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Zhang J, Ren Y, Teng Y, Wu H, Xue J, Chen L, Song X, Li Y, Zhou Y, Pang Z, Wang H. Discovery of novel PRMT1 inhibitors: a combined approach using AI classification model and traditional virtual screening. Front Chem 2025; 13:1548812. [PMID: 39906150 PMCID: PMC11788407 DOI: 10.3389/fchem.2025.1548812] [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: 12/20/2024] [Accepted: 01/06/2025] [Indexed: 02/06/2025] Open
Abstract
Protein arginine methyltransferases (PRMTs) play crucial roles in gene regulation, signal transduction, mRNA splicing, DNA repair, cell differentiation, and embryonic development. Due to its significant impact, PRMTs is a target for the prevention and treatment of various diseases. Among the PRMT family, PRMT1 is the most abundant and ubiquitously expressed in the human body. Although extensive research has been conducted on PRMT1, the reported inhibitors have not successfully passed clinical trials. In this study, deep learning was employed to analyze the characteristics of existing PRMTs inhibitors and to construct a classification model for PRMT1 inhibitors. Through a classification model and molecular docking, a series of potential PRMT1 inhibitors were identified. The representative compound (compound 156) demonstrates stable binding to the PRMT1 protein by molecular hybridization, molecular dynamics simulations, and binding free energy analyses. The study discovered novel scaffolds for potential PRMT1 inhibitors.
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Affiliation(s)
- Jungan Zhang
- School of Pharmacy, Minzu University of China, Beijing, China
| | - Yixin Ren
- School of Pharmacy, Minzu University of China, Beijing, China
- Institute of National Security, Minzu University of China, Beijing, China
| | - Yun Teng
- School of Pharmacy, Minzu University of China, Beijing, China
| | - Han Wu
- School of Pharmacy, Minzu University of China, Beijing, China
| | - Jingsu Xue
- Institute of National Security, Minzu University of China, Beijing, China
| | - Lulu Chen
- Institute of National Security, Minzu University of China, Beijing, China
| | - Xiaoyue Song
- School of Pharmacy, Minzu University of China, Beijing, China
| | - Yan Li
- School of Pharmacy, Minzu University of China, Beijing, China
| | - Ying Zhou
- School of Pharmacy, Minzu University of China, Beijing, China
| | - Zongran Pang
- School of Pharmacy, Minzu University of China, Beijing, China
- Key Laboratory of Ethnomedicine (Minzu University of China), Ministry of Education, Beijing, China
| | - Hao Wang
- School of Pharmacy, Minzu University of China, Beijing, China
- Institute of National Security, Minzu University of China, Beijing, China
- Key Laboratory of Ethnomedicine (Minzu University of China), Ministry of Education, Beijing, China
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2
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Zhang F, Bischof H, Burgstaller S, Bourgeois BMR, Malli R, Madl T. Genetically encoded fluorescent sensor to monitor intracellular arginine methylation. JOURNAL OF PHOTOCHEMISTRY AND PHOTOBIOLOGY. B, BIOLOGY 2024; 252:112867. [PMID: 38368636 DOI: 10.1016/j.jphotobiol.2024.112867] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/26/2023] [Revised: 02/03/2024] [Accepted: 02/12/2024] [Indexed: 02/20/2024]
Abstract
Arginine methylation (ArgMet), as a post-translational modification, plays crucial roles in RNA processing, transcriptional regulation, signal transduction, DNA repair, apoptosis and liquid-liquid phase separation (LLPS). Since arginine methylation is associated with cancer pathogenesis and progression, protein arginine methyltransferases have gained interest as targets for anti-cancer therapy. Despite considerable process made to elucidate (patho)physiological mechanisms regulated by arginine methylation, there remains a lack of tools to visualize arginine methylation with high spatiotemporal resolution in live cells. To address this unmet need, we generated an ArgMet-sensitive genetically encoded, Förster resonance energy transfer-(FRET) based biosensor, called GEMS, capable of quantitative real-time monitoring of ArgMet dynamics. We optimized these biosensors by using different ArgMet-binding domains, arginine-glycine-rich regions and adjusting the linkers within the biosensors to improve their performance. Using a set of mammalian cell lines and modulators, we demonstrated the applicability of GEMS for monitoring changes in arginine methylation with single-cell and temporal resolution. The GEMS can facilitate the in vitro screening to find potential protein arginine methyltransferase inhibitors and will contribute to a better understanding of the regulation of ArgMet related to differentiation, development and disease.
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Affiliation(s)
- Fangrong Zhang
- Key Laboratory of Gastrointestinal Cancer (Fujian Medical University), Ministry of Education, Fuzhou 350122, China; Gottfried Schatz Research Center for Cell Signaling, Metabolism and Aging, Molecular Biology and Biochemistry, Medical University of Graz, 8010 Graz, Austria
| | - Helmut Bischof
- Gottfried Schatz Research Center for Cell Signaling, Metabolism and Aging, Molecular Biology and Biochemistry, Medical University of Graz, 8010 Graz, Austria
| | - Sandra Burgstaller
- Gottfried Schatz Research Center for Cell Signaling, Metabolism and Aging, Molecular Biology and Biochemistry, Medical University of Graz, 8010 Graz, Austria
| | - Benjamin M R Bourgeois
- Gottfried Schatz Research Center for Cell Signaling, Metabolism and Aging, Molecular Biology and Biochemistry, Medical University of Graz, 8010 Graz, Austria; Otto Loewi Research Center, Medicinal Chemistry, Medical University of Graz, 8010 Graz, Austria
| | - Roland Malli
- Gottfried Schatz Research Center for Cell Signaling, Metabolism and Aging, Molecular Biology and Biochemistry, Medical University of Graz, 8010 Graz, Austria; BioTechMed-Graz, 8010 Graz, Austria
| | - Tobias Madl
- Gottfried Schatz Research Center for Cell Signaling, Metabolism and Aging, Molecular Biology and Biochemistry, Medical University of Graz, 8010 Graz, Austria; Otto Loewi Research Center, Medicinal Chemistry, Medical University of Graz, 8010 Graz, Austria; BioTechMed-Graz, 8010 Graz, Austria.
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3
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Shen S, Zhou H, Xiao Z, Zhan S, Tuo Y, Chen D, Pang X, Wang Y, Wang J. PRMT1 in human neoplasm: cancer biology and potential therapeutic target. Cell Commun Signal 2024; 22:102. [PMID: 38326807 PMCID: PMC10851560 DOI: 10.1186/s12964-024-01506-z] [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: 12/06/2023] [Accepted: 01/30/2024] [Indexed: 02/09/2024] Open
Abstract
Protein arginine methyltransferase 1 (PRMT1), the predominant type I protein arginine methyltransferase, plays a crucial role in normal biological functions by catalyzing the methylation of arginine side chains, specifically monomethylarginine (MMA) and asymmetric dimethylarginine (ADMA), within proteins. Recent investigations have unveiled an association between dysregulated PRMT1 expression and the initiation and progression of tumors, significantly impacting patient prognosis, attributed to PRMT1's involvement in regulating various facets of tumor cell biology, including DNA damage repair, transcriptional and translational regulation, as well as signal transduction. In this review, we present an overview of recent advancements in PRMT1 research across different tumor types, with a specific focus on its contributions to tumor cell proliferation, metastasis, invasion, and drug resistance. Additionally, we expound on the dynamic functions of PRMT1 during distinct stages of cancer progression, elucidating its unique regulatory mechanisms within the same signaling pathway and distinguishing between its promotive and inhibitory effects. Importantly, we sought to provide a comprehensive summary and analysis of recent research progress on PRMT1 in tumors, contributing to a deeper understanding of its role in tumorigenesis, development, and potential treatment strategies.
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Affiliation(s)
- Shiquan Shen
- Department of Neurosurgery, Institute of Neuroscience, The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou, 510260, China
| | - Honglong Zhou
- Department of Neurosurgery, The Second Affiliated Hospital of Nanchang University, Nanchang, 330006, China
| | - Zongyu Xiao
- Department of Neurosurgery, Dushu Lake Hospital Affiliated to Soochow University, Suzhou, 215124, China
| | - Shaofen Zhan
- Department of Neurology, Guangdong Second Provincial General Hospital, Southern Medical University, Guangzhou, 510317, China
| | - Yonghua Tuo
- Department of Neurosurgery, Institute of Neuroscience, The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou, 510260, China
| | - Danmin Chen
- Department of Neurosurgery, Institute of Neuroscience, The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou, 510260, China
| | - Xiao Pang
- Department of Neurosurgery, Institute of Neuroscience, The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou, 510260, China
| | - Yezhong Wang
- Department of Neurosurgery, Institute of Neuroscience, The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou, 510260, China.
| | - Ji Wang
- Department of Neurosurgery, Institute of Neuroscience, The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou, 510260, China.
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4
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Antal CE, Oh TG, Aigner S, Luo EC, Yee BA, Campos T, Tiriac H, Rothamel KL, Cheng Z, Jiao H, Wang A, Hah N, Lenkiewicz E, Lumibao JC, Truitt ML, Estepa G, Banayo E, Bashi S, Esparza E, Munoz RM, Diedrich JK, Sodir NM, Mueller JR, Fraser CR, Borazanci E, Propper D, Von Hoff DD, Liddle C, Yu RT, Atkins AR, Han H, Lowy AM, Barrett MT, Engle DD, Evan GI, Yeo GW, Downes M, Evans RM. A super-enhancer-regulated RNA-binding protein cascade drives pancreatic cancer. Nat Commun 2023; 14:5195. [PMID: 37673892 PMCID: PMC10482938 DOI: 10.1038/s41467-023-40798-6] [Citation(s) in RCA: 15] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2021] [Accepted: 08/10/2023] [Indexed: 09/08/2023] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is a lethal malignancy in need of new therapeutic options. Using unbiased analyses of super-enhancers (SEs) as sentinels of core genes involved in cell-specific function, here we uncover a druggable SE-mediated RNA-binding protein (RBP) cascade that supports PDAC growth through enhanced mRNA translation. This cascade is driven by a SE associated with the RBP heterogeneous nuclear ribonucleoprotein F, which stabilizes protein arginine methyltransferase 1 (PRMT1) to, in turn, control the translational mediator ubiquitin-associated protein 2-like. All three of these genes and the regulatory SE are essential for PDAC growth and coordinately regulated by the Myc oncogene. In line with this, modulation of the RBP network by PRMT1 inhibition reveals a unique vulnerability in Myc-high PDAC patient organoids and markedly reduces tumor growth in male mice. Our study highlights a functional link between epigenetic regulation and mRNA translation and identifies components that comprise unexpected therapeutic targets for PDAC.
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Affiliation(s)
- Corina E Antal
- Gene Expression Laboratory, Salk Institute for Biological Studies, La Jolla, CA, 92037, USA
- Moores Cancer Center, University of California San Diego, La Jolla, CA, 92037, USA
- Department of Pharmacology, University of California San Diego, La Jolla, CA, 92093, USA
| | - Tae Gyu Oh
- Gene Expression Laboratory, Salk Institute for Biological Studies, La Jolla, CA, 92037, USA
- Department of Oncology Science, University of Oklahoma Health Sciences Center, Oklahoma City, OK, 73117, USA
| | - Stefan Aigner
- Department of Cellular and Molecular Medicine, University of California San Diego, La Jolla, CA, 92093, USA
| | - En-Ching Luo
- Department of Cellular and Molecular Medicine, University of California San Diego, La Jolla, CA, 92093, USA
| | - Brian A Yee
- Department of Cellular and Molecular Medicine, University of California San Diego, La Jolla, CA, 92093, USA
| | - Tania Campos
- The Francis Crick Institute, 1 Midland Rd, London, NW1 1AT, UK
| | - Hervé Tiriac
- Moores Cancer Center, University of California San Diego, La Jolla, CA, 92037, USA
- Department of Surgery, Division of Surgical Oncology, University of California San Diego, La Jolla, CA, 92037, USA
| | - Katherine L Rothamel
- Department of Cellular and Molecular Medicine, University of California San Diego, La Jolla, CA, 92093, USA
| | - Zhang Cheng
- Center for Epigenomics, University of California San Diego, La Jolla, CA, 92037, USA
| | - Henry Jiao
- Center for Epigenomics, University of California San Diego, La Jolla, CA, 92037, USA
| | - Allen Wang
- Center for Epigenomics, University of California San Diego, La Jolla, CA, 92037, USA
| | - Nasun Hah
- Gene Expression Laboratory, Salk Institute for Biological Studies, La Jolla, CA, 92037, USA
| | | | - Jan C Lumibao
- Regulatory Biology Laboratory, Salk Institute for Biological Studies, La Jolla, CA, 92037, USA
| | - Morgan L Truitt
- Gene Expression Laboratory, Salk Institute for Biological Studies, La Jolla, CA, 92037, USA
| | - Gabriela Estepa
- Gene Expression Laboratory, Salk Institute for Biological Studies, La Jolla, CA, 92037, USA
| | - Ester Banayo
- Gene Expression Laboratory, Salk Institute for Biological Studies, La Jolla, CA, 92037, USA
| | - Senada Bashi
- Gene Expression Laboratory, Salk Institute for Biological Studies, La Jolla, CA, 92037, USA
| | - Edgar Esparza
- Moores Cancer Center, University of California San Diego, La Jolla, CA, 92037, USA
- Department of Surgery, Division of Surgical Oncology, University of California San Diego, La Jolla, CA, 92037, USA
| | - Ruben M Munoz
- Molecular Medicine Division, Translational Genomics Research Institute, Phoenix, AZ, 85004, USA
| | - Jolene K Diedrich
- Mass Spectrometry Core for Proteomics and Metabolomics, Salk Institute for Biological Studies, La Jolla, CA, 92037, USA
| | - Nicole M Sodir
- The Francis Crick Institute, 1 Midland Rd, London, NW1 1AT, UK
- Genentech, Department of Translational Oncology, 1 DNA Way, South San Francisco, CA, 94080, USA
| | - Jasmine R Mueller
- Department of Cellular and Molecular Medicine, University of California San Diego, La Jolla, CA, 92093, USA
| | - Cory R Fraser
- HonorHealth Research Institute, Scottsdale, AZ, 85258, USA
- Scottsdale Pathology Associates, Scottsdale, AZ, 85260, USA
| | - Erkut Borazanci
- Molecular Medicine Division, Translational Genomics Research Institute, Phoenix, AZ, 85004, USA
- HonorHealth Research Institute, Scottsdale, AZ, 85258, USA
| | - David Propper
- Barts Cancer Institute, Queen Mary University of London, Charterhouse Square, London, EC1M 6BQ, USA
| | - Daniel D Von Hoff
- Molecular Medicine Division, Translational Genomics Research Institute, Phoenix, AZ, 85004, USA
- HonorHealth Research Institute, Scottsdale, AZ, 85258, USA
| | - Christopher Liddle
- Storr Liver Centre, Westmead Institute for Medical Research and Sydney Medical School, University of Sydney, Westmead Hospital, Westmead, NSW, 2145, Australia
| | - Ruth T Yu
- Gene Expression Laboratory, Salk Institute for Biological Studies, La Jolla, CA, 92037, USA
| | - Annette R Atkins
- Gene Expression Laboratory, Salk Institute for Biological Studies, La Jolla, CA, 92037, USA
| | - Haiyong Han
- Molecular Medicine Division, Translational Genomics Research Institute, Phoenix, AZ, 85004, USA
| | - Andrew M Lowy
- The Francis Crick Institute, 1 Midland Rd, London, NW1 1AT, UK
- Department of Surgery, Division of Surgical Oncology, University of California San Diego, La Jolla, CA, 92037, USA
| | - Michael T Barrett
- Molecular Medicine Division, Translational Genomics Research Institute, Phoenix, AZ, 85004, USA
| | - Dannielle D Engle
- Regulatory Biology Laboratory, Salk Institute for Biological Studies, La Jolla, CA, 92037, USA
| | - Gerard I Evan
- The Francis Crick Institute, 1 Midland Rd, London, NW1 1AT, UK
| | - Gene W Yeo
- Department of Cellular and Molecular Medicine, University of California San Diego, La Jolla, CA, 92093, USA
- Sanford Stem Cell Institute, University of California San Diego, La Jolla, CA, 92037, USA
| | - Michael Downes
- Gene Expression Laboratory, Salk Institute for Biological Studies, La Jolla, CA, 92037, USA.
| | - Ronald M Evans
- Gene Expression Laboratory, Salk Institute for Biological Studies, La Jolla, CA, 92037, USA.
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5
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Sandoval C, Torrens F, Godoy K, Reyes C, Farías J. Application of Quantitative Structure-Activity Relationships in the Prediction of New Compounds with Anti-Leukemic Activity. Int J Mol Sci 2023; 24:12258. [PMID: 37569634 PMCID: PMC10418467 DOI: 10.3390/ijms241512258] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2023] [Revised: 07/24/2023] [Accepted: 07/25/2023] [Indexed: 08/13/2023] Open
Abstract
Leukemia invades the bone marrow progressively and, through unknown mechanisms, outcompetes healthy hematopoiesis. Protein arginine methyltransferases 1 (PRMT1) are found in prokaryotes and eukaryotes cells. They are necessary for a number of biological processes and have been linked to several human diseases, including cancer. Small compounds that target PRMT1 have a significant impact on both functional research and clinical disease treatment. In fact, numerous PRMT1 inhibitors targeting the S-adenosyl-L-methionine binding region have been studied. Through topographical descriptors, quantitative structure-activity relationships (QSAR) were developed in order to identify the most effective PRMT1 inhibitors among 17 compounds. The model built using linear discriminant analysis allows us to accurately classify over 90% of the investigated active substances. Antileukemic activity is predicted using a multilinear regression analysis, and it can account for more than 56% of the variation. Both analyses are validated using an internal "leave some out" test. The developed model could be utilized in future preclinical experiments with novel drugs.
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Affiliation(s)
- Cristian Sandoval
- Escuela de Tecnología Médica, Facultad de Salud, Universidad Santo Tomás, Los Carreras 753, Osorno 5310431, Chile
- Departamento de Ingeniería Química, Facultad de Ingeniería y Ciencias, Universidad de La Frontera, Temuco 4811230, Chile
- Departamento de Ciencias Preclínicas, Facultad de Medicina, Universidad de La Frontera, Temuco 4811230, Chile
| | - Francisco Torrens
- Institut Universitari de Ciència Molecular, Universitat de València, 46071 València, Spain;
| | - Karina Godoy
- Nucleo Científico y Tecnológico en Biorecursos (BIOREN), Universidad de La Frontera, Temuco 4811230, Chile;
| | - Camila Reyes
- Carrera de Tecnología Médica, Facultad de Medicina, Universidad de La Frontera, Temuco 4811230, Chile;
| | - Jorge Farías
- Departamento de Ingeniería Química, Facultad de Ingeniería y Ciencias, Universidad de La Frontera, Temuco 4811230, Chile
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6
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Sandoval C, Torrens F, Godoy K, Reyes C, Farías J. Application of Quantitative Structure-Activity Relationships in the Prediction of New Compounds with Anti-Leukemic Activity. Int J Mol Sci 2023; 24:12258. [DOI: https:/doi.org/10.3390/ijms241512258] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 09/01/2023] Open
Abstract
Leukemia invades the bone marrow progressively and, through unknown mechanisms, outcompetes healthy hematopoiesis. Protein arginine methyltransferases 1 (PRMT1) are found in prokaryotes and eukaryotes cells. They are necessary for a number of biological processes and have been linked to several human diseases, including cancer. Small compounds that target PRMT1 have a significant impact on both functional research and clinical disease treatment. In fact, numerous PRMT1 inhibitors targeting the S-adenosyl-L-methionine binding region have been studied. Through topographical descriptors, quantitative structure-activity relationships (QSAR) were developed in order to identify the most effective PRMT1 inhibitors among 17 compounds. The model built using linear discriminant analysis allows us to accurately classify over 90% of the investigated active substances. Antileukemic activity is predicted using a multilinear regression analysis, and it can account for more than 56% of the variation. Both analyses are validated using an internal “leave some out” test. The developed model could be utilized in future preclinical experiments with novel drugs.
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Affiliation(s)
- Cristian Sandoval
- Escuela de Tecnología Médica, Facultad de Salud, Universidad Santo Tomás, Los Carreras 753, Osorno 5310431, Chile
- Departamento de Ingeniería Química, Facultad de Ingeniería y Ciencias, Universidad de La Frontera, Temuco 4811230, Chile
- Departamento de Ciencias Preclínicas, Facultad de Medicina, Universidad de La Frontera, Temuco 4811230, Chile
| | - Francisco Torrens
- Institut Universitari de Ciència Molecular, Universitat de València, 46071 València, Spain
| | - Karina Godoy
- Nucleo Científico y Tecnológico en Biorecursos (BIOREN), Universidad de La Frontera, Temuco 4811230, Chile
| | - Camila Reyes
- Carrera de Tecnología Médica, Facultad de Medicina, Universidad de La Frontera, Temuco 4811230, Chile
| | - Jorge Farías
- Departamento de Ingeniería Química, Facultad de Ingeniería y Ciencias, Universidad de La Frontera, Temuco 4811230, Chile
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7
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Qin J, Xu J. Arginine methylation in the epithelial-to-mesenchymal transition. FEBS J 2022; 289:7292-7303. [PMID: 34358413 PMCID: PMC10181118 DOI: 10.1111/febs.16152] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2021] [Revised: 07/23/2021] [Accepted: 08/04/2021] [Indexed: 01/13/2023]
Abstract
Epithelial cells acquire mesenchymal characteristics during embryonic development, wound healing, fibrosis, and in cancer in a processed termed epithelial-to-mesenchymal transition (EMT). Regulatory networks of EMT are controlled by post-transcriptional, translational, and post-translational mechanisms, in which arginine methylation is critically involved. Here, we review arginine methylation-dependent mechanisms that regulate EMT in the aspects of signaling, transcriptional, and splicing regulation.
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Affiliation(s)
- Jian Qin
- Central laboratory, Renmin Hospital of Wuhan University, China
| | - Jian Xu
- Center for Craniofacial Molecular Biology, Herman Ostrow School of Dentistry, University of Southern California, Los Angeles, CA, USA.,Biochemistry and Molecular Medicine, University of Southern California, Los Angeles, CA, USA.,Norris Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA
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8
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Brekker MA, Sartawi T, Sawatzky TM, Causey CP, Rehman FK, Knuckley B. A peptoid-based inhibitor of protein arginine methyltransferase 1 (PRMT1) induces apoptosis and autophagy in cancer cells. J Biol Chem 2022; 298:102205. [PMID: 35764172 PMCID: PMC9307946 DOI: 10.1016/j.jbc.2022.102205] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2022] [Revised: 06/14/2022] [Accepted: 06/17/2022] [Indexed: 01/11/2023] Open
Abstract
Protein arginine methyltransferases (PRMTs) are S-adenosylmethionine-dependent enzymes that transfer a methyl group to arginine residues within proteins, most notably histones. The nine characterized PRMT family members are divided into three types depending on the resulting methylated product: asymmetric dimethylarginine (Type I PRMT), symmetric dimethylarginine (Type II PRMT), or monomethylated arginine (Type III PRMT). In some cancers, the resulting product can lead to either increased or decreased transcription of cancer-related genes, suggesting PRMT family members may be valid therapeutic targets. Traditionally, peptide-based compounds have been employed to target this family of enzymes, which has resulted in multiple tool and lead compounds being developed. However, peptide-based therapeutics suffer from poor stability and short half-lives, as proteases can render them useless by hydrolytic degradation. Conversely, peptoids, which are peptide-mimetics composed of N-substituted glycine monomers, are less susceptible to hydrolysis, resulting in improved stability and longer half-lives. Herein, we report the development of a bioavailable, peptoid-based PRMT1 inhibitor that induces cell death in MDA468 and HCT116 cancer cell lines while not exhibiting any significant impact on nontumorigenic HepaRG or normal human mammary epithelial cells. Furthermore, the inhibitor described herein appears to induce both apoptosis and autophagy, suggesting it may be a less toxic cytostatic agent. In conclusion, we propose this peptoid-based inhibitor has significant anticancer and therapeutic potential by reducing cell viability, growth, and size in breast and colon cancer. Further experimentation will help determine the mechanism of action and downstream effects of this compound.
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Affiliation(s)
- Mollie A. Brekker
- Department of Chemistry, University of North Florida, Jacksonville, Florida, USA
| | - Tala Sartawi
- Department of Biology, University of North Florida, Jacksonville, Florida, USA
| | - Tina M. Sawatzky
- Department of Chemistry, University of North Florida, Jacksonville, Florida, USA
| | - Corey P. Causey
- Department of Chemistry, University of North Florida, Jacksonville, Florida, USA
| | | | - Bryan Knuckley
- Department of Chemistry, University of North Florida, Jacksonville, Florida, USA.
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9
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Malbeteau L, Pham HT, Eve L, Stallcup MR, Poulard C, Le Romancer M. How Protein Methylation Regulates Steroid Receptor Function. Endocr Rev 2022; 43:160-197. [PMID: 33955470 PMCID: PMC8755998 DOI: 10.1210/endrev/bnab014] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/16/2021] [Indexed: 02/06/2023]
Abstract
Steroid receptors (SRs) are members of the nuclear hormonal receptor family, many of which are transcription factors regulated by ligand binding. SRs regulate various human physiological functions essential for maintenance of vital biological pathways, including development, reproduction, and metabolic homeostasis. In addition, aberrant expression of SRs or dysregulation of their signaling has been observed in a wide variety of pathologies. SR activity is tightly and finely controlled by post-translational modifications (PTMs) targeting the receptors and/or their coregulators. Whereas major attention has been focused on phosphorylation, growing evidence shows that methylation is also an important regulator of SRs. Interestingly, the protein methyltransferases depositing methyl marks are involved in many functions, from development to adult life. They have also been associated with pathologies such as inflammation, as well as cardiovascular and neuronal disorders, and cancer. This article provides an overview of SR methylation/demethylation events, along with their functional effects and biological consequences. An in-depth understanding of the landscape of these methylation events could provide new information on SR regulation in physiology, as well as promising perspectives for the development of new therapeutic strategies, illustrated by the specific inhibitors of protein methyltransferases that are currently available.
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Affiliation(s)
- Lucie Malbeteau
- Université de Lyon, F-69000 Lyon, France.,Inserm U1052, Centre de Recherche en Cancérologie de Lyon, F-69000 Lyon, France.,CNRS UMR5286, Centre de Recherche en Cancérologie de Lyon, F-69000 Lyon, France
| | - Ha Thuy Pham
- Université de Lyon, F-69000 Lyon, France.,Inserm U1052, Centre de Recherche en Cancérologie de Lyon, F-69000 Lyon, France.,CNRS UMR5286, Centre de Recherche en Cancérologie de Lyon, F-69000 Lyon, France
| | - Louisane Eve
- Université de Lyon, F-69000 Lyon, France.,Inserm U1052, Centre de Recherche en Cancérologie de Lyon, F-69000 Lyon, France.,CNRS UMR5286, Centre de Recherche en Cancérologie de Lyon, F-69000 Lyon, France
| | - Michael R Stallcup
- Department of Biochemistry and Molecular Medicine, Norris Comprehensive Center, University of Southern California, Los Angeles, CA 90089, USA
| | - Coralie Poulard
- Université de Lyon, F-69000 Lyon, France.,Inserm U1052, Centre de Recherche en Cancérologie de Lyon, F-69000 Lyon, France.,CNRS UMR5286, Centre de Recherche en Cancérologie de Lyon, F-69000 Lyon, France
| | - Muriel Le Romancer
- Université de Lyon, F-69000 Lyon, France.,Inserm U1052, Centre de Recherche en Cancérologie de Lyon, F-69000 Lyon, France.,CNRS UMR5286, Centre de Recherche en Cancérologie de Lyon, F-69000 Lyon, France
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10
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Suresh S, Huard S, Brisson A, Némati F, Dakroub R, Poulard C, Ye M, Martel E, Reyes C, Silvestre DC, Meseure D, Nicolas A, Gentien D, Fayyad-Kazan H, Le Romancer M, Decaudin D, Roman-Roman S, Dubois T. PRMT1 Regulates EGFR and Wnt Signaling Pathways and Is a Promising Target for Combinatorial Treatment of Breast Cancer. Cancers (Basel) 2022; 14:cancers14020306. [PMID: 35053470 PMCID: PMC8774276 DOI: 10.3390/cancers14020306] [Citation(s) in RCA: 23] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2021] [Revised: 01/04/2022] [Accepted: 01/06/2022] [Indexed: 02/04/2023] Open
Abstract
Simple Summary Patients with triple-negative breast cancer (TNBC) respond well to chemotherapy initially but are prone to relapse. Searching for new therapeutic targets, we found that PRMT1 is highly expressed in TNBC tumor samples and is essential for breast cancer cell survival. Furthermore, this study proposes that targeting PRMT1 in combination with chemotherapies could improve the survival outcome of TNBC patients. Abstract Identifying new therapeutic strategies for triple-negative breast cancer (TNBC) patients is a priority as these patients are highly prone to relapse after chemotherapy. Here, we found that protein arginine methyltransferase 1 (PRMT1) is highly expressed in all breast cancer subtypes. PRMT1 depletion decreases cell survival by inducing DNA damage and apoptosis in various breast cancer cell lines. Transcriptomic analysis and chromatin immunoprecipitation revealed that PRMT1 regulates the epidermal growth factor receptor (EGFR) and the Wnt signaling pathways, reported to be activated in TNBC. PRMT1 enzymatic activity is also required to stimulate the canonical Wnt pathway. Type I PRMT inhibitors decrease breast cancer cell proliferation and show anti-tumor activity in a TNBC xenograft model. These inhibitors display synergistic interactions with some chemotherapies used to treat TNBC patients as well as erlotinib, an EGFR inhibitor. Therefore, targeting PRMT1 in combination with these chemotherapies may improve existing treatments for TNBC patients.
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Affiliation(s)
- Samyuktha Suresh
- Breast Cancer Biology Group, Translational Research Department, Institut Curie-PSL Research University, 75005 Paris, France; (S.S.); (S.H.); (A.B.); (R.D.); (M.Y.); (D.C.S.)
| | - Solène Huard
- Breast Cancer Biology Group, Translational Research Department, Institut Curie-PSL Research University, 75005 Paris, France; (S.S.); (S.H.); (A.B.); (R.D.); (M.Y.); (D.C.S.)
| | - Amélie Brisson
- Breast Cancer Biology Group, Translational Research Department, Institut Curie-PSL Research University, 75005 Paris, France; (S.S.); (S.H.); (A.B.); (R.D.); (M.Y.); (D.C.S.)
| | - Fariba Némati
- Pre-Clinical Investigation Laboratory, Translational Research Department, Institut Curie-PSL Research University, 75005 Paris, France; (F.N.); (D.D.)
| | - Rayan Dakroub
- Breast Cancer Biology Group, Translational Research Department, Institut Curie-PSL Research University, 75005 Paris, France; (S.S.); (S.H.); (A.B.); (R.D.); (M.Y.); (D.C.S.)
- Laboratory of Cancer Biology and Molecular Immunology, Faculty of Sciences-I, Lebanese University, Hadath, Beirut 1003, Lebanon;
| | - Coralie Poulard
- Cancer Research Center of Lyon, CNRS UMR5286, Inserm U1052, University of Lyon, 69000 Lyon, France; (C.P.); (M.L.R.)
| | - Mengliang Ye
- Breast Cancer Biology Group, Translational Research Department, Institut Curie-PSL Research University, 75005 Paris, France; (S.S.); (S.H.); (A.B.); (R.D.); (M.Y.); (D.C.S.)
| | - Elise Martel
- Platform of Experimental Pathology, Department of Diagnostic and Theranostic Medicine, Institut Curie-Hospital, 75005 Paris, France; (E.M.); (D.M.); (A.N.)
| | - Cécile Reyes
- Genomics Core Facility, Translational Research Department, Institut Curie-PSL Research University, 75005 Paris, France; (C.R.); (D.G.)
| | - David C. Silvestre
- Breast Cancer Biology Group, Translational Research Department, Institut Curie-PSL Research University, 75005 Paris, France; (S.S.); (S.H.); (A.B.); (R.D.); (M.Y.); (D.C.S.)
| | - Didier Meseure
- Platform of Experimental Pathology, Department of Diagnostic and Theranostic Medicine, Institut Curie-Hospital, 75005 Paris, France; (E.M.); (D.M.); (A.N.)
| | - André Nicolas
- Platform of Experimental Pathology, Department of Diagnostic and Theranostic Medicine, Institut Curie-Hospital, 75005 Paris, France; (E.M.); (D.M.); (A.N.)
| | - David Gentien
- Genomics Core Facility, Translational Research Department, Institut Curie-PSL Research University, 75005 Paris, France; (C.R.); (D.G.)
| | - Hussein Fayyad-Kazan
- Laboratory of Cancer Biology and Molecular Immunology, Faculty of Sciences-I, Lebanese University, Hadath, Beirut 1003, Lebanon;
| | - Muriel Le Romancer
- Cancer Research Center of Lyon, CNRS UMR5286, Inserm U1052, University of Lyon, 69000 Lyon, France; (C.P.); (M.L.R.)
| | - Didier Decaudin
- Pre-Clinical Investigation Laboratory, Translational Research Department, Institut Curie-PSL Research University, 75005 Paris, France; (F.N.); (D.D.)
| | - Sergio Roman-Roman
- Translational Research Department, Institut Curie-PSL Research University, 75005 Paris, France;
| | - Thierry Dubois
- Breast Cancer Biology Group, Translational Research Department, Institut Curie-PSL Research University, 75005 Paris, France; (S.S.); (S.H.); (A.B.); (R.D.); (M.Y.); (D.C.S.)
- Correspondence: ; Tel.: +33-1-56246250
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11
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Su H, Jiang M, Senevirathne C, Aluri S, Zhang T, Guo H, Xavier-Ferrucio J, Jin S, Tran NT, Liu SM, Sun CW, Zhu Y, Zhao Q, Chen Y, Cable L, Shen Y, Liu J, Qu CK, Han X, Klug CA, Bhatia R, Chen Y, Nimer SD, Zheng YG, Iancu-Rubin C, Jin J, Deng H, Krause DS, Xiang J, Verma A, Luo M, Zhao X. Methylation of dual-specificity phosphatase 4 controls cell differentiation. Cell Rep 2021; 36:109421. [PMID: 34320342 PMCID: PMC9110119 DOI: 10.1016/j.celrep.2021.109421] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2020] [Revised: 02/17/2021] [Accepted: 06/28/2021] [Indexed: 12/11/2022] Open
Abstract
Mitogen-activated protein kinases (MAPKs) are inactivated by dual-specificity phosphatases (DUSPs), the activities of which are tightly regulated during cell differentiation. Using knockdown screening and single-cell transcriptional analysis, we demonstrate that DUSP4 is the phosphatase that specifically inactivates p38 kinase to promote megakaryocyte (Mk) differentiation. Mechanistically, PRMT1-mediated methylation of DUSP4 triggers its ubiquitinylation by an E3 ligase HUWE1. Interestingly, the mechanistic axis of the DUSP4 degradation and p38 activation is also associated with a transcriptional signature of immune activation in Mk cells. In the context of thrombocytopenia observed in myelodysplastic syndrome (MDS), we demonstrate that high levels of p38 MAPK and PRMT1 are associated with low platelet counts and adverse prognosis, while pharmacological inhibition of p38 MAPK or PRMT1 stimulates megakaryopoiesis. These findings provide mechanistic insights into the role of the PRMT1-DUSP4-p38 axis on Mk differentiation and present a strategy for treatment of thrombocytopenia associated with MDS.
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Affiliation(s)
- Hairui Su
- Department of Biochemistry and Molecular Genetics, The University of Alabama at Birmingham, Birmingham, AL 35294, USA
| | - Ming Jiang
- Chemical Biology Program, Memorial Sloan Kettering Cancer Center, New York, NY 10021, USA; Program of Pharmacology, Weill Cornell Medical College of Cornell University, New York, NY 10021, USA
| | - Chamara Senevirathne
- Chemical Biology Program, Memorial Sloan Kettering Cancer Center, New York, NY 10021, USA
| | - Srinivas Aluri
- Department of Oncology, Albert Einstein College of Medicine, Montefiore Medical Center, Bronx, NY 10461, USA
| | - Tuo Zhang
- Genomics and Epigenomics Core Facility, Weill Cornell Medical College of Cornell University, New York, NY 10021, USA
| | - Han Guo
- Chemical Biology Program, Memorial Sloan Kettering Cancer Center, New York, NY 10021, USA; Tri-Institutional PhD Program in Chemical Biology, Memorial Sloan Kettering Cancer Center, New York, NY 10021, USA
| | - Juliana Xavier-Ferrucio
- Department of Laboratory Medicine, Yale Stem Cell Center, Yale School of Medicine, New Haven, CT 06520, USA
| | - Shuiling Jin
- Department of Biochemistry and Molecular Genetics, The University of Alabama at Birmingham, Birmingham, AL 35294, USA
| | - Ngoc-Tung Tran
- Department of Biochemistry and Molecular Genetics, The University of Alabama at Birmingham, Birmingham, AL 35294, USA
| | - Szu-Mam Liu
- Department of Biochemistry and Molecular Genetics, The University of Alabama at Birmingham, Birmingham, AL 35294, USA
| | - Chiao-Wang Sun
- Department of Biochemistry and Molecular Genetics, The University of Alabama at Birmingham, Birmingham, AL 35294, USA
| | - Yongxia Zhu
- Chemical Biology Program, Memorial Sloan Kettering Cancer Center, New York, NY 10021, USA
| | - Qing Zhao
- Department of Medicine, The University of Alabama at Birmingham, Birmingham, AL 35294, USA
| | - Yuling Chen
- Department of School of Life Sciences, Tsinghua University, Beijing 100084, China
| | | | - Yudao Shen
- Mount Sinai Center for Therapeutics Discovery, Departments of Pharmacological Sciences and Oncological Sciences, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
| | - Jing Liu
- Mount Sinai Center for Therapeutics Discovery, Departments of Pharmacological Sciences and Oncological Sciences, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
| | - Cheng-Kui Qu
- Aflac Cancer and Blood Disorders Center, Winship Cancer Institute, Emory University, Atlanta, GA 30322, USA
| | - Xiaosi Han
- Department of Neurology, School of Medicine, The University of Alabama at Birmingham, Birmingham, AL 35294, USA
| | - Christopher A Klug
- Department of Microbiology, The University of Alabama at Birmingham, Birmingham, AL 35294, USA
| | - Ravi Bhatia
- Division of Hematology and Oncology, School of Medicine, The University of Alabama at Birmingham, Birmingham, AL 35294, USA
| | - Yabing Chen
- Department of Pathology, The University of Alabama at Birmingham, Birmingham, AL 35294, USA; Veterans Affairs Birmingham Medical Center, Research Department, Birmingham, AL 35294, USA
| | - Stephen D Nimer
- Sylvester Comprehensive Cancer Center, University of Miami, Miami, FL 33146 USA
| | - Y George Zheng
- Department of Pharmaceutical and Biomedical Sciences, College of Pharmacy, University of Georgia, Athens, GA 30602, USA
| | - Camelia Iancu-Rubin
- Department of Medicine, Hematology and Oncology Division, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
| | - Jian Jin
- Mount Sinai Center for Therapeutics Discovery, Departments of Pharmacological Sciences and Oncological Sciences, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
| | - Haiteng Deng
- Department of School of Life Sciences, Tsinghua University, Beijing 100084, China
| | - Diane S Krause
- Department of Laboratory Medicine, Yale Stem Cell Center, Yale School of Medicine, New Haven, CT 06520, USA
| | - Jenny Xiang
- Genomics and Epigenomics Core Facility, Weill Cornell Medical College of Cornell University, New York, NY 10021, USA
| | - Amit Verma
- Department of Oncology, Albert Einstein College of Medicine, Montefiore Medical Center, Bronx, NY 10461, USA.
| | - Minkui Luo
- Chemical Biology Program, Memorial Sloan Kettering Cancer Center, New York, NY 10021, USA; Program of Pharmacology, Weill Cornell Medical College of Cornell University, New York, NY 10021, USA.
| | - Xinyang Zhao
- Department of Biochemistry and Molecular Genetics, The University of Alabama at Birmingham, Birmingham, AL 35294, USA.
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12
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Naegleria fowleri: Protein structures to facilitate drug discovery for the deadly, pathogenic free-living amoeba. PLoS One 2021; 16:e0241738. [PMID: 33760815 PMCID: PMC7990177 DOI: 10.1371/journal.pone.0241738] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2020] [Accepted: 01/25/2021] [Indexed: 12/19/2022] Open
Abstract
Naegleria fowleri is a pathogenic, thermophilic, free-living amoeba which causes primary amebic meningoencephalitis (PAM). Penetrating the olfactory mucosa, the brain-eating amoeba travels along the olfactory nerves, burrowing through the cribriform plate to its destination: the brain’s frontal lobes. The amoeba thrives in warm, freshwater environments, with peak infection rates in the summer months and has a mortality rate of approximately 97%. A major contributor to the pathogen’s high mortality is the lack of sensitivity of N. fowleri to current drug therapies, even in the face of combination-drug therapy. To enable rational drug discovery and design efforts we have pursued protein production and crystallography-based structure determination efforts for likely drug targets from N. fowleri. The genes were selected if they had homology to drug targets listed in Drug Bank or were nominated by primary investigators engaged in N. fowleri research. In 2017, 178 N. fowleri protein targets were queued to the Seattle Structural Genomics Center of Infectious Disease (SSGCID) pipeline, and to date 89 soluble recombinant proteins and 19 unique target structures have been produced. Many of the new protein structures are potential drug targets and contain structural differences compared to their human homologs, which could allow for the development of pathogen-specific inhibitors. Five of the structures were analyzed in more detail, and four of five show promise that selective inhibitors of the active site could be found. The 19 solved crystal structures build a foundation for future work in combating this devastating disease by encouraging further investigation to stimulate drug discovery for this neglected pathogen.
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13
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Dhiman N, Kaur K, Jaitak V. Tetrazoles as anticancer agents: A review on synthetic strategies, mechanism of action and SAR studies. Bioorg Med Chem 2020; 28:115599. [PMID: 32631569 DOI: 10.1016/j.bmc.2020.115599] [Citation(s) in RCA: 64] [Impact Index Per Article: 12.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2020] [Revised: 06/14/2020] [Accepted: 06/15/2020] [Indexed: 12/22/2022]
Abstract
Cancer is a leading cause of death worldwide. Even after the availability of numerous drugs and treatments in the market, scientists and researchers are focusing on new therapies because of their resistance and toxicity issues. The newly synthesized drug candidates are able to demonstrate in vitro activity but are unable to reach clinical trials due to their rapid metabolism and low bioavailability. Therefore there is an imperative requisite to expand novel anticancer negotiators with tremendous activity as well as in vivo efficacy. Tetrazole is a promising pharmacophore which is metabolically more stable and acts as a bioisosteric analogue for many functional groups. Tetrazole fragment is often castoff with other pharmacophores in the expansion of novel anticancer drugs. This is the first systematic review that emphasizes on contemporary strategies used for the inclusion of tetrazole moiety, mechanistic targets along with comprehensive structural activity relationship studies to provide perspective into the rational design of high-efficiency tetrazole-based anticancer drug candidates.
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Affiliation(s)
- Neha Dhiman
- Department of Pharmaceutical Sciences and Natural Products, School of Basic and Applied Sciences, Central University of Punjab, Bathinda 151 001, India
| | - Kamalpreet Kaur
- Department of Pharmaceutical Sciences and Natural Products, School of Basic and Applied Sciences, Central University of Punjab, Bathinda 151 001, India
| | - Vikas Jaitak
- Department of Pharmaceutical Sciences and Natural Products, School of Basic and Applied Sciences, Central University of Punjab, Bathinda 151 001, India.
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14
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Wang YC, Chang CP, Tsai YJ, Lee YJ, Li C. Alternative 3' splice site selection of intron 5 within the prmt8 gene results in a novel variant widely distributed in vertebrates and specifically abundant in Aves. Gene 2020; 747:144684. [PMID: 32311412 DOI: 10.1016/j.gene.2020.144684] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2019] [Revised: 04/14/2020] [Accepted: 04/16/2020] [Indexed: 11/18/2022]
Abstract
PRMT8 is a neuron-specific protein arginine methyltransferase in vertebrates. From data mining, we found a novel prmt8e6+43 splicing variant with a 43-nucleotide (nt) extension at the 5' of exon 6 in chicken. RT-PCR analyses confirmed the existence of two splicing variants but also detected a third upper signal. The triplet pattern detected in chicken suggests that one strand from the prmt8e6+43 transcript and one strand from the regular splicing products form a heteroduplex with a bulb conformation and the two transcripts are of similar abundance. One short plus one faint upper heteroduplex signal detected in mouse and human indicate that the level of the variant is much less than the normal one in mammals. The relative expression of the normal and prmt8e6+43 variants in different species can be inferred from the reads of intron 5 that contains the 43-nt extension or not in the RNA-seq data of NCBI Gene database. The results of the analyses showed that the prmt8e6+43 variant is relatively abundant in birds but much less or even not detected in mammalian species. As conserved intron 5 sequences and evidences of alternative splicing (AS) are detected in elephant shark, a cartilaginous fish with the slowest-evolving genome, we propose that the prmt8e6+43 variant is present in the common ancestor of jawed vertebrates. The prmt8e6+43 variant includes a premature termination codon and thus should encode a truncated PRMT8 with deletion from the dimerization arm. Western blot analyses showed very weak low-molecular-weight signals in chicken, which might be the C-terminal truncated PRMT8. Why avian species maintain high RNA but not protein levels of the prmt8e6+43 variant and whether the evolutionary conserved sequence and AS might regulate PRMT8 expression require further investigation.
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Affiliation(s)
- Yi-Chun Wang
- Department of Biomedical Sciences, Chung Shan Medical University, Taichung, Taiwan; Department of Medical Research, Chung Shan Medical University Hospital, Taichung, Taiwan
| | - Chien-Ping Chang
- Department of Biomedical Sciences, Chung Shan Medical University, Taichung, Taiwan
| | - Yun-Jung Tsai
- Department of Biomedical Sciences, Chung Shan Medical University, Taichung, Taiwan
| | - Yu-Jen Lee
- Department of Biomedical Sciences, Chung Shan Medical University, Taichung, Taiwan
| | - Chuan Li
- Department of Biomedical Sciences, Chung Shan Medical University, Taichung, Taiwan; Department of Medical Research, Chung Shan Medical University Hospital, Taichung, Taiwan.
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15
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Zhao J, O'Neil M, Schonfeld M, Komatz A, Weinman SA, Tikhanovich I. Hepatocellular Protein Arginine Methyltransferase 1 Suppresses Alcohol-Induced Hepatocellular Carcinoma Formation by Inhibition of Inducible Nitric Oxide Synthase. Hepatol Commun 2020; 4:790-808. [PMID: 32490317 PMCID: PMC7262284 DOI: 10.1002/hep4.1488] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/23/2019] [Accepted: 01/29/2020] [Indexed: 12/17/2022] Open
Abstract
Alcohol is a well-established risk factor for hepatocellular carcinoma (HCC), but the mechanisms by which alcohol promotes liver cancer are not well understood. Studies suggest that ethanol may enhance tumor progression by increasing hepatocyte proliferation and through alcohol-induced liver inflammation. Protein arginine methyltransferase 1 (PRMT1) is the main enzyme responsible for cellular arginine methylation. Asymmetric dimethyl arginine, produced by PRMT1, is a potent inhibitor of nitric oxide synthases. PRMT1 is implicated in the development of several types of tumors and cardiovascular disease. Our previous work has shown that PRMT1 in the liver regulates hepatocyte proliferation and oxidative stress and protects from alcohol-induced liver injury. However, its role in HCC development remains controversial. In this study, we found that hepatocyte-specific PRMT1-knockout mice develop an increased number of tumors in an N-nitrosodiethylamine (DEN) alcohol model of liver tumorigenesis in mice. This effect was specific to the alcohol-related component because wild-type and knockout mice developed similar tumor numbers in the DEN model without the addition of alcohol. We found that in the presence of alcohol, the increase in tumor number was associated with increased proliferation in liver and tumor, increased WNT/β-catenin signaling, and increased inflammation. We hypothesized that increased inflammation was due to increased oxidative and nitrosative stress in knockout mice. By blocking excess nitric oxide production using an inducible nitric oxide synthase inhibitor, we reduced hepatocyte death and inflammation in the liver and prevented the increase in WNT/β-catenin signaling, proliferation, and tumor number in livers of knockout mice. Conclusion: PRMT1 is an important protection factor from alcohol-induced liver injury, inflammation, and HCC development.
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Affiliation(s)
- Jie Zhao
- Department of Internal Medicine University of Kansas Medical Center Kansas City KS
| | - Maura O'Neil
- Department of Pathology University of Kansas Medical Center Kansas City KS
| | - Michael Schonfeld
- Department of Internal Medicine University of Kansas Medical Center Kansas City KS
| | - Amberly Komatz
- Liver Center University of Kansas Medical Center Kansas City KS
| | - Steven A Weinman
- Department of Internal Medicine University of Kansas Medical Center Kansas City KS.,Liver Center University of Kansas Medical Center Kansas City KS
| | - Irina Tikhanovich
- Department of Internal Medicine University of Kansas Medical Center Kansas City KS
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16
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Spadotto V, Giambruno R, Massignani E, Mihailovich M, Maniaci M, Patuzzo F, Ghini F, Nicassio F, Bonaldi T. PRMT1-mediated methylation of the microprocessor-associated proteins regulates microRNA biogenesis. Nucleic Acids Res 2020; 48:96-115. [PMID: 31777917 PMCID: PMC6943135 DOI: 10.1093/nar/gkz1051] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2018] [Revised: 10/04/2019] [Accepted: 11/22/2019] [Indexed: 12/17/2022] Open
Abstract
MicroRNA (miRNA) biogenesis is a tightly controlled multi-step process operated in the nucleus by the activity of the Microprocessor and its associated proteins. Through high resolution mass spectrometry (MS)- proteomics we discovered that this complex is extensively methylated, with 84 methylated sites associated to 19 out of its 24 subunits. The majority of the modifications occurs on arginine (R) residues (61), leading to 81 methylation events, while 30 lysine (K)-methylation events occurs on 23 sites of the complex. Interestingly, both depletion and pharmacological inhibition of the Type-I Protein Arginine Methyltransferases (PRMTs) lead to a widespread change in the methylation state of the complex and induce global decrease of miRNA expression, as a consequence of the impairment of the pri-to-pre-miRNA processing step. In particular, we show that the reduced methylation of the Microprocessor subunit ILF3 is linked to its diminished binding to the pri-miRNAs miR-15a/16, miR-17-92, miR-301a and miR-331. Our study uncovers a previously uncharacterized role of R-methylation in the regulation of miRNA biogenesis in mammalian cells.
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Affiliation(s)
- Valeria Spadotto
- Department of Experimental Oncology, IEO, European Institute of Oncology IRCCS, Milan, Italy
| | - Roberto Giambruno
- Department of Experimental Oncology, IEO, European Institute of Oncology IRCCS, Milan, Italy
| | - Enrico Massignani
- Department of Experimental Oncology, IEO, European Institute of Oncology IRCCS, Milan, Italy
| | - Marija Mihailovich
- Department of Experimental Oncology, IEO, European Institute of Oncology IRCCS, Milan, Italy
| | - Marianna Maniaci
- Department of Experimental Oncology, IEO, European Institute of Oncology IRCCS, Milan, Italy
| | - Francesca Patuzzo
- Department of Experimental Oncology, IEO, European Institute of Oncology IRCCS, Milan, Italy
| | - Francesco Ghini
- Center for Genomic Science of IIT@SEMM, Istituto Italiano di Tecnologia, Milan, Italy
| | - Francesco Nicassio
- Center for Genomic Science of IIT@SEMM, Istituto Italiano di Tecnologia, Milan, Italy
| | - Tiziana Bonaldi
- Department of Experimental Oncology, IEO, European Institute of Oncology IRCCS, Milan, Italy
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17
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Zhang Y, van Haren MJ, Martin NI. Peptidic transition state analogues as PRMT inhibitors. Methods 2019; 175:24-29. [PMID: 31421210 DOI: 10.1016/j.ymeth.2019.08.003] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2019] [Revised: 08/02/2019] [Accepted: 08/06/2019] [Indexed: 12/21/2022] Open
Abstract
Protein arginine N-methyltransferases (PRMTs) methylate arginine residues in target proteins using the ubiquitous methyl donor S-adenosyl-l-methionine (AdoMet) as a cofactor. PRMTs play important roles in both healthy and disease states and as such inhibition of PRMTs has gained increasing interest. A primary challenge in the development of PRMT inhibitors is achieving specificity for the PRMT of interest as the active sites are highly conserved for all nine members of the PRMT family. Notably, PRMTs show very little redundancy in vivo due to their specific sets of protein substrates. However, relatively little is known about the interactions of PRMTs with their protein substrates that drive this substrate specificity. We here describe the extended application of a methodology recently developed in our group for the production of peptide-based transition state mimicking PRMT inhibitors. Using this approach, an adenosine moiety, mimicking that of the AdoMet cofactor, is covalently linked to the guanidine side chain of a target arginine residue contained in a peptidic fragment derived from a PRMT substrate protein. Using this approach, histone H4 tail peptide-based transition state mimics were synthesized wherein the adenosine group was linked to the Arg3 residue. H4R3 is a substrate for multiple PRMTs, including PRMT1 and PRMT6. The inhibition results obtained with these new H4-based transition state mimics show low micromolar IC50 values against PRMT1 and PRMT6, indicating that the methodology is applicable to the broader family of PRMTs.
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Affiliation(s)
- Yurui Zhang
- Biological Chemistry Group, Institute of Biology Leiden, Leiden University, Sylviusweg 72, 2333 BE Leiden, The Netherlands
| | - Matthijs J van Haren
- Biological Chemistry Group, Institute of Biology Leiden, Leiden University, Sylviusweg 72, 2333 BE Leiden, The Netherlands
| | - Nathaniel I Martin
- Biological Chemistry Group, Institute of Biology Leiden, Leiden University, Sylviusweg 72, 2333 BE Leiden, The Netherlands.
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18
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The Development of Tetrazole Derivatives as Protein Arginine Methyltransferase I (PRMT I) Inhibitors. Int J Mol Sci 2019; 20:ijms20153840. [PMID: 31390828 PMCID: PMC6695598 DOI: 10.3390/ijms20153840] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2019] [Revised: 08/01/2019] [Accepted: 08/01/2019] [Indexed: 02/07/2023] Open
Abstract
Protein arginine methyltransferase 1 (PRMT1) can catalyze protein arginine methylation by transferring the methyl group from S-adenosyl-L-methionine (SAM) to the guanidyl nitrogen atom of protein arginine, which influences a variety of biological processes. The dysregulation of PRMT1 is involved in a diverse range of diseases, including cancer. Therefore, there is an urgent need to develop novel and potent PRMT1 inhibitors. In the current manuscript, a series of 1-substituted 1H-tetrazole derivatives were designed and synthesized by targeting at the substrate arginine-binding site on PRMT1, and five compounds demonstrated significant inhibitory effects against PRMT1. The most potent PRMT1 inhibitor, compound 9a, displayed non-competitive pattern with respect to either SAM or substrate arginine, and showed the strong selectivity to PRMT1 compared to PRMT5, which belongs to the type II PRMT family. It was observed that the compound 9a inhibited the functions of PRMT1 and relative factors within this pathway, and down-regulated the canonical Wnt/β-catenin signaling pathway. The binding of compound 9a to PRMT1 was carefully analyzed by using molecular dynamic simulations and binding free energy calculations. These studies demonstrate that 9a was a potent PRMT1 inhibitor, which could be used as lead compound for further drug discovery.
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19
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The regulation, functions and clinical relevance of arginine methylation. Nat Rev Mol Cell Biol 2019; 20:642-657. [PMID: 31350521 DOI: 10.1038/s41580-019-0155-x] [Citation(s) in RCA: 409] [Impact Index Per Article: 68.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 06/20/2019] [Indexed: 12/15/2022]
Abstract
Methylation of arginine residues by protein arginine methyltransferases (PRMTs) is involved in the regulation of fundamental cellular processes, including transcription, RNA processing, signal transduction cascades, the DNA damage response and liquid-liquid phase separation. Recent studies have provided considerable advances in the development of experimental tools and the identification of clinically relevant PRMT inhibitors. In this review, we discuss the regulation of PRMTs, their various cellular roles and the clinical relevance of PRMT inhibitors for the therapy of neurodegenerative diseases and cancer.
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20
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Zhao J, Adams A, Weinman SA, Tikhanovich I. Hepatocyte PRMT1 protects from alcohol induced liver injury by modulating oxidative stress responses. Sci Rep 2019; 9:9111. [PMID: 31235809 PMCID: PMC6591482 DOI: 10.1038/s41598-019-45585-2] [Citation(s) in RCA: 26] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2018] [Accepted: 02/11/2019] [Indexed: 01/23/2023] Open
Abstract
Protein Arginine methyltransferase 1 (PRMT1) is the main enzyme of cellular arginine methylation. Previously we found that PRMT1 activity in the liver is altered after alcohol exposure resulting in epigenetic changes. To determine the impact of these PRMT1 changes on the liver's response to alcohol, we induced a hepatocyte specific PRMT1 knockout using AAV mediated Cre delivery in mice fed either alcohol or control Lieber-DeCarli liquid diet. We found that in alcohol fed mice, PRMT1 prevents oxidative stress and promotes hepatocyte survival. PRMT1 knockout in alcohol fed mice resulted in a dramatic increase in hepatocyte death, inflammation and fibrosis. Additionally, we found that alcohol promotes PRMT1 dephosphorylation at S297. Phosphorylation at this site is necessary for PRMT1-dependent protein arginine methylation. PRMT1 S297A, a dephosphorylation mimic of PRMT1 had reduced ability to promote gene expression of pro-inflammatory cytokines, pro-apoptotic genes BIM and TRAIL and expression of a suppressor of hepatocyte proliferation, Hnf4α. On the other hand, several functions of PRMT1 were phosphorylation-independent, including expression of oxidative stress response genes, Sod1, Sod2 and others. In vitro, both wild type and S297A PRMT1 protected hepatocytes from oxidative stress induced apoptosis, however S297D phosphorylation mimic PRMT1 promoted cell death. Taken together these data suggest that PRMT1 is an essential factor of liver adaptation to alcohol; alcohol-induced dephosphorylation shifts PRMT1 toward a less pro-inflammatory, more pro-proliferative and pro-survival form.
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Affiliation(s)
- Jie Zhao
- Department of Internal Medicine, University of Kansas Medical Center, Kansas, United States
| | - Abby Adams
- Department of Internal Medicine, University of Kansas Medical Center, Kansas, United States.,Liver Center, University of Kansas Medical Center, Kansas, United States
| | - Steven A Weinman
- Department of Internal Medicine, University of Kansas Medical Center, Kansas, United States.,Liver Center, University of Kansas Medical Center, Kansas, United States
| | - Irina Tikhanovich
- Department of Internal Medicine, University of Kansas Medical Center, Kansas, United States.
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21
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Wang SCM, Dowhan DH, Muscat GEO. Epigenetic arginine methylation in breast cancer: emerging therapeutic strategies. J Mol Endocrinol 2019; 62:R223-R237. [PMID: 30620710 DOI: 10.1530/jme-18-0224] [Citation(s) in RCA: 27] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/11/2018] [Accepted: 01/07/2019] [Indexed: 02/06/2023]
Abstract
Breast cancer is a heterogeneous disease, and the complexity of breast carcinogenesis is associated with epigenetic modification. There are several major classes of epigenetic enzymes that regulate chromatin activity. This review will focus on the nine mammalian protein arginine methyltransferases (PRMTs) and the dysregulation of PRMT expression and function in breast cancer. This class of enzymes catalyse the mono- and (symmetric and asymmetric) di-methylation of arginine residues on histone and non-histone target proteins. PRMT signalling (and R methylation) drives cellular proliferation, cell invasion and metastasis, targeting (i) nuclear hormone receptor signalling, (ii) tumour suppressors, (iii) TGF-β and EMT signalling and (iv) alternative splicing and DNA/chromatin stability, influencing the clinical and survival outcomes in breast cancer. Emerging reports suggest that PRMTs are also implicated in the development of drug/endocrine resistance providing another prospective avenue for the treatment of hormone resistance and associated metastasis. The complexity of PRMT signalling is further underscored by the degree of alternative splicing and the scope of variant isoforms (with distinct properties) within each PRMT family member. The evolution of PRMT inhibitors, and the ongoing clinical trials of PRMT inhibitors against a subgroup of solid cancers, coupled to the track record of lysine methyltransferases inhibitors in phase I/II clinical trials against cancer underscores the potential therapeutic utility of targeting PRMT epigenetic enzymes to improve survival outcomes in aggressive and metastatic breast cancer.
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Affiliation(s)
- Shu-Ching M Wang
- Cell Biology and Molecular Medicine Division, The University of Queensland, Institute for Molecular Bioscience, St Lucia, Australia
| | - Dennis H Dowhan
- Cell Biology and Molecular Medicine Division, The University of Queensland, Institute for Molecular Bioscience, St Lucia, Australia
| | - George E O Muscat
- Cell Biology and Molecular Medicine Division, The University of Queensland, Institute for Molecular Bioscience, St Lucia, Australia
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22
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Fulton MD, Brown T, Zheng YG. Mechanisms and Inhibitors of Histone Arginine Methylation. CHEM REC 2018; 18:1792-1807. [PMID: 30230223 PMCID: PMC6348102 DOI: 10.1002/tcr.201800082] [Citation(s) in RCA: 63] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2018] [Accepted: 08/27/2018] [Indexed: 12/16/2022]
Abstract
Histone methylation plays an important regulatory role in chromatin restructuring and RNA transcription. Arginine methylation that is enzymatically catalyzed by the family of protein arginine methyltransferases (PRMTs) can either activate or repress gene expression depending on cellular contexts. Given the strong correlation of PRMTs with pathophysiology, great interest is seen in understanding molecular mechanisms of PRMTs in diseases and in developing potent PRMT inhibitors. Herein, we reviewed key research advances in the study of biochemical mechanisms of PRMT catalysis and their relevance to cell biology. We highlighted how a random binary, ordered ternary kinetic model for PRMT1 catalysis reconciles the literature reports and endorses a distributive mechanism that the enzyme active site utilizes for multiple turnovers of arginine methylation. We discussed the impacts of histone arginine methylation and its biochemical interplays with other key epigenetic marks. Challenges in developing small-molecule PRMT inhibitors were also discussed.
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Affiliation(s)
- Melody D Fulton
- Department of Pharmaceutical and Biomedical Sciences College of Pharmacy, University of Georgia, Athens, GA 30602
| | - Tyler Brown
- Department of Pharmaceutical and Biomedical Sciences College of Pharmacy, University of Georgia, Athens, GA 30602
| | - Y George Zheng
- Department of Pharmaceutical and Biomedical Sciences College of Pharmacy, University of Georgia, Athens, GA 30602
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23
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Bao J, Di Lorenzo A, Lin K, Lu Y, Zhong Y, Sebastian MM, Muller WJ, Yang Y, Bedford MT. Mouse Models of Overexpression Reveal Distinct Oncogenic Roles for Different Type I Protein Arginine Methyltransferases. Cancer Res 2018; 79:21-32. [PMID: 30352814 DOI: 10.1158/0008-5472.can-18-1995] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2018] [Revised: 09/03/2018] [Accepted: 10/16/2018] [Indexed: 01/22/2023]
Abstract
Protein arginine methyltransferases (PRMT) are generally not mutated in diseased states, but they are overexpressed in a number of cancers, including breast cancer. To address the possible roles of PRMT overexpression in mammary gland tumorigenesis, we generated Cre-activated PRMT1, CARM1, and PRMT6 overexpression mouse models. These three enzymes are the primary type I PRMTs and are responsible for the majority of the asymmetric arginine methylation deposited in the cells. Using either a keratin 5-Cre recombinase (K5-Cre) cross or an MMTV-NIC mouse, we investigated the impact of PRMT overexpression alone or in the context of a HER2-driven model of breast cancer, respectively. The overexpression of all three PRMTs induced hyper-branching of the mammary glands and increased Ki-67 staining. When combined with the MMTV-NIC model, these in vivo experiments provided the first genetic evidence implicating elevated levels of these three PRMTs in mammary gland tumorigenesis, albeit with variable degrees of tumor promotion and latency. In addition, these mouse models provided valuable tools for exploring the biological roles and molecular mechanisms of PRMT overexpression in the mammary gland. For example, transcriptome analysis of purified mammary epithelial cells isolated from bigenic NIC-PRMT1 Tg and NIC-PRMT6 Tg mice revealed a deregulated PI3K-AKT pathway. In the future, these PRMT Tg lines can be leveraged to investigate the roles of arginine methylation in other tissues and tumor model systems using different tissue-specific Cre crosses, and they can also be used for testing the in vivo efficacy of small molecule inhibitors that target these PRMT. SIGNIFICANCE: These findings establish Cre-activated mouse models of three different arginine methyltransferases, PRMT1, CARM1, and PRMT6, which are overexpressed in human cancers, providing a valuable tool for the study of PRMT function in tumorigenesis.See related commentary by Watson and Bitler, p. 3.
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Affiliation(s)
- Jianqiang Bao
- Department of Epigenetics and Molecular Carcinogenesis, The University of Texas MD Anderson Cancer Center, Smithville, Texas
| | - Alessandra Di Lorenzo
- Department of Epigenetics and Molecular Carcinogenesis, The University of Texas MD Anderson Cancer Center, Smithville, Texas
| | - Kevin Lin
- Department of Epigenetics and Molecular Carcinogenesis, The University of Texas MD Anderson Cancer Center, Smithville, Texas
| | - Yue Lu
- Department of Epigenetics and Molecular Carcinogenesis, The University of Texas MD Anderson Cancer Center, Smithville, Texas
| | - Yi Zhong
- Department of Epigenetics and Molecular Carcinogenesis, The University of Texas MD Anderson Cancer Center, Smithville, Texas
| | - Manu M Sebastian
- Department of Epigenetics and Molecular Carcinogenesis, The University of Texas MD Anderson Cancer Center, Smithville, Texas
| | - William J Muller
- Department of Biochemistry, Rosalind and Morris Goodman Cancer Research Centre, McGill University, Montreal, Quebec, Canada
| | - Yanzhong Yang
- Department of Cancer Genetics and Epigenetics, Beckman Research Institute at City of Hope, Duarte, California
| | - Mark T Bedford
- Department of Epigenetics and Molecular Carcinogenesis, The University of Texas MD Anderson Cancer Center, Smithville, Texas.
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24
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Li Y, McGrail DJ, Xu J, Mills GB, Sahni N, Yi S. Gene Regulatory Network Perturbation by Genetic and Epigenetic Variation. Trends Biochem Sci 2018; 43:576-592. [PMID: 29941230 DOI: 10.1016/j.tibs.2018.05.002] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2018] [Revised: 04/25/2018] [Accepted: 05/27/2018] [Indexed: 01/28/2023]
Abstract
Gene regulatory networks underlie biological function and cellular physiology. Alternative splicing (AS) is a fundamental step in gene regulatory networks and plays a key role in development and disease. In addition to the identification of aberrant AS events, an increasing number of studies are focusing on molecular determinants of AS, including genetic and epigenetic regulators. We review here recent efforts to identify various deregulated AS events as well as their molecular determinants that alter biological functions, and discuss clinical features of AS and their druggable potential.
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Affiliation(s)
- Yongsheng Li
- Department of Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; College of Bioinformatics Science and Technology and Bio-Pharmaceutical Key Laboratory of Heilongjiang Province, Harbin Medical University, Harbin 150081, China
| | - Daniel J McGrail
- Department of Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Juan Xu
- College of Bioinformatics Science and Technology and Bio-Pharmaceutical Key Laboratory of Heilongjiang Province, Harbin Medical University, Harbin 150081, China
| | - Gordon B Mills
- Department of Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Nidhi Sahni
- Department of Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; Program in Quantitative and Computational Biosciences (QCB), Baylor College of Medicine, Houston, TX 77030, USA; Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA; Department of Epigenetics and Molecular Carcinogenesis, The University of Texas MD Anderson Cancer Center, Smithville, TX 78957, USA.
| | - Song Yi
- Department of Oncology, Dell Medical School, The University of Texas at Austin, Austin, TX 78712, USA; Department of Biomedical Engineering, Cockrell School of Engineering, The University of Texas at Austin, Austin, TX 78712, USA.
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25
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Smith E, Zhou W, Shindiapina P, Sif S, Li C, Baiocchi RA. Recent advances in targeting protein arginine methyltransferase enzymes in cancer therapy. Expert Opin Ther Targets 2018; 22:527-545. [PMID: 29781349 PMCID: PMC6311705 DOI: 10.1080/14728222.2018.1474203] [Citation(s) in RCA: 32] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
INTRODUCTION Exploration in the field of epigenetics has revealed the diverse roles of the protein arginine methyltransferase (PRMT) family of proteins in multiple disease states. These findings have led to the development of specific inhibitors and discovery of several new classes of drugs with potential to treat both benign and malignant conditions. Areas covered: We provide an overview on the role of PRMT enzymes in healthy and malignant cells, highlighting the role of arginine methylation in specific pathways relevant to cancer pathogenesis. Additionally, we describe structure and catalytic activity of PRMT and discuss the mechanisms of action of novel small molecule inhibitors of specific members of the arginine methyltransferase family. Expert opinion: As the field of PRMT biology advances, it's becoming clear that this class of enzymes is highly relevant to maintaining normal physiologic processes as well and disease pathogenesis. We discuss the potential impact of PRMT inhibitors as a broad class of drugs, including the pleiotropic effects, off target effects the need for more detailed PRMT-centric interactomes, and finally, the potential for targeting this class of enzymes in clinical development of experimental therapeutics for cancer.
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Affiliation(s)
- Emily Smith
- The Division of Hematology, Department of Internal Medicine, The Ohio State University, Columbus, OH 43210, USA
| | - Wei Zhou
- Department of Biochemistry and Molecular Biology, College of Medicine, University of Florida, Gainesville, FL 32610, USA
| | - Polina Shindiapina
- The Division of Hematology, Department of Internal Medicine, The Ohio State University, Columbus, OH 43210, USA
| | - Said Sif
- Department of Biological and Environmental Sciences, College of Arts and Sciences, Qatar University, Doha, Qatar
| | - Chenglong Li
- Department of Biochemistry and Molecular Biology, College of Medicine, University of Florida, Gainesville, FL 32610, USA
- Department of Medicinal Chemistry, College of Pharmacy, University of Florida, Gainesville, FL 32610, USA
| | - Robert A. Baiocchi
- The Division of Hematology, Department of Internal Medicine, The Ohio State University, Columbus, OH 43210, USA
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26
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Zhao J, Adams A, Roberts B, O'Neil M, Vittal A, Schmitt T, Kumer S, Cox J, Li Z, Weinman SA, Tikhanovich I. Protein arginine methyl transferase 1- and Jumonji C domain-containing protein 6-dependent arginine methylation regulate hepatocyte nuclear factor 4 alpha expression and hepatocyte proliferation in mice. Hepatology 2018; 67:1109-1126. [PMID: 29023917 PMCID: PMC5826837 DOI: 10.1002/hep.29587] [Citation(s) in RCA: 48] [Impact Index Per Article: 6.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/25/2017] [Revised: 09/13/2017] [Accepted: 10/02/2017] [Indexed: 12/27/2022]
Abstract
UNLABELLED Alcohol is a well-established risk factor for hepatocellular carcinoma (HCC), but the mechanisms by which it promotes liver cancer are not well understood. Several studies have shown that cellular protein arginine methylation is inhibited by alcohol. Arginine methylation is controlled by the reciprocal activity of protein arginine methyltransferases, primarily protein arginine methyl transferase 1 (PRMT1), and a demethylase Jumonji C domain-containing protein 6 (JMJD6). The aim of this study was to explore the role of arginine methylation changes in alcohol pathogenesis. We found that PRMT1 activity is inhibited in livers of mice fed with alcohol compared to pair-fed mice. Using hepatocyte-specific PRMT1 knockout mice, we identified that loss of PRMT1 results in enhanced hepatocyte proliferation and a 33% increase in liver size. This increased hepatocyte proliferation was associated with reduced expression of hepatocyte nuclear factor 4 alpha (Hnf4α), an important regulator of liver tumorigenesis. We found that PRMT1 regulates Hnf4α expression directly through arginine methylation at the (Hnf4α) promoter. In the absence of PRMT1, JMJD6 can demethylate the Hnf4α promoter and suppress its expression. We were able to restore Hnf4α expression and abolish the increase in hepatocyte proliferation by knockdown of JMJD6 in PRMT1 knockout mice. Knockdown of JMJD6 in alcohol-fed mice similarly increased Hnf4α expression. We then examined whether loss of arginine methylation might play a role in alcohol-associated liver cancers. We examined 25 human HCC specimens and found a strong correlation (R = 0.8; P < 0.01) between arginine methylation levels and Hnf4α expression in these specimens, suggesting that the above mechanism is relevant in patients. CONCLUSION Taken together, these data suggest that PRMT1 inhibition, such as induced by alcohol, may result in epigenetic changes leading to loss of Hnf4α. This effect may contribute to alcohol's ability to promote liver tumors. (Hepatology 2018;67:1109-1126).
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Affiliation(s)
- Jie Zhao
- Department of Internal Medicine, Kansas City, KS 66160, U.S.A
| | - Abby Adams
- Department of Internal Medicine, Kansas City, KS 66160, U.S.A,Liver Center, University of Kansas Medical Center, Kansas City, KS 66160, U.S.A
| | - Ben Roberts
- Liver Center, University of Kansas Medical Center, Kansas City, KS 66160, U.S.A
| | - Maura O'Neil
- Department of Pathology, Kansas City, KS 66160, U.S.A
| | - Anusha Vittal
- Department of Internal Medicine, Kansas City, KS 66160, U.S.A
| | | | - Sean Kumer
- Department of Surgery, Kansas City, KS 66160, U.S.A
| | - Josiah Cox
- Department of Internal Medicine, Kansas City, KS 66160, U.S.A
| | - Zhuan Li
- Department of Internal Medicine, Kansas City, KS 66160, U.S.A
| | - Steven A. Weinman
- Department of Internal Medicine, Kansas City, KS 66160, U.S.A,Liver Center, University of Kansas Medical Center, Kansas City, KS 66160, U.S.A
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27
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Poulard C, Corbo L, Le Romancer M. Protein arginine methylation/demethylation and cancer. Oncotarget 2018; 7:67532-67550. [PMID: 27556302 PMCID: PMC5341895 DOI: 10.18632/oncotarget.11376] [Citation(s) in RCA: 90] [Impact Index Per Article: 12.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2016] [Accepted: 08/09/2016] [Indexed: 12/13/2022] Open
Abstract
Protein arginine methylation is a common post-translational modification involved in numerous cellular processes including transcription, DNA repair, mRNA splicing and signal transduction. Currently, there are nine known members of the protein arginine methyltransferase (PRMT) family, but only one arginine demethylase has been identified, namely the Jumonji domain-containing 6 (JMJD6). Although its demethylase activity was initially challenged, its dual activity as an arginine demethylase and a lysine hydroxylase is now recognized. Interestingly, a growing number of substrates for arginine methylation and demethylation play key roles in tumorigenesis. Though alterations in the sequence of these enzymes have not been identified in cancer, their overexpression is associated with various cancers, suggesting that they could constitute targets for therapeutic strategies. In this review, we present the recent knowledge of the involvement of PRMTs and JMJD6 in tumorigenesis.
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Affiliation(s)
- Coralie Poulard
- Department of Biochemistry and Molecular Biology, University of Southern California Norris Comprehensive Cancer Center, University of Southern California Los Angeles, Los Angeles, CA, USA.,Université de Lyon, F-69000 Lyon, France.,Université Lyon 1, F-69000 Lyon, France.,Inserm U1052, Centre de Recherche en Cancérologie de Lyon, F-69000 Lyon, France.,CNRS UMR5286, Centre de Recherche en Cancérologie de Lyon, F-69000 Lyon, France.,Equipe Labellisée, La Ligue Contre le Cancer, 75013 Paris, France
| | - Laura Corbo
- Université de Lyon, F-69000 Lyon, France.,Université Lyon 1, F-69000 Lyon, France.,Inserm U1052, Centre de Recherche en Cancérologie de Lyon, F-69000 Lyon, France.,CNRS UMR5286, Centre de Recherche en Cancérologie de Lyon, F-69000 Lyon, France.,Equipe Labellisée, La Ligue Contre le Cancer, 75013 Paris, France
| | - Muriel Le Romancer
- Université de Lyon, F-69000 Lyon, France.,Université Lyon 1, F-69000 Lyon, France.,Inserm U1052, Centre de Recherche en Cancérologie de Lyon, F-69000 Lyon, France.,CNRS UMR5286, Centre de Recherche en Cancérologie de Lyon, F-69000 Lyon, France.,Equipe Labellisée, La Ligue Contre le Cancer, 75013 Paris, France
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28
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Jin S, Mi Y, Song J, Zhang P, Liu Y. PRMT1-RBM15 axis regulates megakaryocytic differentiation of human umbilical cord blood CD34 + cells. Exp Ther Med 2018; 15:2563-2568. [PMID: 29456659 DOI: 10.3892/etm.2018.5693] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2017] [Accepted: 09/13/2017] [Indexed: 12/26/2022] Open
Abstract
Protein arginine methyltransferase 1 (PRMT1) serves pivotal roles in various cellular processes. However, its role in megakaryocytic differentiation has not been clearly reported. The aim of the present study was to explore the role of the PRMT-RNA binding motif protein 15 (RBM15) axis in human MK differentiation and the feasibility of targeting PRMT1 for leukemia treatment. In the present study, PRMT1 was overexpressed and the RBM15 protein was knocked down in human umbilical cord blood cluster of differentiation (CD)34+ cells and the cells were then cultured in megakaryocytic differentiation medium. Flow cytometry was used to analyze CD41 and CD42 double-positive cells, as well as the protein expression levels of PRMT1 and RBM15. The results demonstrated that human cord blood CD34+ cells differentiate into mature MKs in high thrombopoitin medium, as demonstrated by CD41 and CD42 expression. Overexpression of PRMT1 in human umbilical cord blood CD34+ cells blocked the maturation of megakaryocytic cells. Knockdown of RBM15 by short hairpin RNA produced less mature MKs. PRMT1 inhibitor rescued PRMT1-blocked megakaryocytic differentiation. These results provide evidence for a novel role of PRMT1 in the negative regulation of megakaryocytic differentiation. PRMT1 may be a therapeutic target for leukemia treatment.
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Affiliation(s)
- Shuiling Jin
- Department of Internal Medicine, The Second Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450014, P.R. China
| | - Yanfang Mi
- Department of Otolaryngology Head and Neck Surgery, The Second Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450014, P.R. China
| | - Jing Song
- Department of Internal Medicine, The Second Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450014, P.R. China
| | - Peipei Zhang
- Department of Internal Medicine, Henan Cancer Hospital and Affiliated Cancer Hospital of Zhengzhou University, Zhengzhou, Henan 450008, P.R. China
| | - Yanyan Liu
- Department of Internal Medicine, Henan Cancer Hospital and Affiliated Cancer Hospital of Zhengzhou University, Zhengzhou, Henan 450008, P.R. China
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29
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Chiang K, Zielinska AE, Shaaban AM, Sanchez-Bailon MP, Jarrold J, Clarke TL, Zhang J, Francis A, Jones LJ, Smith S, Barbash O, Guccione E, Farnie G, Smalley MJ, Davies CC. PRMT5 Is a Critical Regulator of Breast Cancer Stem Cell Function via Histone Methylation and FOXP1 Expression. Cell Rep 2017; 21:3498-3513. [PMID: 29262329 PMCID: PMC5746596 DOI: 10.1016/j.celrep.2017.11.096] [Citation(s) in RCA: 136] [Impact Index Per Article: 17.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2017] [Revised: 11/01/2017] [Accepted: 11/28/2017] [Indexed: 12/26/2022] Open
Abstract
Breast cancer progression, treatment resistance, and relapse are thought to originate from a small population of tumor cells, breast cancer stem cells (BCSCs). Identification of factors critical for BCSC function is therefore vital for the development of therapies. Here, we identify the arginine methyltransferase PRMT5 as a key in vitro and in vivo regulator of BCSC proliferation and self-renewal and establish FOXP1, a winged helix/forkhead transcription factor, as a critical effector of PRMT5-induced BCSC function. Mechanistically, PRMT5 recruitment to the FOXP1 promoter facilitates H3R2me2s, SET1 recruitment, H3K4me3, and gene expression. Our findings are clinically significant, as PRMT5 depletion within established tumor xenografts or treatment of patient-derived BCSCs with a pre-clinical PRMT5 inhibitor substantially reduces BCSC numbers. Together, our findings highlight the importance of PRMT5 in BCSC maintenance and suggest that small-molecule inhibitors of PRMT5 or downstream targets could be an effective strategy eliminating this cancer-causing population.
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Affiliation(s)
- Kelly Chiang
- Institute of Cancer and Genomic Sciences, College of Medical and Dental Sciences, University of Birmingham, Birmingham B15 2TT, UK
| | - Agnieszka E Zielinska
- Institute of Cancer and Genomic Sciences, College of Medical and Dental Sciences, University of Birmingham, Birmingham B15 2TT, UK
| | - Abeer M Shaaban
- Department of Cellular Pathology, Queen Elizabeth Hospital Birmingham, and Institute of Cancer and Genomic Sciences, University of Birmingham, Birmingham B15 2GW, UK
| | - Maria Pilar Sanchez-Bailon
- Institute of Cancer and Genomic Sciences, College of Medical and Dental Sciences, University of Birmingham, Birmingham B15 2TT, UK
| | - James Jarrold
- Institute of Cancer and Genomic Sciences, College of Medical and Dental Sciences, University of Birmingham, Birmingham B15 2TT, UK
| | - Thomas L Clarke
- Institute of Cancer and Genomic Sciences, College of Medical and Dental Sciences, University of Birmingham, Birmingham B15 2TT, UK
| | - Jingxian Zhang
- Institute of Molecular and Cell Biology (IMCB), A(∗)STAR (Agency for Science, Technology and Research), 61 Biopolis Drive, Proteos Building #3-06, 138673 Singapore, Singapore
| | - Adele Francis
- Department of Cellular Pathology, Queen Elizabeth Hospital Birmingham, and Institute of Cancer and Genomic Sciences, University of Birmingham, Birmingham B15 2GW, UK
| | - Louise J Jones
- Centre for Tumour Biology, Barts Cancer Institute, A Cancer Research UK Centre of Excellence, Queen Mary University of London, John Vane Science Centre, London EC1M 6BQ, UK
| | - Sally Smith
- Centre for Tumour Biology, Barts Cancer Institute, A Cancer Research UK Centre of Excellence, Queen Mary University of London, John Vane Science Centre, London EC1M 6BQ, UK
| | - Olena Barbash
- Cancer Epigenetics DPU, GlaxoSmithKline, Collegeville, PA 19426, USA
| | - Ernesto Guccione
- Institute of Molecular and Cell Biology (IMCB), A(∗)STAR (Agency for Science, Technology and Research), 61 Biopolis Drive, Proteos Building #3-06, 138673 Singapore, Singapore; Department of Oncological Sciences and Pharmacological Sciences, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Gillian Farnie
- Structural Genomics Consortium, Botnar Research Centre, NDORMS, University of Oxford, Oxford OX3 7LD, UK
| | - Matthew J Smalley
- European Cancer Stem Cell Research Institute, Cardiff School of Biosciences, Cardiff University, Cardiff CF24 4HQ, UK
| | - Clare C Davies
- Institute of Cancer and Genomic Sciences, College of Medical and Dental Sciences, University of Birmingham, Birmingham B15 2TT, UK.
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30
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Zhang Y, Wang D, Zhang M, Wei H, Lu Y, Sun Y, Zhou M, Gu S, Feng W, Wang H, Zeng J, Gong A, Xu M. Protein arginine methyltransferase 1 coordinates the epithelial-mesenchymal transition/proliferation dichotomy in gastric cancer cells. Exp Cell Res 2017; 362:43-50. [PMID: 29097184 DOI: 10.1016/j.yexcr.2017.10.035] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2017] [Revised: 10/26/2017] [Accepted: 10/28/2017] [Indexed: 02/06/2023]
Abstract
Protein arginine methyltransferase 1 (PRMT1) is up-regulated and promotes migration, invasion and proliferation in wide range of cancers. However, we for the first time identify that PRMT1 promotes migration and invasion and inhibits proliferation in gastric cancer cells, a phenomenon called "migration-proliferation dichotomy". First, we find that PRMT1 overexpression promotes migration and invasion and inhibits proliferation, whereas PRMT1 knockdown reverses the above abilities. Next, PRMT1 reduces the expression of epithelial marker E-cadherin and increases the expression of mesenchymal markers including N-cadherin, Vimentin, snail and β-catenin in gastric cancer cells. Furthermore, our studies show that PRMT1 silencing promotes the phosphorylation of LATS1, and then induces YAP phosphorylation, while overexpression of PRMT1 down-regulates the phosphorylation of LATS1 and YAP, indicating that PRMT1 inhibits EMT probably via Hippo signaling. Collectively, the present study reveals important roles of PRMT1 in progression of gastric cancer. Given the dual functions of PRMT1, it is as a potential drug target of gastric cancer with extreme caution.
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Affiliation(s)
- Youli Zhang
- Department of Gastroenterology, Affiliated Hospital of Jiangsu University, Jiangsu University, Zhenjiang, Jiangsu, China
| | - Dawei Wang
- Department of Gastroenterology, Affiliated Hospital of Jiangsu University, Jiangsu University, Zhenjiang, Jiangsu, China
| | - Meiting Zhang
- Department of Gastroenterology, Affiliated Hospital of Jiangsu University, Jiangsu University, Zhenjiang, Jiangsu, China
| | - Hong Wei
- Department of Gastroenterology, Affiliated Hospital of Jiangsu University, Jiangsu University, Zhenjiang, Jiangsu, China
| | - Ying Lu
- Department of Gastroenterology, Affiliated Hospital of Jiangsu University, Jiangsu University, Zhenjiang, Jiangsu, China
| | - Yaocheng Sun
- Department of General Surgery, Affiliated Hospital of Jiangsu University, Jiangsu University, Zhenjiang, Jiangsu, China
| | - Meng Zhou
- Department of Gastroenterology, Affiliated Hospital of Jiangsu University, Jiangsu University, Zhenjiang, Jiangsu, China
| | - Shuming Gu
- Department of Gastroenterology, Affiliated Hospital of Jiangsu University, Jiangsu University, Zhenjiang, Jiangsu, China
| | - Wen Feng
- Department of Gastroenterology, Affiliated Hospital of Jiangsu University, Jiangsu University, Zhenjiang, Jiangsu, China
| | - Huizhi Wang
- Department of Gastroenterology, Affiliated Hospital of Jiangsu University, Jiangsu University, Zhenjiang, Jiangsu, China
| | - Jian Zeng
- Department of Cell Biology, School of Medicine, Jiangsu University, Zhenjiang, Jiangsu, China
| | - Aihua Gong
- Department of Cell Biology, School of Medicine, Jiangsu University, Zhenjiang, Jiangsu, China.
| | - Min Xu
- Department of Gastroenterology, Affiliated Hospital of Jiangsu University, Jiangsu University, Zhenjiang, Jiangsu, China.
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Wang C, Jiang H, Jin J, Xie Y, Chen Z, Zhang H, Lian F, Liu YC, Zhang C, Ding H, Chen S, Zhang N, Zhang Y, Jiang H, Chen K, Ye F, Yao Z, Luo C. Development of Potent Type I Protein Arginine Methyltransferase (PRMT) Inhibitors of Leukemia Cell Proliferation. J Med Chem 2017; 60:8888-8905. [PMID: 29019697 DOI: 10.1021/acs.jmedchem.7b01134] [Citation(s) in RCA: 45] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
Protein Arginine Methyltransferases (PRMTs) are crucial players in diverse biological processes, and dysregulation of PRMTs has been linked to various human diseases, especially cancer. Therefore, small molecules targeting PRMTs have profound impact for both academic functional studies and clinical disease treatment. Here, we report the discovery of N1-(2-((2-chlorophenyl)thio)benzyl)-N1-methylethane-1,2-diamine (28d, DCPR049_12), a highly potent inhibitor of type I PRMTs that has good selectivity against a panel of other methyltransferases. Compound 28d effectively inhibits cell proliferation in several leukemia cell lines and reduces the cellular asymmetric arginine dimethylation levels. Serving as an effective inhibitor, 28d demonstrates the mechanism of cell killing in both cell cycle arrest and apoptotic effect as well as downregulation of the pivotal mixed lineage leukemia (MLL) fusion target genes such as HOXA9 and MEIS1, which reflects the critical roles of type I PRMTs in MLL leukemia. These studies present 28d as a valuable inhibitor to investigate the role of type I PRMTs in cancer and other diseases.
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Affiliation(s)
- Chen Wang
- College of Life Sciences, Zhejiang Sci-Tech University , Hangzhou 310018, China.,Drug Discovery and Design Center, CAS Key Laboratory of Receptor Research, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences , 555 Zuchongzhi Road, Shanghai 201203, China.,University of Chinese Academy of Sciences , 19 Yuquan Road, Beijing 100049, China
| | - Hao Jiang
- Drug Discovery and Design Center, CAS Key Laboratory of Receptor Research, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences , 555 Zuchongzhi Road, Shanghai 201203, China.,University of Chinese Academy of Sciences , 19 Yuquan Road, Beijing 100049, China
| | - Jia Jin
- College of Life Sciences, Zhejiang Sci-Tech University , Hangzhou 310018, China
| | - Yiqian Xie
- Drug Discovery and Design Center, CAS Key Laboratory of Receptor Research, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences , 555 Zuchongzhi Road, Shanghai 201203, China
| | - Zhifeng Chen
- School of Life Science and Technology, ShanghaiTech University , 100 Haike Road, Shanghai 201210, China
| | - Hao Zhang
- Drug Discovery and Design Center, CAS Key Laboratory of Receptor Research, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences , 555 Zuchongzhi Road, Shanghai 201203, China
| | - Fulin Lian
- Drug Discovery and Design Center, CAS Key Laboratory of Receptor Research, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences , 555 Zuchongzhi Road, Shanghai 201203, China
| | - Yu-Chih Liu
- Shanghai ChemPartner Co., Ltd. , #5 Building, 998, Halei Road, Shanghai 201203, China
| | - Chenhua Zhang
- Shanghai ChemPartner Co., Ltd. , #5 Building, 998, Halei Road, Shanghai 201203, China
| | - Hong Ding
- Drug Discovery and Design Center, CAS Key Laboratory of Receptor Research, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences , 555 Zuchongzhi Road, Shanghai 201203, China
| | - Shijie Chen
- Drug Discovery and Design Center, CAS Key Laboratory of Receptor Research, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences , 555 Zuchongzhi Road, Shanghai 201203, China
| | - Naixia Zhang
- Drug Discovery and Design Center, CAS Key Laboratory of Receptor Research, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences , 555 Zuchongzhi Road, Shanghai 201203, China
| | - Yuanyuan Zhang
- Drug Discovery and Design Center, CAS Key Laboratory of Receptor Research, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences , 555 Zuchongzhi Road, Shanghai 201203, China
| | - Hualiang Jiang
- Drug Discovery and Design Center, CAS Key Laboratory of Receptor Research, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences , 555 Zuchongzhi Road, Shanghai 201203, China
| | - Kaixian Chen
- Drug Discovery and Design Center, CAS Key Laboratory of Receptor Research, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences , 555 Zuchongzhi Road, Shanghai 201203, China.,School of Life Science and Technology, ShanghaiTech University , 100 Haike Road, Shanghai 201210, China
| | - Fei Ye
- College of Life Sciences, Zhejiang Sci-Tech University , Hangzhou 310018, China
| | - Zhiyi Yao
- College of Chemical and Environmental Engineering, Shanghai Institute of Technology , Shanghai 210032, China
| | - Cheng Luo
- Drug Discovery and Design Center, CAS Key Laboratory of Receptor Research, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences , 555 Zuchongzhi Road, Shanghai 201203, China
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Patounas O, Papacharalampous I, Eckerich C, Markopoulos GS, Kolettas E, Fackelmayer FO. A novel splicing isoform of protein arginine methyltransferase 1 (PRMT1) that lacks the dimerization arm and correlates with cellular malignancy. J Cell Biochem 2017; 119:2110-2123. [PMID: 28857308 DOI: 10.1002/jcb.26373] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2017] [Accepted: 08/24/2017] [Indexed: 02/02/2023]
Abstract
Methylation of arginine residues is an important modulator of protein function that is involved in epigenetic gene regulation, DNA damage response and RNA maturation, as well as in cellular signaling. The enzymes that catalyze this post-translational modification are called protein arginine methyltransferases (PRMTs), of which PRMT1 is the predominant enzyme. Human PRMT1 has previously been shown to occur in seven splicing isoforms, which are differentially abundant in different tissues, and have distinct substrate specificity and intracellular localization. Here we characterize a novel splicing isoform which does not affect the amino-terminus of the protein like the seven known isoforms, but rather lacks exons 8 and 9 which encode the dimerization arm of the enzyme that is essential for enzymatic activity. Consequently, the isoform does not form catalytically active oligomers with the other endogenous PRMT1 isoforms. Photobleaching experiments reveal an immobile fraction of the enzyme in the nucleus, in accordance with earlier results from our laboratory that had shown a tight association of inhibited or inactivated PRMT1 with chromatin and the nuclear scaffold. Thus, it apparently is able to bind to the same substrates as catalytically active PRMT1. This isoform is found in a variety of cell lines, but is increased in those of cancer origin or after expression of the EMT-inducing transcriptional repressor Snail1. We discuss that the novel isoform could act as a modulator of PRMT1 activity in cancer cells by acting as a competitive inhibitor that shields substrates from access to active PRMT1 oligomers.
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Affiliation(s)
- Odysseas Patounas
- Institute of Molecular Biology and Biotechnology (IMBB-FORTH), Laboratory for Epigenetics and Chromosome Biology, Ioannina, Greece
| | - Ioanna Papacharalampous
- Cardiothoracic Pharmacology, National Heart and Lung Institute, Imperial College, London, UK
| | - Carmen Eckerich
- Institute of Molecular Biology and Biotechnology (IMBB-FORTH), Laboratory for Epigenetics and Chromosome Biology, Ioannina, Greece
| | - Georgios S Markopoulos
- Laboratory of Biology, School of Medicine, University of Ioannina, Ioannina, Greece.,Department of Biomedical Research, Institute of Molecular Biology and Biotechnology (IMBB-FORTH), Ioannina, Greece
| | - Evangelos Kolettas
- Laboratory of Biology, School of Medicine, University of Ioannina, Ioannina, Greece.,Department of Biomedical Research, Institute of Molecular Biology and Biotechnology (IMBB-FORTH), Ioannina, Greece
| | - Frank O Fackelmayer
- Institute of Molecular Biology and Biotechnology (IMBB-FORTH), Laboratory for Epigenetics and Chromosome Biology, Ioannina, Greece
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Cornella N, Tebaldi T, Gasperini L, Singh J, Padgett RA, Rossi A, Macchi P. The hnRNP RALY regulates transcription and cell proliferation by modulating the expression of specific factors including the proliferation marker E2F1. J Biol Chem 2017; 292:19674-19692. [PMID: 28972179 DOI: 10.1074/jbc.m117.795591] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2017] [Revised: 09/18/2017] [Indexed: 12/31/2022] Open
Abstract
The heterogeneous nuclear ribonucleoproteins (hnRNP) form a large family of RNA-binding proteins that exert numerous functions in RNA metabolism. RALY is a member of the hnRNP family that binds poly-U-rich elements within several RNAs and regulates the expression of specific transcripts. RALY is up-regulated in different types of cancer, and its down-regulation impairs cell cycle progression. However, the RALY's role in regulating RNA levels remains elusive. Here, we show that numerous genes coding for factors involved in transcription and cell cycle regulation exhibit an altered expression in RALY-down-regulated HeLa cells, consequently causing impairments in transcription, cell proliferation, and cell cycle progression. Interestingly, by comparing the list of RALY targets with the list of genes affected by RALY down-regulation, we found an enrichment of RALY mRNA targets in the down-regulated genes upon RALY silencing. The affected genes include the E2F transcription factor family. Given its role as proliferation-promoting transcription factor, we focused on E2F1. We demonstrate that E2F1 mRNA stability and E2F1 protein levels are reduced in cells lacking RALY expression. Finally, we also show that RALY interacts with transcriptionally active chromatin in both an RNA-dependent and -independent manner and that this association is abolished in the absence of active transcription. Taken together, our results highlight the importance of RALY as an indirect regulator of transcription and cell cycle progression through the regulation of specific mRNA targets, thus strengthening the possibility of a direct gene expression regulation exerted by RALY.
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Affiliation(s)
- Nicola Cornella
- From the Laboratory of Molecular and Cellular Neurobiology, Centre for Integrative Biology, University of Trento, via Sommarive 9, 38123 Trento, Italy
| | - Toma Tebaldi
- the Laboratory of Translational Genomics, Centre for Integrative Biology, University of Trento, via Sommarive 9, 38123 Trento, Italy
| | - Lisa Gasperini
- From the Laboratory of Molecular and Cellular Neurobiology, Centre for Integrative Biology, University of Trento, via Sommarive 9, 38123 Trento, Italy
| | | | | | - Annalisa Rossi
- From the Laboratory of Molecular and Cellular Neurobiology, Centre for Integrative Biology, University of Trento, via Sommarive 9, 38123 Trento, Italy,
| | - Paolo Macchi
- From the Laboratory of Molecular and Cellular Neurobiology, Centre for Integrative Biology, University of Trento, via Sommarive 9, 38123 Trento, Italy,
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35
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Bondy-Chorney E, Baldwin RM, Didillon A, Chabot B, Jasmin BJ, Côté J. RNA binding protein RALY promotes Protein Arginine Methyltransferase 1 alternatively spliced isoform v2 relative expression and metastatic potential in breast cancer cells. Int J Biochem Cell Biol 2017; 91:124-135. [PMID: 28733251 DOI: 10.1016/j.biocel.2017.07.008] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2017] [Revised: 07/09/2017] [Accepted: 07/15/2017] [Indexed: 01/24/2023]
Abstract
Aberrant expression of Protein Arginine Methyltransferases (PRMTs) has been observed in several cancer types, including breast cancer. We previously reported that the PRMT1v2 isoform, which is generated through inclusion of alternative exon 2, is overexpressed in breast cancer cells and promotes their invasiveness. However, the precise mechanism by which expression of this isoform is controlled and how it is dysregulated in breast cancer remains unknown. Using a custom RNA interference-based screen, we identified several RNA binding proteins (RBP) which, when knocked down, altered the relative abundance of the alternatively spliced PRMT1v2 isoform. Amongst the top hits were SNW Domain containing 1 (SNW1) and RBP-associated with lethal yellow mutation (RALY), which both associated with the PRMT1 pre-mRNA and upon depletion caused an increase or decrease in the relative abundance of PRMT1v2 isoform mRNA and protein. Most importantly, a significant decrease in invasion was observed upon RALY knockdown in aggressive breast cancer cells, consistent with targeting PRMT1v2 directly, and this effect was rescued by the exogenous re-expression of PRMT1v2. We show that SNW1 expression is decreased, while RALY expression is increased in breast cancer cells and tumours, which correlates with decreased patient survival. This work revealed crucial insight into the mechanisms regulating the expression of the PRMT1 alternatively spliced isoform v2 and its dysregulation in breast cancer. It also provides proof-of-concept support for the development of therapeutic strategies where regulators of PRMT1 exon 2 alternative splicing are targeted as an approach to selectively reduce PRMT1v2 levels and metastasis in breast cancer.
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Affiliation(s)
- Emma Bondy-Chorney
- Department of Cellular and Molecular Medicine, University of Ottawa, Centre for Neuromuscular Disease, Ottawa, Ontario, K1H 8L1, Canada
| | - R Mitchell Baldwin
- Department of Cellular and Molecular Medicine, University of Ottawa, Centre for Neuromuscular Disease, Ottawa, Ontario, K1H 8L1, Canada
| | - Andréanne Didillon
- Department of Cellular and Molecular Medicine, University of Ottawa, Centre for Neuromuscular Disease, Ottawa, Ontario, K1H 8L1, Canada
| | - Benoît Chabot
- Département de microbiologie et d'infectiologie, Faculté de Médecine et des sciences de la santé, Université de Sherbrooke, Sherbrooke, Québec, J1 K 2R1, Canada
| | - Bernard J Jasmin
- Department of Cellular and Molecular Medicine, University of Ottawa, Centre for Neuromuscular Disease, Ottawa, Ontario, K1H 8L1, Canada
| | - Jocelyn Côté
- Department of Cellular and Molecular Medicine, University of Ottawa, Centre for Neuromuscular Disease, Ottawa, Ontario, K1H 8L1, Canada.
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36
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Tudor Domain Containing Protein 3 Promotes Tumorigenesis and Invasive Capacity of Breast Cancer Cells. Sci Rep 2017; 7:5153. [PMID: 28698590 PMCID: PMC5506013 DOI: 10.1038/s41598-017-04955-4] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2017] [Accepted: 05/23/2017] [Indexed: 02/07/2023] Open
Abstract
Tudor domain containing protein 3 (TDRD3) is a modular protein identified based on its ability to recognize methylated arginine motifs through its Tudor domain. We have previously shown that TDRD3 localizes to cytoplasmic stress granules, a structure shown to promote survival upon treatment with chemotherapeutic drugs in cancer cells. Here, we report TDRD3 as a novel regulator of cell proliferation and invasion in breast cancer cells. Our study also demonstrates that TDRD3 depletion inhibits tumor formation and metastasis to the lung in vivo. Furthermore, we show that TDRD3 regulates the expression of a number of key genes associated with promotion of breast cancer tumorigenesis and disease progression. Strikingly, we report that TDRD3 regulates some of these key targets at the level of translation. These findings provide the first experimental demonstration of a functional role for TDRD3 in promoting breast cancer development and progression, and identify TDRD3 as a potential new therapeutic target for breast cancer.
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Zhong J, Chen YJ, Chen L, Shen YY, Zhang QH, Yang J, Cao RX, Zu XY, Wen GB. PRMT2β, a C-terminal splice variant of PRMT2, inhibits the growth of breast cancer cells. Oncol Rep 2017; 38:1303-1311. [PMID: 28677794 DOI: 10.3892/or.2017.5786] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2017] [Accepted: 06/27/2017] [Indexed: 11/06/2022] Open
Abstract
Our previous study reported several alternative splicing variants of arginine N-methyltransferase 2 (PRMT2), which lose different exons in the C-terminals of the wild-type PRMT2 gene. Particularly, due to frame-shifting, PRMT2β encodes a novel amino acid sequence at the C-terminus of the protein, the function of which is not understood. In the present study, we determined the role of PRMT2β in breast cancer cell proliferation, apoptosis and its effect on the Akt signaling pathway. Stable breast cancer MCF7 cell line with lentivirus-mediated PRMT2β overexpression was obtained after selection by puromycin for 2 weeks. The effect of lentivirus-mediated PRMT2β overexpression on breast cancer cellular oncogenic properties was evaluated by MTT, colony formation, cell cycle analysis and apoptosis assays in MCF7 cells. Luciferase activity assay and western blot analysis were performed to characterize the effects of PRMT2β on cyclin D1 promoter activities and the Akt signaling pathway. Tissue microarray was performed to investigate the association of PRMT2β with breast cancer progression. Lentivirus-mediated PRMT2β overexpression suppressed the cell proliferation and colony formation of breast cancer MCF7 cells. PRMT2β overexpression induced cell cycle arrest and apoptosis of MCF7 cells. Furthermore, PRMT2β was revealed to suppress the transcription activity of the cyclin D1 promoter, and PRMT2β was also found to inhibit cyclin D1 expression via the suppression of Akt/GSK-3β signaling in breast cancer cells. Clinically, it was revealed that PRMT2β expression was negatively correlated with human epidermal growth factor receptor 2 (HER2) (p=0.033) in breast tumors. Our results revealed that PRMT2β, a novel splice variant of PRMT2, plays potential antitumor effect by suppressing cyclin D1 expression and inhibiting Akt signaling activity. This also opens a new avenue for treating breast cancer.
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Affiliation(s)
- Jing Zhong
- Institute of Clinical Medicine, The First Affiliated Hospital of University of South China, Hengyang, Hunan 421001, P.R. China
| | - Ya-Jun Chen
- Institute of Clinical Medicine, The First Affiliated Hospital of University of South China, Hengyang, Hunan 421001, P.R. China
| | - Ling Chen
- Institute of Clinical Medicine, The First Affiliated Hospital of University of South China, Hengyang, Hunan 421001, P.R. China
| | - Ying-Ying Shen
- Institute of Clinical Medicine, The First Affiliated Hospital of University of South China, Hengyang, Hunan 421001, P.R. China
| | - Qing-Hai Zhang
- Institute of Clinical Medicine, The First Affiliated Hospital of University of South China, Hengyang, Hunan 421001, P.R. China
| | - Jing Yang
- Department of Metabolism and Endocrinology, The First Affiliated Hospital of University of South China, Hengyang, Hunan 421001, P.R. China
| | - Ren-Xian Cao
- Institute of Clinical Medicine, The First Affiliated Hospital of University of South China, Hengyang, Hunan 421001, P.R. China
| | - Xu-Yu Zu
- Institute of Clinical Medicine, The First Affiliated Hospital of University of South China, Hengyang, Hunan 421001, P.R. China
| | - Ge-Bo Wen
- Institute of Clinical Medicine, The First Affiliated Hospital of University of South China, Hengyang, Hunan 421001, P.R. China
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Abstract
BACKGROUND Epidermal growth factor receptor (EGFR) is often overexpressed in triple-negative breast cancer (TNBC). However, clinical studies have shown that therapies against EGFR are not effective in patients with TNBC. Recently, it has been reported that arginine 198/200 in EGFR extracellular domain is methylated by PRMT1 and that the methylation confers resistance to EGFR monoclonal antibody cetuximab in colorectal cancer cells. To explore a potential mechanism underlying intrinsic resistance to anti-EGFR therapy in TNBC, we investigated the role of PRMT1 in EGFR methylation and signaling in MDA-MB-468 (468) TNBC cells. METHODS We knocked down PRMT1 in 468 cells by shRNA, and subjected the cell lysates to Western blot analysis to examine EGFR activation and its downstream molecules. We also evaluated cell proliferation and sphere formation of PRMT1-knockdown cells. Finally, we examined the effects of pan-PRMT inhibitor, AMI-1, on cetuximab by colony formation and soft agar assays. RESULTS EGFR methylation and activity was significantly reduced in PRMT1-knockdown cells compared to the parental cells. Knockdown of PRMT1 also reduced cell proliferation and sphere formation. Moreover, AMI-1 sensitized 468 cells to cetuximab. CONCLUSION The results indicate that PRMT1 is critical for EGFR activity in 468 cells. Our data also suggest that inhibition of PRMT1 sensitizes TNBC cells to cetuximab. Thus, inhibition of PRMT1 may be an effective therapeutic strategy to overcome intrinsic resistance to cetuximab in TNBC.
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Chuang CY, Chang CP, Lee YJ, Lin WL, Chang WW, Wu JS, Cheng YW, Lee H, Li C. PRMT1 expression is elevated in head and neck cancer and inhibition of protein arginine methylation by adenosine dialdehyde or PRMT1 knockdown downregulates proliferation and migration of oral cancer cells. Oncol Rep 2017; 38:1115-1123. [PMID: 28656289 DOI: 10.3892/or.2017.5737] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2016] [Accepted: 04/05/2017] [Indexed: 11/05/2022] Open
Abstract
Protein arginine methylation is a post-translational modification that has been implicated in signal transduction, gene transcription, DNA repair and RNA processing. Overexpression or deregulation of protein arginine methyltransferases (PRMTs) have been reported to be associated with various cancers but have not been studied in head and neck cancer (HNC). We investigated the involvement of the modification in HNC using oral cancer cell lines (SAS, OECM-1 and HSC-3) and an immortalized normal oral cells (S-G). The expression levels of the predominant PRMT1 were generally consistent with the levels of asymmetric dimethylarginine (ADMA), highest in SAS and OECM1, then S-G and low in HSC-3. Upon the treatment with an indirect methyltransferase inhibitor adenosine dialdehyde (AdOx), the ADMA levels in SAS and OECM1, but not that in S-G and HSC-3, decreased significantly. SAS and OECM with high ADMA levels grew faster than HSC-3 and S-G. The growth rate of the fast growing SAS and OECM, but not that of the other two cell lines, decreased significantly upon AdOx treatment. The migration activity of SAS and HSC-3, two cell lines with migration ability also decreased after the AdOx treatment. Immunohistochemical analyses of specimens from typical HNC patients showed strong PRMT1 expression in the tumor cells compared with neighboring normal cells. Knockdown of PRMT1 in SAS cells decreased the levels of PRMT1 and ADMA-containing proteins significantly. These cells showed decreased growth rate, reduced migration activity but increased expression of the epithelial marker E-cadherin. The present study thus provides fundamental background for evaluation of the PRMT1 gene as the therapeutic targets of HNC.
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Affiliation(s)
- Chun-Yi Chuang
- School of Medicine, Chung Shan Medical University, Taichung, Taiwan, R.O.C
| | - Chien-Ping Chang
- Department of Biomedical Sciences, Chung Shan Medical University, Taichung, Taiwan, R.O.C
| | - Yu-Jen Lee
- Department of Biomedical Sciences, Chung Shan Medical University, Taichung, Taiwan, R.O.C
| | - Wei-Long Lin
- School of Medicine, Chung Shan Medical University, Taichung, Taiwan, R.O.C
| | - Wen-Wei Chang
- Department of Biomedical Sciences, Chung Shan Medical University, Taichung, Taiwan, R.O.C
| | - Jia-Sian Wu
- Department of Biomedical Sciences, Chung Shan Medical University, Taichung, Taiwan, R.O.C
| | - Ya-Wen Cheng
- Graduate Institute of Cancer Biology and Drug Discovery, Taipei Medical University, Taipei 110, Taiwan, R.O.C
| | - Huei Lee
- Graduate Institute of Cancer Biology and Drug Discovery, Taipei Medical University, Taipei 110, Taiwan, R.O.C
| | - Chuan Li
- Department of Biomedical Sciences, Chung Shan Medical University, Taichung, Taiwan, R.O.C
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40
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Abstract
![]()
Post-translational
modifications of histones by protein methyltransferases
(PMTs) and histone demethylases (KDMs) play an important role in the
regulation of gene expression and transcription and are implicated
in cancer and many other diseases. Many of these enzymes also target
various nonhistone proteins impacting numerous crucial biological
pathways. Given their key biological functions and implications in
human diseases, there has been a growing interest in assessing these
enzymes as potential therapeutic targets. Consequently, discovering
and developing inhibitors of these enzymes has become a very active
and fast-growing research area over the past decade. In this review,
we cover the discovery, characterization, and biological application
of inhibitors of PMTs and KDMs with emphasis on key advancements in
the field. We also discuss challenges, opportunities, and future directions
in this emerging, exciting research field.
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Affiliation(s)
- H Ümit Kaniskan
- Departments of Pharmacological Sciences and Oncological Sciences, Icahn School of Medicine at Mount Sinai , New York, New York 10029, United States
| | - Michael L Martini
- Departments of Pharmacological Sciences and Oncological Sciences, Icahn School of Medicine at Mount Sinai , New York, New York 10029, United States
| | - Jian Jin
- Departments of Pharmacological Sciences and Oncological Sciences, Icahn School of Medicine at Mount Sinai , New York, New York 10029, United States
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PRMT1 promotes mitosis of cancer cells through arginine methylation of INCENP. Oncotarget 2016; 6:35173-82. [PMID: 26460953 PMCID: PMC4742097 DOI: 10.18632/oncotarget.6050] [Citation(s) in RCA: 29] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2015] [Accepted: 09/25/2015] [Indexed: 11/25/2022] Open
Abstract
Inner centromere protein (INCENP) is a part of a protein complex known as the chromosomal passenger complex (CPC) that is essential for correcting non-bipolar chromosome attachments and for cytokinesis. We here demonstrate that a protein arginine methyltransferase PRMT1, which are overexpressed in various types of cancer including lung and bladder cancer, methylates arginine 887 in an Aurora Kinase B (AURKB)-binding region of INCENP both in vitro and in vivo. R887-substituted INCENP revealed lower binding-affinity to AURKB than wild-type INCENP in the presence of PRMT1. Knockdown of PRMT1 as well as overexpression of methylation-inactive INCENP attenuated the AURKB activity in cancer cells, and resulted in abnormal chromosomal alignment and segregation. Furthermore, introduction of methylation-inactive INCENP into cancer cells reduced the growth rate, compared with those introduced wild-type INCENP or Mock. Our data unveils a novel mechanism of PRMT1-mediated CPC regulation through methylation of INCENP.
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Zhu S, Xu Y, Song M, Chen G, Wang H, Zhao Y, Wang Z, Li F. PRDM16 is associated with evasion of apoptosis by prostatic cancer cells according to RNA interference screening. Mol Med Rep 2016; 14:3357-61. [DOI: 10.3892/mmr.2016.5605] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2015] [Accepted: 06/27/2016] [Indexed: 11/06/2022] Open
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Eram MS, Shen Y, Szewczyk M, Wu H, Senisterra G, Li F, Butler KV, Kaniskan HÜ, Speed BA, dela Seña C, Dong A, Zeng H, Schapira M, Brown PJ, Arrowsmith CH, Barsyte-Lovejoy D, Liu J, Vedadi M, Jin J. A Potent, Selective, and Cell-Active Inhibitor of Human Type I Protein Arginine Methyltransferases. ACS Chem Biol 2016; 11:772-781. [PMID: 26598975 PMCID: PMC4798913 DOI: 10.1021/acschembio.5b00839] [Citation(s) in RCA: 198] [Impact Index Per Article: 22.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Protein arginine methyltransferases (PRMTs) play a crucial role in a variety of biological processes. Overexpression of PRMTs has been implicated in various human diseases including cancer. Consequently, selective small-molecule inhibitors of PRMTs have been pursued by both academia and the pharmaceutical industry as chemical tools for testing biological and therapeutic hypotheses. PRMTs are divided into three categories: type I PRMTs which catalyze mono- and asymmetric dimethylation of arginine residues, type II PRMTs which catalyze mono- and symmetric dimethylation of arginine residues, and type III PRMT which catalyzes only monomethylation of arginine residues. Here, we report the discovery of a potent, selective, and cell-active inhibitor of human type I PRMTs, MS023, and characterization of this inhibitor in a battery of biochemical, biophysical, and cellular assays. MS023 displayed high potency for type I PRMTs including PRMT1, -3, -4, -6, and -8 but was completely inactive against type II and type III PRMTs, protein lysine methyltransferases and DNA methyltransferases. A crystal structure of PRMT6 in complex with MS023 revealed that MS023 binds the substrate binding site. MS023 potently decreased cellular levels of histone arginine asymmetric dimethylation. It also reduced global levels of arginine asymmetric dimethylation and concurrently increased levels of arginine monomethylation and symmetric dimethylation in cells. We also developed MS094, a close analog of MS023, which was inactive in biochemical and cellular assays, as a negative control for chemical biology studies. MS023 and MS094 are useful chemical tools for investigating the role of type I PRMTs in health and disease.
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Affiliation(s)
- Mohammad S. Eram
- Structural Genomics Consortium, University of Toronto, Toronto, Ontario, M5G 1L7, Canada
| | - Yudao Shen
- Departments of Structural and Chemical Biology, Oncological Sciences, and Pharmacology and Systems Therapeutics, Icahn School of Medicine at Mount Sinai, New York, New York 10029, United States
| | - Magdalena Szewczyk
- Structural Genomics Consortium, University of Toronto, Toronto, Ontario, M5G 1L7, Canada
| | - Hong Wu
- Structural Genomics Consortium, University of Toronto, Toronto, Ontario, M5G 1L7, Canada
| | - Guillermo Senisterra
- Structural Genomics Consortium, University of Toronto, Toronto, Ontario, M5G 1L7, Canada
| | - Fengling Li
- Structural Genomics Consortium, University of Toronto, Toronto, Ontario, M5G 1L7, Canada
| | - Kyle V. Butler
- Departments of Structural and Chemical Biology, Oncological Sciences, and Pharmacology and Systems Therapeutics, Icahn School of Medicine at Mount Sinai, New York, New York 10029, United States
| | - H. Ümit Kaniskan
- Departments of Structural and Chemical Biology, Oncological Sciences, and Pharmacology and Systems Therapeutics, Icahn School of Medicine at Mount Sinai, New York, New York 10029, United States
| | - Brandon A. Speed
- Departments of Structural and Chemical Biology, Oncological Sciences, and Pharmacology and Systems Therapeutics, Icahn School of Medicine at Mount Sinai, New York, New York 10029, United States
| | - Carlo dela Seña
- Structural Genomics Consortium, University of Toronto, Toronto, Ontario, M5G 1L7, Canada
| | - Aiping Dong
- Structural Genomics Consortium, University of Toronto, Toronto, Ontario, M5G 1L7, Canada
| | - Hong Zeng
- Structural Genomics Consortium, University of Toronto, Toronto, Ontario, M5G 1L7, Canada
| | - Matthieu Schapira
- Structural Genomics Consortium, University of Toronto, Toronto, Ontario, M5G 1L7, Canada
- Department of Pharmacology and Toxicology, University of Toronto, Toronto, Ontario, M5S 1A8, Canada
| | - Peter J. Brown
- Structural Genomics Consortium, University of Toronto, Toronto, Ontario, M5G 1L7, Canada
| | - Cheryl H. Arrowsmith
- Structural Genomics Consortium, University of Toronto, Toronto, Ontario, M5G 1L7, Canada
- Princess Margaret Cancer Centre and Department of Medical Biophysics, University of Toronto, Toronto, Ontario, M5G 2M9, Canada
| | - Dalia Barsyte-Lovejoy
- Structural Genomics Consortium, University of Toronto, Toronto, Ontario, M5G 1L7, Canada
| | - Jing Liu
- Departments of Structural and Chemical Biology, Oncological Sciences, and Pharmacology and Systems Therapeutics, Icahn School of Medicine at Mount Sinai, New York, New York 10029, United States
| | - Masoud Vedadi
- Structural Genomics Consortium, University of Toronto, Toronto, Ontario, M5G 1L7, Canada
- Department of Pharmacology and Toxicology, University of Toronto, Toronto, Ontario, M5S 1A8, Canada
| | - Jian Jin
- Departments of Structural and Chemical Biology, Oncological Sciences, and Pharmacology and Systems Therapeutics, Icahn School of Medicine at Mount Sinai, New York, New York 10029, United States
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Hu H, Qian K, Ho MC, Zheng YG. Small Molecule Inhibitors of Protein Arginine Methyltransferases. Expert Opin Investig Drugs 2016; 25:335-58. [PMID: 26789238 DOI: 10.1517/13543784.2016.1144747] [Citation(s) in RCA: 99] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/03/2023]
Abstract
INTRODUCTION Arginine methylation is an abundant posttranslational modification occurring in mammalian cells and catalyzed by protein arginine methyltransferases (PRMTs). Misregulation and aberrant expression of PRMTs are associated with various disease states, notably cancer. PRMTs are prominent therapeutic targets in drug discovery. AREAS COVERED The authors provide an updated review of the research on the development of chemical modulators for PRMTs. Great efforts are seen in screening and designing potent and selective PRMT inhibitors, and a number of micromolar and submicromolar inhibitors have been obtained for key PRMT enzymes such as PRMT1, CARM1, and PRMT5. The authors provide a focus on their chemical structures, mechanism of action, and pharmacological activities. Pros and cons of each type of inhibitors are also discussed. EXPERT OPINION Several key challenging issues exist in PRMT inhibitor discovery. Structural mechanisms of many PRMT inhibitors remain unclear. There lacks consistency in potency data due to divergence of assay methods and conditions. Physiologically relevant cellular assays are warranted. Substantial engagements are needed to investigate pharmacodynamics and pharmacokinetics of the new PRMT inhibitors in pertinent disease models. Discovery and evaluation of potent, isoform-selective, cell-permeable and in vivo-active PRMT modulators will continue to be an active arena of research in years ahead.
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Affiliation(s)
- Hao Hu
- a Department of Pharmaceutical and Biomedical Sciences , The University of Georgia , Athens , GA , USA
| | - Kun Qian
- a Department of Pharmaceutical and Biomedical Sciences , The University of Georgia , Athens , GA , USA
| | - Meng-Chiao Ho
- b Institute of Biological Chemistry , Academia Sinica , Nankang , Taipei , Taiwan
| | - Y George Zheng
- a Department of Pharmaceutical and Biomedical Sciences , The University of Georgia , Athens , GA , USA
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The dual function of PRMT1 in modulating epithelial-mesenchymal transition and cellular senescence in breast cancer cells through regulation of ZEB1. Sci Rep 2016; 6:19874. [PMID: 26813495 PMCID: PMC4728496 DOI: 10.1038/srep19874] [Citation(s) in RCA: 77] [Impact Index Per Article: 8.6] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2015] [Accepted: 12/18/2015] [Indexed: 12/31/2022] Open
Abstract
Although the involvement of protein arginine methyltransferase 1 (PRMT1) in tumorigenesis has been reported, its roles in breast cancer progression and metastasis has not been elucidated. Here we identified PRMT1 as a key regulator of the epithelial-mesenchymal transition (EMT) in breast cancer. We showed that the EMT program induced by PRMT1 endowed the human mammary epithelial cells with cancer stem cell properties. Moreover, PRMT1 promoted the migratory and invasive behaviors in breast cancer cells. We also demonstrated that abrogation of PRMT1 expression in breast cancer cells abated metastasis in vivo in mouse model. In addition, knockdown of PRMT1 arrested cell growth in G1 tetraploidy and induced cellular senescence. Mechanistically, PRMT1 impacted EMT process and cellular senescence by mediating the asymmetric dimethylation of arginine 3 of histone H4 (H4R3me2as) at the ZEB1 promoter to activate its transcription, indicating the essential roles of this epigenetic control both in EMT and in senescence. Thus, we unraveled a dual function of PRMT1 in modulation of both EMT and senescence via regulating ZEB1. This finding points to the potent value of PRMT1 as a dual therapeutic target for preventing metastasis and for inhibiting cancer cell growth in malignant breast cancer patients.
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Chen Y, Wang L, Li L, Zhang H, Yuan Z. Informative gene selection and the direct classification of tumors based on relative simplicity. BMC Bioinformatics 2016; 17:44. [PMID: 26792270 PMCID: PMC4721022 DOI: 10.1186/s12859-016-0893-0] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2015] [Accepted: 01/19/2016] [Indexed: 12/15/2022] Open
Abstract
BACKGROUND Selecting a parsimonious set of informative genes to build highly generalized performance classifier is the most important task for the analysis of tumor microarray expression data. Many existing gene pair evaluation methods cannot highlight diverse patterns of gene pairs only used one strategy of vertical comparison and horizontal comparison, while individual-gene-ranking method ignores redundancy and synergy among genes. RESULTS Here we proposed a novel score measure named relative simplicity (RS). We evaluated gene pairs according to integrating vertical comparison with horizontal comparison, finally built RS-based direct classifier (RS-based DC) based on a set of informative genes capable of binary discrimination with a paired votes strategy. Nine multi-class gene expression datasets involving human cancers were used to validate the performance of new method. Compared with the nine reference models, RS-based DC received the highest average independent test accuracy (91.40%), the best generalization performance and the smallest informative average gene number (20.56). Compared with the four reference feature selection methods, RS also received the highest average test accuracy in three classifiers (Naïve Bayes, k-Nearest Neighbor and Support Vector Machine), and only RS can improve the performance of SVM. CONCLUSIONS Diverse patterns of gene pairs could be highlighted more fully while integrating vertical comparison with horizontal comparison strategy. DC core classifier can effectively control over-fitting. RS-based feature selection method combined with DC classifier can lead to more robust selection of informative genes and classification accuracy.
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Affiliation(s)
- Yuan Chen
- Hunan Provincial Key Laboratory for Biology and Control of Plant Diseases and Insect Pests, Changsha, China. .,Hunan Provincial Key Laboratory for Germplasm Innovation and Utilization of Crop, Hunan Agricultural University, Changsha, China.
| | - Lifeng Wang
- Biotechnology Research Center, Hunan Academy of Agricultural Sciences, Changsha, China.
| | - Lanzhi Li
- Hunan Provincial Key Laboratory for Germplasm Innovation and Utilization of Crop, Hunan Agricultural University, Changsha, China.
| | - Hongyan Zhang
- Hunan Provincial Key Laboratory for Germplasm Innovation and Utilization of Crop, Hunan Agricultural University, Changsha, China.
| | - Zheming Yuan
- Hunan Provincial Key Laboratory for Biology and Control of Plant Diseases and Insect Pests, Changsha, China. .,Hunan Provincial Key Laboratory for Germplasm Innovation and Utilization of Crop, Hunan Agricultural University, Changsha, China.
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Baldwin RM, Haghandish N, Daneshmand M, Amin S, Paris G, Falls TJ, Bell JC, Islam S, Côté J. Protein arginine methyltransferase 7 promotes breast cancer cell invasion through the induction of MMP9 expression. Oncotarget 2015; 6:3013-32. [PMID: 25605249 PMCID: PMC4413634 DOI: 10.18632/oncotarget.3072] [Citation(s) in RCA: 57] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2014] [Accepted: 12/18/2014] [Indexed: 12/05/2022] Open
Abstract
Recent evidence points to the protein arginine methyltransferase (PRMT) family of enzymes playing critical roles in cancer. PRMT7 has been identified in several gene expression studies to be associated with increased metastasis and decreased survival in breast cancer patients. However, this has not been extensively studied. Here we report that PRMT7 expression is significantly upregulated in both primary breast tumour tissues and in breast cancer lymph node metastases. We have demonstrated that reducing PRMT7 levels in invasive breast cancer cells using RNA interference significantly decreased cell invasion in vitro and metastasis in vivo. Conversely, overexpression of PRMT7 in non-aggressive MCF7 cells enhanced their invasiveness. Furthermore, we show that PRMT7 induces the expression of matrix metalloproteinase 9 (MMP9), a well-known mediator of breast cancer metastasis. Importantly, we significantly rescued invasion of aggressive breast cancer cells depleted of PRMT7 by the exogenous expression of MMP9. Our results demonstrate that upregulation of PRMT7 in breast cancer may have a significant role in promoting cell invasion through the regulation of MMP9. This identifies PRMT7 as a novel and potentially significant biomarker and therapeutic target for breast cancer.
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Affiliation(s)
- R Mitchell Baldwin
- Department of Cellular and Molecular Medicine, Ottawa, Ontario, Canada.,Faculty of Medicine, University of Ottawa, Ottawa, Ontario, Canada
| | - Nasim Haghandish
- Department of Cellular and Molecular Medicine, Ottawa, Ontario, Canada.,Faculty of Medicine, University of Ottawa, Ottawa, Ontario, Canada
| | - Manijeh Daneshmand
- Center for Innovative Cancer Therapeutics, Ottawa Hospital Research Institute, Ottawa, Ontario, Canada.,Department of Pathology and Laboratory Medicine, University of Ottawa, Ottawa, Ontario, Canada
| | - Shahrier Amin
- Department of Pathology and Laboratory Medicine, University of Ottawa, Ottawa, Ontario, Canada.,Department of Pathology, Ottawa Hospital, Ottawa, Ontario, Canada
| | - Geneviève Paris
- Department of Cellular and Molecular Medicine, Ottawa, Ontario, Canada.,Faculty of Medicine, University of Ottawa, Ottawa, Ontario, Canada
| | - Theresa J Falls
- Center for Innovative Cancer Therapeutics, Ottawa Hospital Research Institute, Ottawa, Ontario, Canada
| | - John C Bell
- Center for Innovative Cancer Therapeutics, Ottawa Hospital Research Institute, Ottawa, Ontario, Canada.,Department of Biochemistry, Microbiology and Immunology, University of Ottawa, Ottawa, Ontario, Canada
| | - Shahidul Islam
- Department of Pathology and Laboratory Medicine, University of Ottawa, Ottawa, Ontario, Canada.,Department of Pathology, Ottawa Hospital, Ottawa, Ontario, Canada
| | - Jocelyn Côté
- Department of Cellular and Molecular Medicine, Ottawa, Ontario, Canada.,Faculty of Medicine, University of Ottawa, Ottawa, Ontario, Canada
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Zhang L, Tran NT, Su H, Wang R, Lu Y, Tang H, Aoyagi S, Guo A, Khodadadi-Jamayran A, Zhou D, Qian K, Hricik T, Côté J, Han X, Zhou W, Laha S, Abdel-Wahab O, Levine RL, Raffel G, Liu Y, Chen D, Li H, Townes T, Wang H, Deng H, Zheng YG, Leslie C, Luo M, Zhao X. Cross-talk between PRMT1-mediated methylation and ubiquitylation on RBM15 controls RNA splicing. eLife 2015; 4:07938. [PMID: 26575292 PMCID: PMC4775220 DOI: 10.7554/elife.07938] [Citation(s) in RCA: 133] [Impact Index Per Article: 13.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2015] [Accepted: 11/16/2015] [Indexed: 12/24/2022] Open
Abstract
RBM15, an RNA binding protein, determines cell-fate specification of many tissues including blood. We demonstrate that RBM15 is methylated by protein arginine methyltransferase 1 (PRMT1) at residue R578, leading to its degradation via ubiquitylation by an E3 ligase (CNOT4). Overexpression of PRMT1 in acute megakaryocytic leukemia cell lines blocks megakaryocyte terminal differentiation by downregulation of RBM15 protein level. Restoring RBM15 protein level rescues megakaryocyte terminal differentiation blocked by PRMT1 overexpression. At the molecular level, RBM15 binds to pre-messenger RNA intronic regions of genes important for megakaryopoiesis such as GATA1, RUNX1, TAL1 and c-MPL. Furthermore, preferential binding of RBM15 to specific intronic regions recruits the splicing factor SF3B1 to the same sites for alternative splicing. Therefore, PRMT1 regulates alternative RNA splicing via reducing RBM15 protein concentration. Targeting PRMT1 may be a curative therapy to restore megakaryocyte differentiation for acute megakaryocytic leukemia. DOI:http://dx.doi.org/10.7554/eLife.07938.001 The many different cell types in an adult animal all develop from a single fertilized egg. The development of cells into more specialized cell types is called ‘differentiation’. Proteins and other molecules from both inside and outside of the cells regulate the differentiation process. RNA is a molecule that is similar to DNA, and performs several important roles inside cells. Perhaps most importantly, RNA molecules act as messengers and carry genetic instructions during gene expression. RBM15 is an RNA-binding protein that is found throughout nature, and is involved in a number of developmental processes. Previous research has linked the incorrect control of RBM15 with an increased risk of certain cancers, including megakaryocytic leukemia. However, it is not clear what role RNA-binding proteins such as RBM15 play during differentiation. Now, Zhang, Tran, Su et al. have investigated the role of RBM15 during the development of large cells found in human bone marrow (called megakaryocytes). First, the experiments demonstrated that an enzyme called PRMT1 modifies RBM15. This enzyme adds a chemical mark called a methyl group at a specific site (an arginine amino acid) on the RNA-binding protein. Next, Zhang, Tran, Su et al. showed that the addition of this methyl group earmarks RBM15 for destruction. This means that an increase in PRMT1 levels reduces the amount of RBM15 in cells, while decreases in PRMT1 have the opposite effect. Further experiments showed that RBM15 normally processes the RNA messengers that carry the genetic instructions needed for the differentiation of bone marrow cells. An excess of PRMT1 enzyme leads to a lack of this RNA-binding protein. This in turn interferes with the differentiation process, and can contribute to the development of cancers such as megakaryocytic leukemia. Future work will therefore explore whether targeting PRMT1 with drugs could represent an effective treatment for these kinds of cancers. DOI:http://dx.doi.org/10.7554/eLife.07938.002
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Affiliation(s)
- Li Zhang
- Department of Biochemistry and Molecular Genetics, UAB Stem Cell Institute, The University of Alabama at Birmingham, Birmingham, United States
| | - Ngoc-Tung Tran
- Department of Biochemistry and Molecular Genetics, UAB Stem Cell Institute, The University of Alabama at Birmingham, Birmingham, United States
| | - Hairui Su
- Department of Biochemistry and Molecular Genetics, UAB Stem Cell Institute, The University of Alabama at Birmingham, Birmingham, United States
| | - Rui Wang
- Program of Molecular Pharmacology, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, United States
| | - Yuheng Lu
- Computational Biology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, United States
| | - Haiping Tang
- School of Life Sciences, Tsinghua University, Beijing, China
| | - Sayura Aoyagi
- Cell Signaling Technology, Inc., Danvers, United States
| | - Ailan Guo
- Cell Signaling Technology, Inc., Danvers, United States
| | - Alireza Khodadadi-Jamayran
- Department of Biochemistry and Molecular Genetics, UAB Stem Cell Institute, The University of Alabama at Birmingham, Birmingham, United States
| | - Dewang Zhou
- Department of Biochemistry and Molecular Genetics, UAB Stem Cell Institute, The University of Alabama at Birmingham, Birmingham, United States
| | - Kun Qian
- Department of Pharmaceutical and Biomedical Sciences, The University of Georgia, Athens, United States
| | - Todd Hricik
- Human Oncology and Pathogenesis Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, United States
| | - Jocelyn Côté
- Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, Canada
| | - Xiaosi Han
- Department of Neurology, Comprehensive Cancer Center, The University of Alabama at Birmingham, Birmingham, United States
| | - Wenping Zhou
- Department of Internal Medicine, Zhengzhou - Henan Cancer Hospital, Zhengzhou, China
| | - Suparna Laha
- Division of Hematology and Oncology, University of Massachusetts Medical School, Worcester, United States
| | - Omar Abdel-Wahab
- Human Oncology and Pathogenesis Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, United States
| | - Ross L Levine
- Human Oncology and Pathogenesis Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, United States
| | - Glen Raffel
- Division of Hematology and Oncology, University of Massachusetts Medical School, Worcester, United States
| | - Yanyan Liu
- Department of Internal Medicine, Zhengzhou - Henan Cancer Hospital, Zhengzhou, China
| | - Dongquan Chen
- Division of Preventive Medicine, The University of Alabama at Birmingham, Birmingham, United States
| | - Haitao Li
- School of Life Sciences, Tsinghua University, Beijing, China
| | - Tim Townes
- Department of Biochemistry and Molecular Genetics, UAB Stem Cell Institute, The University of Alabama at Birmingham, Birmingham, United States
| | - Hengbin Wang
- Department of Biochemistry and Molecular Genetics, UAB Stem Cell Institute, The University of Alabama at Birmingham, Birmingham, United States
| | - Haiteng Deng
- School of Life Sciences, Tsinghua University, Beijing, China
| | - Y George Zheng
- Department of Pharmaceutical and Biomedical Sciences, The University of Georgia, Athens, United States
| | - Christina Leslie
- Computational Biology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, United States
| | - Minkui Luo
- Program of Molecular Pharmacology, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, United States
| | - Xinyang Zhao
- Department of Biochemistry and Molecular Genetics, UAB Stem Cell Institute, The University of Alabama at Birmingham, Birmingham, United States
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Yu XR, Tang Y, Wang WJ, Ji S, Ma S, Zhong L, Zhang CH, Yang J, Wu XA, Fu ZY, Li LL, Yang SY. Discovery and structure–activity analysis of 4-((5-nitropyrimidin-4-yl)amino)benzimidamide derivatives as novel protein arginine methyltransferase 1 (PRMT1) inhibitors. Bioorg Med Chem Lett 2015; 25:5449-53. [DOI: 10.1016/j.bmcl.2015.06.095] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2015] [Revised: 06/10/2015] [Accepted: 06/25/2015] [Indexed: 01/04/2023]
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Akter KA, Mansour MA, Hyodo T, Ito S, Hamaguchi M, Senga T. FAM98A is a novel substrate of PRMT1 required for tumor cell migration, invasion, and colony formation. Tumour Biol 2015; 37:4531-9. [DOI: 10.1007/s13277-015-4310-5] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2015] [Accepted: 10/20/2015] [Indexed: 11/29/2022] Open
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