Naples, Italy
| | | | - Matilde Tirelli
- CEINGE Biotecnologie Avanzate, Naples, Italy.,European School of Molecular Medicine, Università Degli Studi di Milano, Milan, Italy
| | - Teresa Maiorino
- Dipartimento di Medicina Molecolare e Biotecnologie Mediche, Università degli Studi di Napoli Federico II, Naples, Italy.,CEINGE Biotecnologie Avanzate, Naples, Italy
| | - Sueva Cantalupo
- Dipartimento di Medicina Molecolare e Biotecnologie Mediche, Università degli Studi di Napoli Federico II, Naples, Italy.,CEINGE Biotecnologie Avanzate, Naples, Italy
| | - Achille Iolascon
- Dipartimento di Medicina Molecolare e Biotecnologie Mediche, Università degli Studi di Napoli Federico II, Naples, Italy.,CEINGE Biotecnologie Avanzate, Naples, Italy
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41
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Ramazi S, Allahverdi A, Zahiri J. Evaluation of post-translational modifications in histone proteins: A review on histone modification defects in developmental and neurological disorders. J Biosci 2020. [DOI: 10.1007/s12038-020-00099-2] [Citation(s) in RCA: 23] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/28/2022]
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42
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Semmes EC, Shen E, Cohen JL, Zhang C, Wei Q, Hurst JH, Walsh KM. Genetic variation associated with childhood and adult stature and risk of MYCN-amplified neuroblastoma. Cancer Med 2020; 9:8216-8225. [PMID: 32945147 PMCID: PMC7643638 DOI: 10.1002/cam4.3458] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2020] [Revised: 08/07/2020] [Accepted: 08/25/2020] [Indexed: 12/16/2022] Open
Abstract
Background Neuroblastoma is the most common pediatric solid tumor. MYCN‐amplification is an important negative prognostic indicator and inherited genetic contributions to risk are incompletely understood. Genetic determinants of stature increase risk of several adult and childhood cancers, but have not been studied in neuroblastoma despite elevated neuroblastoma incidence in children with congenital overgrowth syndromes. Methods We investigated the association between genetic determinants of height and neuroblastoma risk in 1538 neuroblastoma cases, stratified by MYCN‐amplification status, and compared to 3390 European‐ancestry controls using polygenic scores for birth length (five variants), childhood height (six variants), and adult height (413 variants). We further examined the UK Biobank to evaluate the association of known neuroblastoma risk loci and stature. Results An increase in the polygenic score for childhood stature, corresponding to a ~0.5 cm increase in pre‐pubertal height, was associated with greater risk of MYCN‐amplified neuroblastoma (OR = 1.14, P = .047). An increase in the polygenic score for adult stature, corresponding to a ~1.7 cm increase in adult height attainment, was associated with decreased risk of MYCN‐amplified neuroblastoma (OR = 0.87, P = .047). These associations persisted in case‐case analyses comparing MYCN‐amplified to MYCN‐unamplified neuroblastoma. No polygenic height scores were associated with MYCN‐unamplified neuroblastoma risk. Previously identified genome‐wide association study hits for neuroblastoma (N = 10) were significantly enriched for association with both childhood (P = 4.0 × 10−3) and adult height (P = 8.9 × 10−3) in >250 000 UK Biobank study participants. Conclusions Genetic propensity to taller childhood height and shorter adult height were associated with MYCN‐amplified neuroblastoma risk, suggesting that biological pathways affecting growth trajectories and pubertal timing may contribute to MYCN‐amplified neuroblastoma etiology.
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Affiliation(s)
- Eleanor C Semmes
- Medical Scientist Training Program, Duke University, Durham, NC, USA.,Department of Pediatrics, Children's Health and Discovery Institute, Duke University, Durham, NC, USA
| | - Erica Shen
- Division of Neuro-epidemiology, Department of Neurosurgery, Duke University, Durham, NC, USA
| | - Jennifer L Cohen
- Division of Medical Genetics, Department of Pediatrics, Duke University, Durham, NC, USA
| | - Chenan Zhang
- Department of Epidemiology and Biostatistics, University of California, San Francisco, CA, USA
| | - Qingyi Wei
- Department of Population Health Sciences, Duke University School of Medicine, Durham, NC, USA.,Duke Cancer Institute, Duke University Medical Center, Durham, NC, USA
| | - Jillian H Hurst
- Department of Pediatrics, Children's Health and Discovery Institute, Duke University, Durham, NC, USA
| | - Kyle M Walsh
- Department of Pediatrics, Children's Health and Discovery Institute, Duke University, Durham, NC, USA.,Division of Neuro-epidemiology, Department of Neurosurgery, Duke University, Durham, NC, USA.,Department of Epidemiology and Biostatistics, University of California, San Francisco, CA, USA.,Department of Population Health Sciences, Duke University School of Medicine, Durham, NC, USA.,Duke Cancer Institute, Duke University Medical Center, Durham, NC, USA
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43
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Fahrner JA, Bjornsson HT. Mendelian disorders of the epigenetic machinery: postnatal malleability and therapeutic prospects. Hum Mol Genet 2020; 28:R254-R264. [PMID: 31595951 DOI: 10.1093/hmg/ddz174] [Citation(s) in RCA: 98] [Impact Index Per Article: 19.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2019] [Revised: 07/10/2019] [Accepted: 07/11/2019] [Indexed: 12/14/2022] Open
Abstract
The epigenetic machinery in conjunction with the transcriptional machinery is responsible for maintaining genome-wide chromatin states and dynamically regulating gene expression. Mendelian disorders of the epigenetic machinery (MDEMs) are genetic disorders resulting from mutations in components of the epigenetic apparatus. Though individually rare, MDEMs have emerged as a collectively common etiology for intellectual disability (ID) and growth disruption. Studies in model organisms and humans have demonstrated dosage sensitivity of this gene group with haploinsufficiency as a predominant disease mechanism. The epigenetic machinery consists of three enzymatic components (writers, erasers and chromatin remodelers) as well as one non-enzymatic group (readers). A tally of the entire census of such factors revealed that although multiple enzymatic activities never coexist within a single component, individual enzymatic activities often coexist with a reader domain. This group of disorders disrupts both the chromatin and transcription states of target genes downstream of the given component but also DNA methylation on a global scale. Elucidation of these global epigenetic changes may inform our understanding of disease pathogenesis and have diagnostic utility. Moreover, many therapies targeting epigenetic marks already exist, and some have proven successful in treating cancer. This, along with the recent observation that neurological dysfunction in these disorders may in fact be treatable in postnatal life, suggests that the scientific community should prioritize this group as a potentially treatable cause of ID. Here we summarize the recent expansion and major characteristics of MDEMs, as well as the unique therapeutic prospects for this group of disorders.
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Affiliation(s)
- Jill A Fahrner
- McKusick-Nathans Institute of Genetic Medicine, 21205.,Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
| | - Hans T Bjornsson
- McKusick-Nathans Institute of Genetic Medicine, 21205.,Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.,Landspitali University Hospital, Reykjavik 101, Iceland.,Faculty of Medicine, University of Iceland, Reykjavik 101, Iceland
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44
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Kim T, Shin H, Song B, Won C, Yoshida H, Yamaguchi M, Cho KS, Lee I. Overexpression of
H3K36
methyltransferase
NSD
in glial cells affects brain development in
Drosophila. Glia 2020; 68:2503-2516. [DOI: 10.1002/glia.23867] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2019] [Revised: 04/21/2020] [Accepted: 05/16/2020] [Indexed: 11/09/2022]
Affiliation(s)
- Taejoon Kim
- Department of Biological Sciences, CHANS Research Center Konkuk University Seoul South Korea
| | - Hyewon Shin
- Department of Biological Sciences, CHANS Research Center Konkuk University Seoul South Korea
| | - Bokyeong Song
- Department of Biological Sciences, CHANS Research Center Konkuk University Seoul South Korea
| | - Chihyun Won
- Department of Biological Sciences, CHANS Research Center Konkuk University Seoul South Korea
| | - Hideki Yoshida
- Department of Applied Biology Kyoto Institute of Technology Kyoto Japan
| | | | - Kyoung Sang Cho
- Department of Biological Sciences, CHANS Research Center Konkuk University Seoul South Korea
| | - Im‐Soon Lee
- Department of Biological Sciences, CHANS Research Center Konkuk University Seoul South Korea
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45
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Leonards K, Almosailleakh M, Tauchmann S, Bagger FO, Thirant C, Juge S, Bock T, Méreau H, Bezerra MF, Tzankov A, Ivanek R, Losson R, Peters AHFM, Mercher T, Schwaller J. Nuclear interacting SET domain protein 1 inactivation impairs GATA1-regulated erythroid differentiation and causes erythroleukemia. Nat Commun 2020; 11:2807. [PMID: 32533074 PMCID: PMC7293310 DOI: 10.1038/s41467-020-16179-8] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2019] [Accepted: 04/17/2020] [Indexed: 12/20/2022] Open
Abstract
The nuclear receptor binding SET domain protein 1 (NSD1) is recurrently mutated in human cancers including acute leukemia. We show that NSD1 knockdown alters erythroid clonogenic growth of human CD34+ hematopoietic cells. Ablation of Nsd1 in the hematopoietic system of mice induces a transplantable erythroleukemia. In vitro differentiation of Nsd1−/− erythroblasts is majorly impaired despite abundant expression of GATA1, the transcriptional master regulator of erythropoiesis, and associated with an impaired activation of GATA1-induced targets. Retroviral expression of wildtype NSD1, but not a catalytically-inactive NSD1N1918Q SET-domain mutant induces terminal maturation of Nsd1−/− erythroblasts. Despite similar GATA1 protein levels, exogenous NSD1 but not NSDN1918Q significantly increases the occupancy of GATA1 at target genes and their expression. Notably, exogenous NSD1 reduces the association of GATA1 with the co-repressor SKI, and knockdown of SKI induces differentiation of Nsd1−/− erythroblasts. Collectively, we identify the NSD1 methyltransferase as a regulator of GATA1-controlled erythroid differentiation and leukemogenesis. Loss of function mutations of NSD1 occur in blood cancers. Here, the authors report that NSD1 loss blocks erythroid differentiation which leads to an erythroleukemia-like disease in mice by impairing GATA1-induced target gene activation.
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Affiliation(s)
- Katharina Leonards
- University Children's Hospital Basel, Basel, Switzerland.,Department of Biomedicine, University of Basel, 4031, Basel, Switzerland
| | - Marwa Almosailleakh
- University Children's Hospital Basel, Basel, Switzerland.,Department of Biomedicine, University of Basel, 4031, Basel, Switzerland
| | - Samantha Tauchmann
- University Children's Hospital Basel, Basel, Switzerland.,Department of Biomedicine, University of Basel, 4031, Basel, Switzerland
| | - Frederik Otzen Bagger
- University Children's Hospital Basel, Basel, Switzerland.,Department of Biomedicine, University of Basel, 4031, Basel, Switzerland.,Swiss Institute of Bioinfomatics, 4031, Basel, Switzerland.,Genomic Medicine, Righospitalet, University of Copenhagen, 2100, Copenhagen, Denmark
| | - Cécile Thirant
- INSERM U1170, Equipe Labellisée Ligue Contre le Cancer, Gustave Roussy Institute, Université Paris Diderot, Université Paris-Sud, Villejuif, 94800, France
| | - Sabine Juge
- University Children's Hospital Basel, Basel, Switzerland.,Department of Biomedicine, University of Basel, 4031, Basel, Switzerland
| | - Thomas Bock
- Proteomics Core Facility, Biozentrum University of Basel, Basel, Switzerland
| | - Hélène Méreau
- Department of Biomedicine, University of Basel, 4031, Basel, Switzerland
| | - Matheus F Bezerra
- University Children's Hospital Basel, Basel, Switzerland.,Department of Biomedicine, University of Basel, 4031, Basel, Switzerland.,Aggeu Magalhães Institute, Oswaldo Cruz Foundation, Recife, Brazil
| | - Alexandar Tzankov
- Institute for Pathology, University Hospital Basel, 4031, Basel, Switzerland
| | - Robert Ivanek
- Department of Biomedicine, University of Basel, 4031, Basel, Switzerland.,Swiss Institute of Bioinfomatics, 4031, Basel, Switzerland
| | - Régine Losson
- Institute de Génétique et de Biologie Moléculaire et Cellulaire (I.G.B.M.C.), CNRS/INSERM Université de Strasbourg, BP10142, 67404, Illkirch Cedex, France
| | - Antoine H F M Peters
- Friedrich Miescher Institute for Biomedical Research, 4058, Basel, Switzerland.,Faculty of Sciences, University of Basel, 4056, Basel, Switzerland
| | - Thomas Mercher
- INSERM U1170, Equipe Labellisée Ligue Contre le Cancer, Gustave Roussy Institute, Université Paris Diderot, Université Paris-Sud, Villejuif, 94800, France
| | - Juerg Schwaller
- University Children's Hospital Basel, Basel, Switzerland. .,Department of Biomedicine, University of Basel, 4031, Basel, Switzerland.
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46
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Yu J, Xu F, Wei Z, Zhang X, Chen T, Pu L. Epigenomic landscape and epigenetic regulation in maize. TAG. THEORETICAL AND APPLIED GENETICS. THEORETISCHE UND ANGEWANDTE GENETIK 2020; 133:1467-1489. [PMID: 31965233 DOI: 10.1007/s00122-020-03549-5] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/18/2019] [Accepted: 01/14/2020] [Indexed: 05/12/2023]
Abstract
Epigenetic regulation has been implicated in the control of multiple agronomic traits in maize. Here, we review current advances in our understanding of epigenetic regulation, which has great potential for improving agronomic traits and the environmental adaptability of crops. Epigenetic regulation plays vital role in the control of complex agronomic traits. Epigenetic variation could contribute to phenotypic diversity and can be used to improve the quality and productivity of crops. Maize (Zea mays L.), one of the most widely cultivated crops for human food, animal feed, and ethanol biofuel, is a model plant for genetic studies. Recent advances in high-throughput sequencing technology have made possible the study of epigenetic regulation in maize on a genome-wide scale. In this review, we discuss recent epigenetic studies in maize many achieved by Chinese research groups. These studies have explored the roles of DNA methylation, posttranslational modifications of histones, chromatin remodeling, and noncoding RNAs in the regulation of gene expression in plant development and environment response. We also provide our future prospects for manipulating epigenetic regulation to improve crops.
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Affiliation(s)
- Jia Yu
- Biotechnology Research Institute, Chinese Academy of Agricultural Sciences, Beijing, China
| | - Fan Xu
- Biotechnology Research Institute, Chinese Academy of Agricultural Sciences, Beijing, China
| | - Ziwei Wei
- School of Life Sciences, Anhui Agricultural University, Hefei, China
| | - Xiangxiang Zhang
- Biotechnology Research Institute, Chinese Academy of Agricultural Sciences, Beijing, China
| | - Tao Chen
- College of Life and Environmental Sciences, Hangzhou Normal University, Hangzhou, China
| | - Li Pu
- Biotechnology Research Institute, Chinese Academy of Agricultural Sciences, Beijing, China.
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47
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D'Afonseca V, Gónzalez G, Salazar M, Arencibia AD. Computational analyses on genetic alterations in the NSD genes family and the implications for colorectal cancer development. Ecancermedicalscience 2020; 14:1001. [PMID: 32153656 PMCID: PMC7032942 DOI: 10.3332/ecancer.2020.1001] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2019] [Indexed: 12/21/2022] Open
Abstract
Colorectal cancer (CRC) is a prevalent tumour throughout the world. CRC symptoms appear only in advanced stages causing decrease in survival of patients. Therefore, it is necessary to establish new strategies to detect CRC through subclinical screening. Genetic alterations and differential expression of genes that codify histone methyltransferases (HMTs) are linked to tumourigenesis of CRC. One important group of genes that codify HMTs are the NSD family composed of NSD1, NSD2 and NSD3 genes. This family participates in several cancer processes as oncogenes, harbouring several genetic alterations and presenting differential expression in tumour cells. To investigate the implications of NSD genes in CRC cancer, we described the genomic landscape of all NSD family members in a cohort of CRC patients from publicly available cancer datasets. We identified associations among recurrent copy number alterations (CNAs), mutations and differential gene expression concerning clinical outcome. We found in CRC repositories that NSD1 harbours a missense mutation in SET domain—the catalytic region—that probably could decrease its activity. In addition, we found an association between the low expressions of NSD1 and NSD2 and decrease of survival probability in CRC patients. Finally, we reported that NSD3 showed the highest rate of gene amplification, which was highly correlated to its mRNA expression, a common feature of many cancer drivers. Our results highlight the potential use of the NSD1 and NSD2 gene as prognostic markers of poor prognosis in CRC patients. Additionally, we appointed the use of the NSD3 gene as a putative cancer driver gene in CRC given that this gene harbours the highest rate of genetic amplification. All our findings are leading to novel strategies to predict and control CRC, however, some studies need to be conducted to validate these findings.
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Affiliation(s)
- Vívian D'Afonseca
- Vicerectory in Research and Postgraduation, University Catholic of Maule, Talca 3605, Chile.,Center of Biotechnology in Naturals Research, University Catholic of Maule, Talca 3605, Chile
| | - Glória Gónzalez
- Center of Biotechnology in Naturals Research, University Catholic of Maule, Talca 3605, Chile
| | - Marcela Salazar
- Vicerectory in Research and Postgraduation, University Catholic of Maule, Talca 3605, Chile.,Center of Biotechnology in Naturals Research, University Catholic of Maule, Talca 3605, Chile
| | - Ariel D Arencibia
- Center of Biotechnology in Naturals Research, University Catholic of Maule, Talca 3605, Chile
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48
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Xue J, Gao HX, Sang W, Cui WL, Liu M, Zhao Y, Wang MB, Wang Q, Zhang W. Identification of core differentially methylated genes in glioma. Oncol Lett 2019; 18:6033-6045. [PMID: 31788078 PMCID: PMC6864971 DOI: 10.3892/ol.2019.10955] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2019] [Accepted: 08/20/2019] [Indexed: 12/17/2022] Open
Abstract
Differentially methylated genes (DMGs) serve a crucial role in the pathogenesis of glioma via the regulation of the cell cycle, proliferation, apoptosis, migration, infiltration, DNA repair and signaling pathways. This study aimed to identify aberrant DMGs and pathways by comprehensive bioinformatics analysis. The gene expression profile of GSE28094 was downloaded from the Gene Expression Omnibus (GEO) database, and the GEO2R online tool was used to find DMGs. Gene Ontology (GO) functional analysis and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analysis of the DMGs were performed by using the Database for Annotation Visualization and Integrated Discovery. A protein-protein interaction (PPI) network was constructed with Search Tool for the Retrieval of Interacting Genes. Analysis of modules in the PPI networks was performed by Molecular Complex Detection in Cytoscape software, and four modules were performed. The hub genes with a high degree of connectivity were verified by The Cancer Genome Atlas database. A total of 349 DMGs, including 167 hypermethylation genes, were enriched in biological processes of negative and positive regulation of cell proliferation and positive regulation of transcription from RNA polymerase II promoter. Pathway analysis enrichment revealed that cancer regulated the pluripotency of stem cells and the PI3K-AKT signaling pathway, whereas 182 hypomethylated genes were enriched in biological processes of immune response, cellular response to lipopolysaccharide and peptidyl-tyrosine phosphorylation. Pathway enrichment analysis revealed cytokine-cytokine receptor interaction, type I diabetes mellitus and TNF signaling pathway. A total of 20 hub genes were identified, of which eight genes were associated with survival, including notch receptor 1 (NOTCH1), SRC proto-oncogene (also known as non-receptor tyrosine kinase, SRC), interleukin 6 (IL6), matrix metallopeptidase 9 (MMP9), interleukin 10 (IL10), caspase 3 (CASP3), erb-b2 receptor tyrosine kinase 2 (ERBB2) and epidermal growth factor (EGF). Therefore, bioinformatics analysis identified a series of core DMGs and pathways in glioma. The results of the present study may facilitate the assessment of the tumorigenicity and progression of glioma. Furthermore, the significant DMGs may provide potential methylation-based biomarkers for the precise diagnosis and targeted treatment of glioma.
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Affiliation(s)
- Jing Xue
- Department of Pathology, The First Affiliated Hospital of Xinjiang Medical University, Urumqi, Xinjiang 830054, P.R. China.,Department of Pathology, Xinjiang Medical University, Urumqi, Xinjiang 830011, P.R. China.,Department of Pathology, The Fourth Affiliated Hospital of Xinjiang Medical University, Urumqi, Xinjiang 830000, P.R. China
| | - Hai-Xia Gao
- Department of Pathology, The First Affiliated Hospital of Xinjiang Medical University, Urumqi, Xinjiang 830054, P.R. China.,Department of Pathology, Xinjiang Medical University, Urumqi, Xinjiang 830011, P.R. China
| | - Wei Sang
- Department of Pathology, The First Affiliated Hospital of Xinjiang Medical University, Urumqi, Xinjiang 830054, P.R. China
| | - Wen-Li Cui
- Department of Pathology, The First Affiliated Hospital of Xinjiang Medical University, Urumqi, Xinjiang 830054, P.R. China
| | - Ming Liu
- Department of Pathology, The First Affiliated Hospital of Xinjiang Medical University, Urumqi, Xinjiang 830054, P.R. China
| | - Yan Zhao
- Department of Pathology, The First Affiliated Hospital of Xinjiang Medical University, Urumqi, Xinjiang 830054, P.R. China
| | - Meng-Bo Wang
- Department of Pathology, The First Affiliated Hospital of Xinjiang Medical University, Urumqi, Xinjiang 830054, P.R. China.,Department of Pathology, Xinjiang Medical University, Urumqi, Xinjiang 830011, P.R. China
| | - Qian Wang
- Department of Pathology, The First Affiliated Hospital of Xinjiang Medical University, Urumqi, Xinjiang 830054, P.R. China
| | - Wei Zhang
- Department of Pathology, The First Affiliated Hospital of Xinjiang Medical University, Urumqi, Xinjiang 830054, P.R. China
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49
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Watanabe H, Higashimoto K, Miyake N, Morita S, Horii T, Kimura M, Suzuki T, Maeda T, Hidaka H, Aoki S, Yatsuki H, Okamoto N, Uemura T, Hatada I, Matsumoto N, Soejima H. DNA methylation analysis of multiple imprinted DMRs in Sotos syndrome reveals IGF2-DMR0 as a DNA methylation-dependent, P0 promoter-specific enhancer. FASEB J 2019; 34:960-973. [PMID: 31914674 PMCID: PMC6973060 DOI: 10.1096/fj.201901757r] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2019] [Revised: 10/01/2019] [Accepted: 11/14/2019] [Indexed: 11/11/2022]
Abstract
Haploinsufficiency of NSD1, which dimethylates histone H3 lysine 36 (H3K36), causes Sotos syndrome (SoS), an overgrowth syndrome. DNMT3A and DNMT3B recognizes H3K36 trimethylation (H3K36me3) through PWWP domain to exert de novo DNA methyltransferase activity and establish imprinted differentially methylated regions (DMRs). Since decrease of H3K36me3 and genome‐wide DNA hypomethylation in SoS were observed, hypomethylation of imprinted DMRs in SoS was suggested. We explored DNA methylation status of 28 imprinted DMRs in 31 SoS patients with NSD1 defect and found that hypomethylation of IGF2‐DMR0 and IG‐DMR in a substantial proportion of SoS patients. Luciferase assay revealed that IGF2‐DMR0 enhanced transcription from the IGF2 P0 promoter but not the P3 and P4 promoters. Chromatin immunoprecipitation‐quantitative PCR (ChIP‐qPCR) revealed active enhancer histone modifications at IGF2‐DMR0, with high enrichment of H3K4me1 and H3 lysine 27 acetylation (H3K27ac). CRISPR‐Cas9 epigenome editing revealed that specifically induced hypomethylation at IGF2‐DMR0 increased transcription from the P0 promoter but not the P3 and P4 promoters. NSD1 knockdown suggested that NSD1 targeted IGF2‐DMR0; however, IGF2‐DMR0 DNA methylation and IGF2 expression were unaltered. This study could elucidate the function of IGF2‐DMR0 as a DNA methylation dependent, P0 promoter‐specific enhancer. NSD1 may play a role in the establishment or maintenance of IGF2‐DMR0 methylation during the postimplantation period.
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Affiliation(s)
- Hidetaka Watanabe
- Division of Molecular Genetics and Epigenetics, Department of Biomolecular Sciences, Faculty of Medicine, Saga University, Saga, Japan.,Department of Plastic and Reconstructive Surgery, Saga University Hospital, Saga, Japan
| | - Ken Higashimoto
- Division of Molecular Genetics and Epigenetics, Department of Biomolecular Sciences, Faculty of Medicine, Saga University, Saga, Japan
| | - Noriko Miyake
- Department of Human Genetics, Yokohama City University Graduate School of Medicine, Yokohama, Japan
| | - Sumiyo Morita
- Laboratory of Genome Science, Biosignal Genome Resource Center, Institute for Molecular and Cellular Regulation, Gunma University, Maebashi, Japan
| | - Takuro Horii
- Laboratory of Genome Science, Biosignal Genome Resource Center, Institute for Molecular and Cellular Regulation, Gunma University, Maebashi, Japan
| | - Mika Kimura
- Laboratory of Genome Science, Biosignal Genome Resource Center, Institute for Molecular and Cellular Regulation, Gunma University, Maebashi, Japan
| | - Takayuki Suzuki
- Avian Bioscience Research Center, Graduate School of Bioagricultural Sciences, Nagoya University, Nagoya, Japan
| | - Toshiyuki Maeda
- Department of Pediatrics, Faculty of Medicine, Saga University, Saga, Japan
| | - Hidenori Hidaka
- Department of Internal Medicine and Gastrointestinal Endoscopy, Faculty of Medicine, Saga University, Saga, Japan
| | - Saori Aoki
- Division of Molecular Genetics and Epigenetics, Department of Biomolecular Sciences, Faculty of Medicine, Saga University, Saga, Japan
| | - Hitomi Yatsuki
- Division of Molecular Genetics and Epigenetics, Department of Biomolecular Sciences, Faculty of Medicine, Saga University, Saga, Japan
| | - Nobuhiko Okamoto
- Department of Medical Genetics, Osaka Women's and Children's Hospital, Izumi, Japan
| | - Tetsuji Uemura
- Department of Plastic and Reconstructive Surgery, Saga University Hospital, Saga, Japan
| | - Izuho Hatada
- Laboratory of Genome Science, Biosignal Genome Resource Center, Institute for Molecular and Cellular Regulation, Gunma University, Maebashi, Japan
| | - Naomichi Matsumoto
- Department of Human Genetics, Yokohama City University Graduate School of Medicine, Yokohama, Japan
| | - Hidenobu Soejima
- Division of Molecular Genetics and Epigenetics, Department of Biomolecular Sciences, Faculty of Medicine, Saga University, Saga, Japan
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50
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Zhang S, Zhang F, Chen Q, Wan C, Xiong J, Xu J. CRISPR/Cas9-mediated knockout of NSD1 suppresses the hepatocellular carcinoma development via the NSD1/H3/Wnt10b signaling pathway. JOURNAL OF EXPERIMENTAL & CLINICAL CANCER RESEARCH : CR 2019; 38:467. [PMID: 31727171 PMCID: PMC6854717 DOI: 10.1186/s13046-019-1462-y] [Citation(s) in RCA: 38] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/08/2019] [Accepted: 10/21/2019] [Indexed: 12/15/2022]
Abstract
Background The NSD family of histone lysine methyltransferases have emerged as important biomarkers that participate in a variety of malignancies. Recent evidence has indicated that somatic dysregulation of the nuclear receptor binding SET domain-containing protein 1 (NSD1) is associated with the tumorigenesis in HCC, suggesting that NSD1 may serve as a prognostic target for this malignant tumor. However, its mechanism in human hepatocellular carcinoma (HCC), the major primary malignant tumor in the human liver, remains unclear. Hence, we investigated how NSD1 regulated HCC progression via regulation of the Wnt/β-catenin signaling pathway. Methods Reverse transcription quantitative polymerase chain reaction (RT-qPCR) and Western blot analysis was performed to identify the expression of NSD1 in HCC cells and clinically obtained tissues. The relationship between NSD1 expression and prognosis was analyzed by Kaplan-Meier survival curve. Further, a NSD1 knockout cell line was constructed by CRISPR/Cas9 genomic editing system, which was investigated in a battery of assays such as HCC cell proliferation, migration and invasion, followed by the investigation into NSD1 regulation on histone H3, Wnt10b and Wnt/β-catenin signaling pathway via ChIP. Finally, a nude mouse xenograft model was conducted in order to assess tumorigenesis affected by NSD1 knockout in vivo. Results NSD1 was overexpressed in HCC tissues and cell lines in association with poor prognosis. Knockout of NSD1 inhibited the proliferation, migration and invasion abilities of HCC cells. CRISPR/Cas9-mediated knockout of NSD1 promoted methylation of H3K27me3 and reduced methylation of H3K36me2, which inhibited Wnt10b expression. The results thereby indicated an inactivation of the Wnt/β-catenin signaling pathway suppressed cell proliferation, migration and invasion in HCC. Moreover, these in vitro findings were reproduced in vivo on tumor xenograft in nude mice. Conclusion In conclusion, the study provides evidence that CRISPR/Cas9-mediated NSD1 knockout suppresses HCC cell proliferation and migration via the NSD1/H3/Wnt10b signaling pathway, suggesting that NSD1, H3 and Wnt10b may serve as potential targets for HCC.
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Affiliation(s)
- Shuhua Zhang
- Department of Hepatobiliary Surgery of General Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, People's Republic of China.
| | - Fan Zhang
- Department of Hepatobiliary Surgery of General Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, People's Republic of China
| | - Qing Chen
- Department of Hepatobiliary Surgery of General Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, People's Republic of China
| | - Chidan Wan
- Department of Hepatobiliary Surgery of General Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, People's Republic of China
| | - Jun Xiong
- Department of Hepatobiliary Surgery of General Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, People's Republic of China
| | - Jianqun Xu
- Department of Respiratory Medicine, Wuhan Third Hospital, Tongren Hospital of Wuhan University, Wuhan, 430060, People's Republic of China
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