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1
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Ayan E, Türk M, Tatlı Ö, Bostan S, Telek E, Dingiloğlu B, Doğan BZ, Alp MI, Katı A, Dinler-Doğanay G, Demirci H. X-ray crystallographic and hydrogen deuterium exchange studies confirm alternate kinetic models for homolog insulin monomers. PLoS One 2025; 20:e0319282. [PMID: 40257998 PMCID: PMC12011231 DOI: 10.1371/journal.pone.0319282] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2024] [Accepted: 01/29/2025] [Indexed: 04/23/2025] Open
Abstract
Despite the crucial role of various insulin analogs in achieving satisfactory glycemic control, a comprehensive understanding of their in-solution dynamic mechanisms still holds the potential to further optimize rapid insulin analogs, thus significantly improving the well-being of individuals with Type 1 Diabetes. Here, we employed hydrogen-deuterium exchange mass spectrometry to decipher the molecular dynamics of newly modified and functional insulin analog. A comparative analysis of H/D dynamics demonstrated that the modified insulin exchanges deuterium atoms faster and more extensively than the intact insulin aspart. Additionally, we present new insights derived from our 2.5 Å resolution X-ray crystal structure of modified hexamer insulin analog at ambient temperature. Furthermore, we obtained a distinctive side-chain conformation of the Asn3 residue on the B chain (AsnB3) by operating a comparative analysis with a previously available cryogenic rapid-acting insulin structure (PDB_ID: 4GBN). The experimental conclusions have demonstrated compatibility with modified insulin's distinct cellular activity, comparably to aspart. Additionally, the hybrid structural approach combined with computational analysis employed in this study provides novel insight into the structural dynamics of newly modified and functional insulin vs insulin aspart monomeric entities. It allows further molecular understanding of intermolecular interrelations driving dissociation kinetics and, therefore, a fast action mechanism.
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Affiliation(s)
- Esra Ayan
- Department of Molecular Biology and Genetics, Faculty of Science, Koç University, Istanbul, Türkiye
- Experimental Medicine Research and Application Center, University of Health Sciences, Istanbul, Türkiye
- Research Institute for Health Sciences and Technologies (SABITA), Neuroscience Research Center, Istanbul Medipol University, Istanbul, Türkiye
| | - Miray Türk
- Department of Molecular Biology-Genetics and Biotechnology, Istanbul Technical University, Istanbul, Türkiye
| | - Özge Tatlı
- Division of Translational Cancer Research, Department of Laboratory Medicine, Lund University, Lund, Sweden
- Department of Molecular Biology and Genetics, Istanbul Medeniyet University, Istanbul, Türkiye
| | - Sevginur Bostan
- Research Institute for Health Sciences and Technologies (SABITA), Neuroscience Research Center, Istanbul Medipol University, Istanbul, Türkiye
- Department of Physiology, International School of Medicine, Istanbul Medipol University, Istanbul, Türkiye
| | - Elek Telek
- Department of Biophysics, Medical School, University of Pécs, Pécs, Hungary
| | - Baran Dingiloğlu
- Department of Molecular Biology-Genetics and Biotechnology, Istanbul Technical University, Istanbul, Türkiye
| | - B. Züleyha Doğan
- Research Institute for Health Sciences and Technologies (SABITA), Neuroscience Research Center, Istanbul Medipol University, Istanbul, Türkiye
| | - Muhammed Ikbal Alp
- Research Institute for Health Sciences and Technologies (SABITA), Neuroscience Research Center, Istanbul Medipol University, Istanbul, Türkiye
| | - Ahmet Katı
- Experimental Medicine Research and Application Center, University of Health Sciences, Istanbul, Türkiye
| | - Gizem Dinler-Doğanay
- Department of Molecular Biology-Genetics and Biotechnology, Istanbul Technical University, Istanbul, Türkiye
- Department of Molecular Biology and Genetics, Faculty of Science and Letters, Istanbul Technical University, Istanbul, Türkiye
| | - Hasan Demirci
- Department of Molecular Biology and Genetics, Faculty of Science, Koç University, Istanbul, Türkiye
- Stanford PULSE Institute, SLAC National Laboratory, Menlo Park, California, United States of America
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Peng J, Ni B, Li D, Cheng B, Yang R. Overview of the PRMT6 modulators in cancer treatment: Current progress and emerged opportunity. Eur J Med Chem 2024; 279:116857. [PMID: 39276585 DOI: 10.1016/j.ejmech.2024.116857] [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: 07/31/2024] [Revised: 08/29/2024] [Accepted: 09/04/2024] [Indexed: 09/17/2024]
Abstract
Protein Arginine Methyltransferase 6 (PRMT6) is a Type I PRMT enzyme that plays a role in the epigenetic regulation of gene expression by methylating histone and non-histone proteins. It is also involved in various cellular processes, including alternative splicing, DNA repair, and cell signaling. Furthermore, PRMT6 exerts multiple effects on cellular processes such as growth, migration, invasion, apoptosis, and drug resistance in various cancers, positioning it as a promising target for anti-tumor therapeutics. In this review, we initially provide an overview of the structure and biological functions of PRMT6, along with its association with cancer. Subsequently, we focus on recent progress in the design and development of modulators targeting PRMT6. This includes a comprehensive review of PRMT6 inhibitors (isoform-selective and non-selective), dual-target inhibitors based on PRMT6, PRMT6 covalent inhibitors, and PRMT6-targeting hydrophobic tagging (HyT) degraders, from the perspectives of rational design, pharmacodynamics, pharmacokinetics, and the clinical status of these modulators. Finally, we also provided the challenges and prospective directions for PRMT6 targeting drug discovery in cancer therapy.
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Affiliation(s)
- Jinjin Peng
- Department of Pharmacy, First Affinity Hospital of Gannan Medical University, Ganzhou 341000, China
| | - Bin Ni
- Department of Pharmacy, First Affinity Hospital of Gannan Medical University, Ganzhou 341000, China
| | - Deping Li
- Department of Pharmacy, First Affinity Hospital of Gannan Medical University, Ganzhou 341000, China.
| | - Binbin Cheng
- School of Medicine, Hubei Polytechnic University, Huangshi 435003, China.
| | - Renze Yang
- Department of Pharmacy, First Affinity Hospital of Gannan Medical University, Ganzhou 341000, China.
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3
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Yang H, Zhang Q, Zhou S, Hu Z, Tang Q, Li Z, Feng Q, Yu L. Discovery of a first-in-class degrader for the protein arginine methyltransferase 6 (PRMT6). Bioorg Chem 2024; 148:107439. [PMID: 38754310 DOI: 10.1016/j.bioorg.2024.107439] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2024] [Revised: 04/27/2024] [Accepted: 05/08/2024] [Indexed: 05/18/2024]
Abstract
PRMT6 is a member of the protein arginine methyltransferase family, which participates in a variety of physical processes and plays an important role in the occurrence and development of tumors. Using small molecules to design and synthesize targeted protein degraders is a new strategy for drug development. Here, we report the first-in-class degrader SKLB-0124 for PRMT6 based on the hydrophobic tagging (HyT) method.Importantly, SKLB-0124 induced proteasome dependent degradation of PRMT6 and significantly inhibited the proliferation of HCC827 and MDA-MB-435 cells. Moreover, SKLB-0124 effectively induced apoptosis and cell cycle arrest in these two cell lines. Our data clarified that SKLB-0124 is a promising selective PRMT6 degrader for cancer therapy which is worthy of further evaluation.
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Affiliation(s)
- Hongling Yang
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, West China Medical School, Sichuan University, and Collaborative Innovation Center for Biotherapy, 17#3rd Section, Ren Min South Road, Chengdu 610041, China
| | - Qiangsheng Zhang
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, West China Medical School, Sichuan University, and Collaborative Innovation Center for Biotherapy, 17#3rd Section, Ren Min South Road, Chengdu 610041, China
| | - Shuyan Zhou
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, West China Medical School, Sichuan University, and Collaborative Innovation Center for Biotherapy, 17#3rd Section, Ren Min South Road, Chengdu 610041, China
| | - Zuli Hu
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, West China Medical School, Sichuan University, and Collaborative Innovation Center for Biotherapy, 17#3rd Section, Ren Min South Road, Chengdu 610041, China
| | - Qing Tang
- School of Life Science and Engineering, Southwest Jiaotong University, Chengdu, China
| | - Zulong Li
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, West China Medical School, Sichuan University, and Collaborative Innovation Center for Biotherapy, 17#3rd Section, Ren Min South Road, Chengdu 610041, China
| | - Qiang Feng
- College of Chemistry and Life Science, Chengdu Normal University, Chengdu 611130, China
| | - Luoting Yu
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, West China Medical School, Sichuan University, and Collaborative Innovation Center for Biotherapy, 17#3rd Section, Ren Min South Road, Chengdu 610041, China.
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4
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Tang J, Yin C, Chen M, Dong M, Xu Y. Yifei Sanjie formula alleviates lung cancer progression via regulating PRMT6-YBX1-CDC25A axis. ENVIRONMENTAL TOXICOLOGY 2024; 39:3225-3237. [PMID: 38357781 DOI: 10.1002/tox.24160] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/02/2023] [Revised: 12/23/2023] [Accepted: 01/18/2024] [Indexed: 02/16/2024]
Abstract
Lung cancer (LC) is the most prevalent cancer type, with a high mortality rate worldwide. The current treatment options for LC have not been particularly successful in improving patient outcomes. Yifei Sanjie (YFSJ), a well-applicated traditional Chinese medicine formula, is widely used to treat pulmonary diseases, especially LC, yet little is known about its molecular mechanisms. This study was conducted to explore the molecular mechanism by which YFSJ ameliorated LC progression. The A549, NCI-H1975, and Calu-3 cells were treated with the YFSJ formula and observed for colony number, apoptosis, migration, and invasion properties recorded via corresponding assays. The PRMT6-YBX1-CDC25A axis was tested and verified through luciferase reporter, RNA immunoprecipitation, and chromatin immunoprecipitation assays and rescue experiments. Our results demonstrated that YFSJ ameliorated LC cell malignant behaviors by increasing apoptosis and suppressing proliferation, migration, and invasion processes. We also noticed that the xenograft mouse model treated with YFSJ significantly reduced tumor growth compared with the control untreated group in vivo. Mechanistically, it was found that YFSJ suppressed the expression of PRMT6, YBX1, and CDC25A, while the knockdown of these proteins significantly inhibited colony growth, migration, and invasion, and boosted apoptosis in LC cells. In summary, our results suggest that YFSJ alleviates LC progression via the PRMT6-YBX1-CDC25A axis, confirming its efficacy in clinical use. The findings of our study provide a new regulatory network for LC growth and metastasis, which could shed new insights into pulmonary medical research.
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Affiliation(s)
- Jie Tang
- Department of Oncology, The Second Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, Jiangsu, China
| | - Chenyan Yin
- Department of Pharmacy, Jiangsu Province Hospital of Chinese Medicine, Nanjing, Jiangsu, China
| | - Meiyun Chen
- Department of Oncology, The Second Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, Jiangsu, China
| | - Mengjia Dong
- Department of Oncology, The Second Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, Jiangsu, China
| | - Youqi Xu
- Department of Oncology, The Second Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, Jiangsu, China
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Zhou S, Zhang Q, Yang H, Zhu Y, Hu X, Wan G, Yu L. Targeting type I PRMTs as promising targets for the treatment of pulmonary disorders: Asthma, COPD, lung cancer, PF, and PH. Life Sci 2024; 342:122538. [PMID: 38428571 DOI: 10.1016/j.lfs.2024.122538] [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: 10/15/2023] [Revised: 02/21/2024] [Accepted: 02/23/2024] [Indexed: 03/03/2024]
Abstract
Pulmonary disorders, including asthma, chronic obstructive pulmonary disease (COPD), pulmonary fibrosis (PF), pulmonary hypertension (PH), and lung cancer, seriously impair the quality of lives of patients. A deeper understanding of the occurrence and development of the above diseases may inspire new strategies to remedy the scarcity of treatments. Type I protein arginine methyltransferases (PRMTs) can affect processes of inflammation, airway remodeling, fibroblast proliferation, mitochondrial mass, and epithelial dysfunction through substrate methylation and non-enzymatic activity, thus affecting the occurrence and development of asthma, COPD, lung cancer, PF, and PH. As potential therapeutic targets, inhibitors of type I PRMTs are developed, moreover, representative compounds such as GSK3368715 and MS023 have also been used for early research. Here, we collated structures of type I PRMTs inhibitors and compared their activity. Finally, we highlighted the physiological and pathological associations of type I PRMTs with asthma, COPD, lung cancer, PF, and PH. The developing of type I PRMTs modulators will be beneficial for the treatment of these diseases.
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Affiliation(s)
- Shuyan Zhou
- Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Qiangsheng Zhang
- Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Honglin Yang
- Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Yongxia Zhu
- Department of Pharmacy, Sichuan Cancer Hospital & Institute, Sichuan Cancer Center, School of Medicine, University of Electronic Science and Technology of China, Chengdu, China
| | - Xiang Hu
- Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Guoquan Wan
- Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Luoting Yu
- Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, China.
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6
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Wu PY, Van Scoyk M, McHale SS, Chou CF, Riddick G, Farouq K, Hu B, Kraskauskiene V, Koblinski J, Lyons C, Rijal A, Vudatha V, Zhang D, Trevino JG, Shah RD, Nana-Sinkam P, Huang Y, Ma SF, Noth I, Hughes-Halbert C, Seewaldt VL, Chen CY, Winn RA. Cooperation between PRMT1 and PRMT6 drives lung cancer health disparities among Black/African American men. iScience 2024; 27:108858. [PMID: 38303720 PMCID: PMC10830871 DOI: 10.1016/j.isci.2024.108858] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2023] [Revised: 09/14/2023] [Accepted: 01/07/2024] [Indexed: 02/03/2024] Open
Abstract
Lung cancer is the third most common cancer with Black/AA men showing higher risk and poorer outcomes than NHW men. Lung cancer disparities are multifactorial, driven by tobacco exposure, inequities in care access, upstream health determinants, and molecular determinants including biological and genetic factors. Elevated expressions of protein arginine methyltransferases (PRMTs) correlating with poorer prognosis have been observed in many cancers. Most importantly, our study shows that PRMT6 displays higher expression in lung cancer tissues of Black/AA men compared to NHW men. In this study, we investigated the underlying mechanism of PRMT6 and its cooperation with PRMT1 to form a heteromer as a driver of lung cancer. Disrupting PRMT1/PRMT6 heteromer by a competitive peptide reduced proliferation in non-small cell lung cancer cell lines and patient-derived organoids, therefore, giving rise to a more strategic approach in the treatment of Black/AA men with lung cancer and to eliminate cancer health disparities.
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Affiliation(s)
- Pei-Ying Wu
- Massey Comprehensive Cancer Center, Virginia Commonwealth University, Richmond, VA, USA
| | - Michelle Van Scoyk
- Massey Comprehensive Cancer Center, Virginia Commonwealth University, Richmond, VA, USA
| | - Stephanie S. McHale
- Massey Comprehensive Cancer Center, Virginia Commonwealth University, Richmond, VA, USA
| | - Chu-Fang Chou
- Massey Comprehensive Cancer Center, Virginia Commonwealth University, Richmond, VA, USA
| | - Gregory Riddick
- Massey Comprehensive Cancer Center, Virginia Commonwealth University, Richmond, VA, USA
| | - Kamran Farouq
- Massey Comprehensive Cancer Center, Virginia Commonwealth University, Richmond, VA, USA
| | - Bin Hu
- Department of Pathology and Massey Comprehensive Cancer Center, Virginia Commonwealth University, Richmond, VA, USA
| | - Vita Kraskauskiene
- Department of Pathology and Massey Comprehensive Cancer Center, Virginia Commonwealth University, Richmond, VA, USA
| | - Jennifer Koblinski
- Department of Pathology and Massey Comprehensive Cancer Center, Virginia Commonwealth University, Richmond, VA, USA
| | - Charles Lyons
- Department of Pathology and Massey Comprehensive Cancer Center, Virginia Commonwealth University, Richmond, VA, USA
| | - Arjun Rijal
- Department of Pathology and Massey Comprehensive Cancer Center, Virginia Commonwealth University, Richmond, VA, USA
| | - Vignesh Vudatha
- Division of Surgical Oncology and Massey Comprehensive Cancer Center, Virginia Commonwealth University, Richmond, VA, USA
| | - Dongyu Zhang
- Division of Surgical Oncology and Massey Comprehensive Cancer Center, Virginia Commonwealth University, Richmond, VA, USA
| | - Jose G. Trevino
- Division of Surgical Oncology and Massey Comprehensive Cancer Center, Virginia Commonwealth University, Richmond, VA, USA
| | - Rachit D. Shah
- Division of Cardiothoracic Surgery, Virginia Commonwealth University, Richmond, VA, USA
| | - Patrick Nana-Sinkam
- Division of Pulmonary Disease and Critical Care Medicine, Virginia Commonwealth University, Richmond, VA, USA
| | - Yong Huang
- Division of Pulmonary and Critical Care, University of Virginia, Charlottesville, VA, USA
| | - Shwu-Fan Ma
- Division of Pulmonary and Critical Care, University of Virginia, Charlottesville, VA, USA
| | - Imre Noth
- Division of Pulmonary and Critical Care, University of Virginia, Charlottesville, VA, USA
| | - Chanita Hughes-Halbert
- Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA, USA
| | | | - Ching-Yi Chen
- Massey Comprehensive Cancer Center, Virginia Commonwealth University, Richmond, VA, USA
| | - Robert A. Winn
- Massey Comprehensive Cancer Center, Virginia Commonwealth University, Richmond, VA, USA
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7
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Discovery of cysteine-targeting covalent histone methyltransferase inhibitors. Eur J Med Chem 2023; 246:115028. [PMID: 36528996 DOI: 10.1016/j.ejmech.2022.115028] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2022] [Revised: 12/02/2022] [Accepted: 12/13/2022] [Indexed: 12/15/2022]
Abstract
Post-translational methylation of histone lysine or arginine residues by histone methyltransferases (HMTs) plays crucial roles in gene regulation and diverse physiological processes and is implicated in a plethora of human diseases, especially cancer. Therefore, histone methyltransferases have been increasingly recognized as potential therapeutic targets. Consequently, the discovery and development of histone methyltransferase inhibitors have been pursued with steadily increasing interest over the past decade. However, the disadvantages of limited clinical efficacy, moderate selectivity, and propensity for acquired resistance have hindered the development of HMTs inhibitors. Targeted covalent modification represents a proven strategy for kinase drug development and has gained increasing attention in HMTs drug discovery. In this review, we focus on the discovery, characterization, and biological applications of covalent inhibitors for HMTs with emphasis on advancements in the field. In addition, we identify the challenges and future directions in this fast-growing research area of drug discovery.
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8
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Chen Z, Gan J, Wei Z, Zhang M, Du Y, Xu C, Zhao H. The Emerging Role of PRMT6 in Cancer. Front Oncol 2022; 12:841381. [PMID: 35311114 PMCID: PMC8931394 DOI: 10.3389/fonc.2022.841381] [Citation(s) in RCA: 28] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2021] [Accepted: 02/09/2022] [Indexed: 01/01/2023] Open
Abstract
Protein arginine methyltransferase 6 (PRMT6) is a type I PRMT that is involved in epigenetic regulation of gene expression through methylating histone or non-histone proteins, and other processes such as alternative splicing, DNA repair, cell proliferation and senescence, and cell signaling. In addition, PRMT6 also plays different roles in various cancers via influencing cell growth, migration, invasion, apoptosis, and drug resistant, which make PRMT6 an anti-tumor therapeutic target for a variety of cancers. As a result, many PRMT6 inhibitors are being utilized to explore their efficacy as potential drugs for various cancers. In this review, we summarize the current knowledge on the function and structure of PRMT6. At the same time, we highlight the role of PRMT6 in different cancers, including the differentiation of its promotive or inhibitory effects and the underlying mechanisms. Apart from the above, current research progress and the potential mechanisms of PRMT6 behind them were also summarized.
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Affiliation(s)
- Zhixian Chen
- Shanghai Key Laboratory of Female Reproductive Endocrine Related Diseases, Obstetrics and Gynecology Hospital, Fudan University, Shanghai, China
- Department of Obstetrics and Gynecology of Shanghai Medical School, Fudan University, Shanghai, China
| | - Jianfeng Gan
- Shanghai Key Laboratory of Female Reproductive Endocrine Related Diseases, Obstetrics and Gynecology Hospital, Fudan University, Shanghai, China
- Department of Obstetrics and Gynecology of Shanghai Medical School, Fudan University, Shanghai, China
| | - Zhi Wei
- Shanghai Key Laboratory of Female Reproductive Endocrine Related Diseases, Obstetrics and Gynecology Hospital, Fudan University, Shanghai, China
- Department of Obstetrics and Gynecology of Shanghai Medical School, Fudan University, Shanghai, China
| | - Mo Zhang
- Shanghai Key Laboratory of Female Reproductive Endocrine Related Diseases, Obstetrics and Gynecology Hospital, Fudan University, Shanghai, China
- Department of Obstetrics and Gynecology of Shanghai Medical School, Fudan University, Shanghai, China
| | - Yan Du
- Shanghai Key Laboratory of Female Reproductive Endocrine Related Diseases, Obstetrics and Gynecology Hospital, Fudan University, Shanghai, China
- Department of Obstetrics and Gynecology of Shanghai Medical School, Fudan University, Shanghai, China
| | - Congjian Xu
- Shanghai Key Laboratory of Female Reproductive Endocrine Related Diseases, Obstetrics and Gynecology Hospital, Fudan University, Shanghai, China
- Department of Obstetrics and Gynecology of Shanghai Medical School, Fudan University, Shanghai, China
- *Correspondence: Hongbo Zhao, ; Congjian Xu,
| | - Hongbo Zhao
- Shanghai Key Laboratory of Female Reproductive Endocrine Related Diseases, Obstetrics and Gynecology Hospital, Fudan University, Shanghai, China
- Department of Obstetrics and Gynecology of Shanghai Medical School, Fudan University, Shanghai, China
- *Correspondence: Hongbo Zhao, ; Congjian Xu,
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9
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Talukdar A, Mukherjee A, Bhattacharya D. Fascinating Transformation of SAM-Competitive Protein Methyltransferase Inhibitors from Nucleoside Analogues to Non-Nucleoside Analogues. J Med Chem 2022; 65:1662-1684. [PMID: 35014841 DOI: 10.1021/acs.jmedchem.1c01208] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
The abnormal expression of protein methyltransferase (PMT) has been linked with many diseases such as diabetes, neurological disorders, and cancer. S-Adenyl-l-methionine (SAM) is a universal methyl donor and gets converted to S-adenyl-l-homocysteine (SAH), an endogenous competitive inhibitor of SAM. Initially developed SAM/SAH mimetic nucleoside analogues were pan methyltransferase inhibitors. The gradual understanding achieved through ligand-receptor interaction paved the way for various rational approaches of drug design leading to potent and selective nucleoside inhibitors. The present perspective is based on the systematic evolution of selective SAM-competitive heterocyclic non-nucleoside inhibitors from nucleoside inhibitors. This fascinating transition has resolved several issues inherent to nucleoside analogues such as poor pharmacokinetics leading to poor in vivo efficacy. The perspective has brought together various concepts and strategies of drug design that contributed to this rational transition. We firmly believe that the strategies described herein will serve as a template for the future development of drugs in general.
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Affiliation(s)
- Arindam Talukdar
- Department of Organic and Medicinal Chemistry, CSIR-Indian Institute of Chemical Biology, 4 Raja S. C. Mullick Road, Kolkata 700032, WB, India.,Academy of Scientific and Innovative Research, Ghaziabad 201002, India
| | - Ayan Mukherjee
- Department of Organic and Medicinal Chemistry, CSIR-Indian Institute of Chemical Biology, 4 Raja S. C. Mullick Road, Kolkata 700032, WB, India.,Academy of Scientific and Innovative Research, Ghaziabad 201002, India
| | - Debomita Bhattacharya
- Department of Organic and Medicinal Chemistry, CSIR-Indian Institute of Chemical Biology, 4 Raja S. C. Mullick Road, Kolkata 700032, WB, India
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10
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Structure, Activity and Function of the Protein Arginine Methyltransferase 6. Life (Basel) 2021; 11:life11090951. [PMID: 34575100 PMCID: PMC8470942 DOI: 10.3390/life11090951] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2021] [Revised: 09/07/2021] [Accepted: 09/08/2021] [Indexed: 12/25/2022] Open
Abstract
Members of the protein arginine methyltransferase (PRMT) family methylate the arginine residue(s) of several proteins and regulate a broad spectrum of cellular functions. Protein arginine methyltransferase 6 (PRMT6) is a type I PRMT that asymmetrically dimethylates the arginine residues of numerous substrate proteins. PRMT6 introduces asymmetric dimethylation modification in the histone 3 at arginine 2 (H3R2me2a) and facilitates epigenetic regulation of global gene expression. In addition to histones, PRMT6 methylates a wide range of cellular proteins and regulates their functions. Here, we discuss (i) the biochemical aspects of enzyme kinetics, (ii) the structural features of PRMT6 and (iii) the diverse functional outcomes of PRMT6 mediated arginine methylation. Finally, we highlight how dysregulation of PRMT6 is implicated in various types of cancers and response to viral infections.
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11
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Al-Hamashi AA, Chen D, Deng Y, Dong G, Huang R. Discovery of a potent and dual-selective bisubstrate inhibitor for protein arginine methyltransferase 4/5. Acta Pharm Sin B 2021; 11:2709-2718. [PMID: 34589391 PMCID: PMC8463262 DOI: 10.1016/j.apsb.2020.10.013] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2020] [Revised: 09/27/2020] [Accepted: 10/13/2020] [Indexed: 02/06/2023] Open
Abstract
Protein arginine methyltransferases (PRMTs) have been implicated in the progression of many diseases. Understanding substrate recognition and specificity of individual PRMT would facilitate the discovery of selective inhibitors towards future drug discovery. Herein, we reported the design and synthesis of bisubstrate analogues for PRMTs that incorporate a S-adenosylmethionine (SAM) analogue moiety and a tripeptide through an alkyl substituted guanidino group. Compound AH237 is a potent and selective inhibitor for PRMT4 and PRMT5 with a half-maximal inhibition concentration (IC50) of 2.8 and 0.42 nmol/L, respectively. Computational studies provided a plausible explanation for the high potency and selectivity of AH237 for PRMT4/5 over other 40 methyltransferases. This proof-of-principle study outlines an applicable strategy to develop potent and selective bisubstrate inhibitors for PRMTs, providing valuable probes for future structural studies.
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Affiliation(s)
- Ayad A. Al-Hamashi
- Department of Medicinal Chemistry and Molecular Pharmacology, Center for Cancer Research, Institute for Drug Discovery, Purdue University, West Lafayette, IN 47907, USA
- Department of Pharmaceutical Chemistry, College of Pharmacy, University of Baghdad, Bab-almoadham, Baghdad 10047, Iraq
| | - Dongxing Chen
- Department of Medicinal Chemistry and Molecular Pharmacology, Center for Cancer Research, Institute for Drug Discovery, Purdue University, West Lafayette, IN 47907, USA
| | - Youchao Deng
- Department of Medicinal Chemistry and Molecular Pharmacology, Center for Cancer Research, Institute for Drug Discovery, Purdue University, West Lafayette, IN 47907, USA
| | - Guangping Dong
- Department of Medicinal Chemistry and Molecular Pharmacology, Center for Cancer Research, Institute for Drug Discovery, Purdue University, West Lafayette, IN 47907, USA
| | - Rong Huang
- Department of Medicinal Chemistry and Molecular Pharmacology, Center for Cancer Research, Institute for Drug Discovery, Purdue University, West Lafayette, IN 47907, USA
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12
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Iyamu ID, Al-Hamashi AA, Huang R. A Pan-Inhibitor for Protein Arginine Methyltransferase Family Enzymes. Biomolecules 2021; 11:854. [PMID: 34201091 PMCID: PMC8230315 DOI: 10.3390/biom11060854] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2021] [Revised: 06/03/2021] [Accepted: 06/03/2021] [Indexed: 01/09/2023] Open
Abstract
Protein arginine methyltransferases (PRMTs) play important roles in transcription, splicing, DNA damage repair, RNA biology, and cellular metabolism. Thus, PRMTs have been attractive targets for various diseases. In this study, we reported the design and synthesis of a potent pan-inhibitor for PRMTs that tethers a thioadenosine and various substituted guanidino groups through a propyl linker. Compound II757 exhibits a half-maximal inhibition concentration (IC50) value of 5 to 555 nM for eight tested PRMTs, with the highest inhibition for PRMT4 (IC50 = 5 nM). The kinetic study demonstrated that II757 competitively binds at the SAM binding site of PRMT1. Notably, II757 is selective for PRMTs over a panel of other methyltransferases, which can serve as a general probe for PRMTs and a lead for further optimization to increase the selectivity for individual PRMT.
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Affiliation(s)
- Iredia D. Iyamu
- Department of Medicinal Chemistry and Molecular Pharmacology, Institute for Drug Discovery, Center for Cancer Research, Purdue University, West Lafayette, IN 47907, USA; (I.D.I.); (A.A.A.-H.)
| | - Ayad A. Al-Hamashi
- Department of Medicinal Chemistry and Molecular Pharmacology, Institute for Drug Discovery, Center for Cancer Research, Purdue University, West Lafayette, IN 47907, USA; (I.D.I.); (A.A.A.-H.)
- Department of Pharmaceutical Chemistry, College of Pharmacy, University of Baghdad, Bab-almoadham, Baghdad 10047, Iraq
| | - Rong Huang
- Department of Medicinal Chemistry and Molecular Pharmacology, Institute for Drug Discovery, Center for Cancer Research, Purdue University, West Lafayette, IN 47907, USA; (I.D.I.); (A.A.A.-H.)
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13
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Hwang JW, Cho Y, Bae GU, Kim SN, Kim YK. Protein arginine methyltransferases: promising targets for cancer therapy. Exp Mol Med 2021; 53:788-808. [PMID: 34006904 PMCID: PMC8178397 DOI: 10.1038/s12276-021-00613-y] [Citation(s) in RCA: 156] [Impact Index Per Article: 39.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2021] [Revised: 03/05/2021] [Accepted: 03/08/2021] [Indexed: 02/08/2023] Open
Abstract
Protein methylation, a post-translational modification (PTM), is observed in a wide variety of cell types from prokaryotes to eukaryotes. With recent and rapid advancements in epigenetic research, the importance of protein methylation has been highlighted. The methylation of histone proteins that contributes to the epigenetic histone code is not only dynamic but is also finely controlled by histone methyltransferases and demethylases, which are essential for the transcriptional regulation of genes. In addition, many nonhistone proteins are methylated, and these modifications govern a variety of cellular functions, including RNA processing, translation, signal transduction, DNA damage response, and the cell cycle. Recently, the importance of protein arginine methylation, especially in cell cycle regulation and DNA repair processes, has been noted. Since the dysregulation of protein arginine methylation is closely associated with cancer development, protein arginine methyltransferases (PRMTs) have garnered significant interest as novel targets for anticancer drug development. Indeed, several PRMT inhibitors are in phase 1/2 clinical trials. In this review, we discuss the biological functions of PRMTs in cancer and the current development status of PRMT inhibitors in cancer therapy.
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Affiliation(s)
- Jee Won Hwang
- grid.412670.60000 0001 0729 3748Research Institute of Pharmaceutical Sciences, College of Pharmacy, Sookmyung Women’s University, Seoul, 04310 Republic of Korea
| | - Yena Cho
- grid.412670.60000 0001 0729 3748Research Institute of Pharmaceutical Sciences, College of Pharmacy, Sookmyung Women’s University, Seoul, 04310 Republic of Korea
| | - Gyu-Un Bae
- grid.412670.60000 0001 0729 3748Research Institute of Pharmaceutical Sciences, College of Pharmacy, Sookmyung Women’s University, Seoul, 04310 Republic of Korea
| | - Su-Nam Kim
- grid.35541.360000000121053345Natural Product Research Institute, Korea Institute of Science and Technology, Gangneung, 25451 Republic of Korea
| | - Yong Kee Kim
- grid.412670.60000 0001 0729 3748Research Institute of Pharmaceutical Sciences, College of Pharmacy, Sookmyung Women’s University, Seoul, 04310 Republic of Korea
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14
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Hamey JJ, Rakow S, Bouchard C, Senst JM, Kolb P, Bauer UM, Wilkins MR, Hart-Smith G. Systematic investigation of PRMT6 substrate recognition reveals broad specificity with a preference for an RG motif or basic and bulky residues. FEBS J 2021; 288:5668-5691. [PMID: 33764612 DOI: 10.1111/febs.15837] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2020] [Revised: 03/17/2021] [Accepted: 03/23/2021] [Indexed: 10/21/2022]
Abstract
Protein arginine methyltransferase 6 (PRMT6) catalyses the asymmetric dimethylation of arginines on numerous substrate proteins within the human cell. In particular, PRMT6 methylates histone H3 arginine 2 (H3R2) which affects both gene repression and activation. However, the substrate specificity of PRMT6 has not been comprehensively analysed. Here, we systematically characterise the substrate recognition motif of PRMT6, finding that it has broad specificity and recognises the RG motif. Working with a H3 tail peptide as a template, on which we made 204 amino acid substitutions, we use targeted mass spectrometry to measure their effect on PRMT6 in vitro activity. We first show that PRMT6 methylates R2 and R8 in the H3 peptide, although H3R8 is methylated with lower efficiency and is not an in vivo PRMT6 substrate. We then quantify the effect of 194 of these amino acid substitutions on methylation at both H3R2 and H3R8. In both cases, we find that PRMT6 tolerates essentially any amino acid substitution in the H3 peptide, but that positively charged and bulky residues are preferred near the target arginine. We show that PRMT6 also has preference for glycine, but only in the position immediately following the target arginine. This indicates that PRMT6 recognises the RG motif rather than the RGG motif. We further confirm this preference for the RG motif on another PRMT6 substrate, histone H4R3. This broad specificity and recognition of RG rather than RGG are distinctive among the PRMT family and has implications for the development of drugs to selectively target PRMT6. DATABASES: Panorama Public (https://panoramaweb.org/PRMT6motif.url); ProteomeXchange (PXD016711).
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Affiliation(s)
- Joshua J Hamey
- School of Biotechnology and Biomolecular Sciences, University of New South Wales, Sydney, NSW, Australia
| | - Sinja Rakow
- Institute for Molecular Biology and Tumor Research (IMT), Philipps-University Marburg, Germany
| | - Caroline Bouchard
- Institute for Molecular Biology and Tumor Research (IMT), Philipps-University Marburg, Germany
| | - Johanna M Senst
- Department of Pharmaceutical Chemistry, Philipps-University Marburg, Germany
| | - Peter Kolb
- Department of Pharmaceutical Chemistry, Philipps-University Marburg, Germany
| | - Uta-Maria Bauer
- Institute for Molecular Biology and Tumor Research (IMT), Philipps-University Marburg, Germany
| | - Marc R Wilkins
- School of Biotechnology and Biomolecular Sciences, University of New South Wales, Sydney, NSW, Australia
| | - Gene Hart-Smith
- School of Biotechnology and Biomolecular Sciences, University of New South Wales, Sydney, NSW, Australia.,Department of Molecular Sciences, Macquarie University, Sydney, NSW, Australia
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15
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Zhang Y, Rong D, Li B, Wang Y. Targeting Epigenetic Regulators with Covalent Small-Molecule Inhibitors. J Med Chem 2021; 64:7900-7925. [PMID: 33599482 DOI: 10.1021/acs.jmedchem.0c02055] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Epigenetic regulation of gene expression plays a critical role in various physiological processes, and epigenetic dysregulation is implicated in a number of diseases, prominently including cancer. Epigenetic regulators have been validated as potential therapeutic targets, and significant progress has been made in the discovery and development of epigenetic-based inhibitors. However, successful epigenetic drug discovery is still facing challenges, including moderate selectivity, limited efficacy, and acquired drug resistance. Inspired by the advantages of covalent small-molecule inhibitors, targeted covalent inhibition has attracted increasing interest in epigenetic drug discovery. In this review, we comprehensively summarize the structure-based design and characterization of covalent inhibitors targeting epigenetic writers, readers, and erasers and highlight their potential benefits in enhancing selectivity across the enzyme family and improving in vivo efficacy. We also discuss the challenges and opportunities of covalent small-molecule inhibitors and hope to shed light on future epigenetic drug discovery.
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Affiliation(s)
- Yi Zhang
- Guangdong Key Laboratory of Chiral Molecule and Drug Discovery, School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou 510006, China
| | - Deqin Rong
- Guangdong Key Laboratory of Chiral Molecule and Drug Discovery, School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou 510006, China
| | - Bingbing Li
- Guangdong Key Laboratory of Chiral Molecule and Drug Discovery, School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou 510006, China
| | - Yuanxiang Wang
- Guangdong Key Laboratory of Chiral Molecule and Drug Discovery, School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou 510006, China
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16
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Shen Y, Li F, Szewczyk MM, Halabelian L, Chau I, Eram MS, Dela Seña C, Park KS, Meng F, Chen H, Zeng H, Dong A, Wu H, Trush VV, McLeod D, Zepeda-Velázquez CA, Campbell RM, Mader MM, Watson BM, Schapira M, Arrowsmith CH, Al-Awar R, Barsyte-Lovejoy D, Kaniskan HÜ, Brown PJ, Vedadi M, Jin J. A First-in-Class, Highly Selective and Cell-Active Allosteric Inhibitor of Protein Arginine Methyltransferase 6. J Med Chem 2021; 64:3697-3706. [PMID: 33591753 DOI: 10.1021/acs.jmedchem.0c02160] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Protein arginine methyltransferase 6 (PRMT6) catalyzes monomethylation and asymmetric dimethylation of arginine residues in various proteins, plays important roles in biological processes, and is associated with multiple cancers. To date, a highly selective PRMT6 inhibitor has not been reported. Here we report the discovery and characterization of a first-in-class, highly selective allosteric inhibitor of PRMT6, (R)-2 (SGC6870). (R)-2 is a potent PRMT6 inhibitor (IC50 = 77 ± 6 nM) with outstanding selectivity for PRMT6 over a broad panel of other methyltransferases and nonepigenetic targets. Notably, the crystal structure of the PRMT6-(R)-2 complex and kinetic studies revealed (R)-2 binds a unique, induced allosteric pocket. Additionally, (R)-2 engages PRMT6 and potently inhibits its methyltransferase activity in cells. Moreover, (R)-2's enantiomer, (S)-2 (SGC6870N), is inactive against PRMT6 and can be utilized as a negative control. Collectively, (R)-2 is a well-characterized PRMT6 chemical probe and a valuable tool for further investigating PRMT6 functions in health and disease.
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Affiliation(s)
- 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, New York 10029, United States
| | - Fengling Li
- Structural Genomics Consortium, University of Toronto, Toronto, Ontario M5G 1L7, Canada
| | - Magdalena M Szewczyk
- Structural Genomics Consortium, University of Toronto, Toronto, Ontario M5G 1L7, Canada
| | - Levon Halabelian
- Structural Genomics Consortium, University of Toronto, Toronto, Ontario M5G 1L7, Canada
| | - Irene Chau
- Structural Genomics Consortium, University of Toronto, Toronto, Ontario M5G 1L7, Canada
| | - Mohammad S Eram
- Structural Genomics Consortium, University of Toronto, Toronto, Ontario M5G 1L7, Canada
| | - Carlo Dela Seña
- Structural Genomics Consortium, University of Toronto, Toronto, Ontario M5G 1L7, Canada
| | - Kwang-Su Park
- 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, New York 10029, United States
| | - Fanye Meng
- 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, New York 10029, United States
| | - He Chen
- 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, New York 10029, United States
| | - Hong Zeng
- 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 Wu
- Structural Genomics Consortium, University of Toronto, Toronto, Ontario M5G 1L7, Canada
| | - Viacheslav V Trush
- Structural Genomics Consortium, University of Toronto, Toronto, Ontario M5G 1L7, Canada
| | - David McLeod
- Ontario Institute for Cancer Research, Toronto, Ontario M5G 0A3, Canada
| | | | - Robert M Campbell
- Eli Lilly and Company, Lilly Research Laboratories, Indianapolis, Indiana 46225, United States
| | - Mary M Mader
- Eli Lilly and Company, Lilly Research Laboratories, Indianapolis, Indiana 46225, United States
| | - Brian M Watson
- Eli Lilly and Company, Lilly Research Laboratories, Indianapolis, Indiana 46225, United States
| | - Matthieu Schapira
- 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.,Department of Medical Biophysics, University of Toronto, Toronto, Ontario M5G 1L7, Canada
| | - Rima Al-Awar
- Ontario Institute for Cancer Research, Toronto, Ontario M5G 0A3, Canada
| | - Dalia Barsyte-Lovejoy
- Structural Genomics Consortium, University of Toronto, Toronto, Ontario M5G 1L7, Canada
| | - H Ümit Kaniskan
- 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, New York 10029, United States
| | - Peter J Brown
- Structural Genomics Consortium, University of Toronto, Toronto, Ontario M5G 1L7, Canada
| | - 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
- 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, New York 10029, United States
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17
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Bryant JP, Heiss J, Banasavadi-Siddegowda YK. Arginine Methylation in Brain Tumors: Tumor Biology and Therapeutic Strategies. Cells 2021; 10:cells10010124. [PMID: 33440687 PMCID: PMC7827394 DOI: 10.3390/cells10010124] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2020] [Revised: 01/05/2021] [Accepted: 01/05/2021] [Indexed: 12/12/2022] Open
Abstract
Protein arginine methylation is a common post-translational modification that plays a pivotal role in cellular regulation. Protein arginine methyltransferases (PRMTs) catalyze the modification of target proteins by adding methyl groups to the guanidino nitrogen atoms of arginine residues. Protein arginine methylation takes part in epigenetic and cellular regulation and has been linked to neurodegenerative diseases, metabolic diseases, and tumor progression. Aberrant expression of PRMTs is associated with the development of brain tumors such as glioblastoma and medulloblastoma. Identifying PRMTs as plausible contributors to tumorigenesis has led to preclinical and clinical investigations of PRMT inhibitors for glioblastoma and medulloblastoma therapy. In this review, we discuss the role of arginine methylation in cancer biology and provide an update on the use of small molecule inhibitors of PRMTs to treat glioblastoma, medulloblastoma, and other cancers.
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18
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Cigarette smoke extract induces airway epithelial cell death via repressing PRMT6/AKT signaling. Aging (Albany NY) 2020; 12:24301-24317. [PMID: 33260152 PMCID: PMC7762507 DOI: 10.18632/aging.202210] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2020] [Accepted: 10/20/2020] [Indexed: 12/13/2022]
Abstract
Chronic obstructive pulmonary disease (COPD) is a severe public health threat world-wide. Cigarette smoke (CS)-induced airway epithelial cell death is a major pathway of pathogenesis in emphysema, a subtype of COPD. Protein arginine methyltransferase 6 (PRMT6) is a type I PRMT that catalyzes mono- and di-methylation on arginine residues within histone and non-histone proteins to modulate a variety of life processes, such as apoptosis. However, its role in CS-induced lung epithelial death has not been fully elucidated. Here we report that PRMT6 was decreased in mouse lung tissues from a cigarette smoke extract (CSE)-mediated experimental emphysematous model and in CSE treated or cigarette smoke exposed lung epithelial cells. Depletion of PRMT6 increased the protein levels of phosphatase PTEN and PI3K regulatory subunit p85 but decreased a downstream kinase PDK1, resulting in AKT dephosphorylation and thereafter, lung epithelial cell death. Knockout of PRMT6 inhibited epithelial survival and promoted CSE-mediated epithelial cell death, while ectopic expression of PRMT6 protein partially reversed epithelial cell death via PI3K/AKT-mediated cell survival signaling in CSE cellular models. These findings demonstrate that PRMT6 plays a crucial role in CS-induced bronchial epithelial cell death that may be a potential therapeutic target against the airway cell death in CS-induced COPD.
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19
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Brown JI, Page BDG, Frankel A. The application of differential scanning fluorimetry in exploring bisubstrate binding to protein arginine N-methyltransferase 1. Methods 2020; 175:10-23. [PMID: 31726226 DOI: 10.1016/j.ymeth.2019.11.004] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2019] [Revised: 11/06/2019] [Accepted: 11/07/2019] [Indexed: 10/25/2022] Open
Abstract
Protein arginine N-methyltransferases (PRMTs) are a family of 9 enzymes that catalyze mono- or di-methylation of arginine residues using S-adenosyl-l-methionine (SAM). Arginine methylation is an important post-translational modification that can regulate the activity and structure of target proteins. Altered PRMT activity can lead to a variety of health issues including neurodevelopmental disease, autoimmune disorders, cancer, and cardiovascular disease. Thus, developing a robust mechanistic understanding of PRMT function may provide insight into these various disease states and enable the development of potential therapeutic agents. Although PRMTs have been studied for nearly two decades, a consensus regarding the mechanism of action for this class of enzymes has remained noticeably elusive. To address this shortcoming, differential scanning fluorimetry (DSF) was used to gain mechanistic insight into the order of PRMT substrate and cofactor binding. This methodology confirms that PRMT cofactor binding precedes target substrate binding and supports the use of DSF to study bisubstrate enzymatic reaction mechanisms.
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Affiliation(s)
- Jennifer I Brown
- Faculty of Pharmaceutical Sciences, University of British Columbia, 2405 Wesbrook Mall, Vancouver, Canada
| | - Brent D G Page
- Faculty of Pharmaceutical Sciences, University of British Columbia, 2405 Wesbrook Mall, Vancouver, Canada; Department of Oncology and Pathology, Karolinska Institutet, Tomtebodavagen 23A, Stockholm, Sweden.
| | - Adam Frankel
- Faculty of Pharmaceutical Sciences, University of British Columbia, 2405 Wesbrook Mall, Vancouver, Canada.
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20
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Vincent A, Ouelkdite-Oumouchal A, Souidi M, Leclerc J, Neve B, Van Seuningen I. Colon cancer stemness as a reversible epigenetic state: Implications for anticancer therapies. World J Stem Cells 2019; 11:920-936. [PMID: 31768220 PMCID: PMC6851010 DOI: 10.4252/wjsc.v11.i11.920] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/25/2019] [Revised: 08/29/2019] [Accepted: 09/11/2019] [Indexed: 02/06/2023] Open
Abstract
The recent discovery of cancer cell plasticity, i.e. their ability to reprogram into cancer stem cells (CSCs) either naturally or under chemotherapy and/or radiotherapy, has changed, once again, the way we consider cancer treatment. If cancer stemness is a reversible epigenetic state rather than a genetic identity, opportunities will arise for therapeutic strategies that remodel epigenetic landscapes of CSCs. However, the systematic use of DNA methyltransferase and histone deacetylase inhibitors, alone or in combination, in advanced solid tumors including colorectal cancers, regardless of their molecular subtypes, does not seem to be the best strategy. In this review, we first summarize the knowledge researchers have gathered on the epigenetic signatures of CSCs with the difficulty of isolating rare populations of cells. We raise questions about the relevant use of currently available epigenetic inhibitors (epidrugs) while the expression of numerous cancer stem cell markers are often repressed by epigenetic mechanisms. These markers include the three cluster of differentiation CD133, CD44 and CD166 that have been extensively used for the isolation of colon CSCs.and . Finally, we describe current treatment strategies using epidrugs, and we hypothesize that, using correlation tools comparing associations of relevant CSC markers with chromatin modifier expression, we could identify better candidates for epienzyme targeting.
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Affiliation(s)
- Audrey Vincent
- Lille University, Institut National de la Santé et de la Recherche Médicale, CHU Lille, UMR-S 1172-Jean-Pierre Aubert Research Center, Lille F-59000, France
| | - Aïcha Ouelkdite-Oumouchal
- Lille University, Institut National de la Santé et de la Recherche Médicale, CHU Lille, UMR-S 1172-Jean-Pierre Aubert Research Center, Lille F-59000, France
| | - Mouloud Souidi
- Lille University, Institut National de la Santé et de la Recherche Médicale, CHU Lille, UMR-S 1172-Jean-Pierre Aubert Research Center, Lille F-59000, France
| | - Julie Leclerc
- Lille University, Institut National de la Santé et de la Recherche Médicale, CHU Lille, UMR-S 1172-Jean-Pierre Aubert Research Center, Lille F-59000, France
- Department of Biochemistry and Molecular Biology, Lille University Hospital, Lille F-59000, France
| | - Bernadette Neve
- Lille University, Institut National de la Santé et de la Recherche Médicale, CHU Lille, UMR-S 1172-Jean-Pierre Aubert Research Center, Lille F-59000, France
| | - Isabelle Van Seuningen
- Lille University, Institut National de la Santé et de la Recherche Médicale, CHU Lille, UMR-S 1172-Jean-Pierre Aubert Research Center, Lille F-59000, France
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21
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Jarrold J, Davies CC. PRMTs and Arginine Methylation: Cancer's Best-Kept Secret? Trends Mol Med 2019; 25:993-1009. [PMID: 31230909 DOI: 10.1016/j.molmed.2019.05.007] [Citation(s) in RCA: 235] [Impact Index Per Article: 39.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2019] [Revised: 05/10/2019] [Accepted: 05/16/2019] [Indexed: 12/19/2022]
Abstract
Post-translational modification (PTM) of proteins is vital for increasing proteome diversity and maintaining cellular homeostasis. If the writing, reading, and removal of modifications are not controlled, cancer can develop. Arginine methylation is an understudied modification that is increasingly associated with cancer progression. Consequently protein arginine methyltransferases (PRMTs), the writers of arginine methylation, have rapidly gained interest as novel drug targets. However, for clinical success a deep mechanistic understanding of the biology of PRMTs is required. In this review we focus on advances made regarding the role of PRMTs in stem cell biology, epigenetics, splicing, immune surveillance and the DNA damage response, and highlight the rapid rise of specific inhibitors that are now in clinical trials for cancer therapy.
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Affiliation(s)
- James Jarrold
- Institute of Cancer and Genomic Sciences, College of Medical and Dental Sciences, University of Birmingham, Birmingham, B15 2TT, 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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22
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Cai XC, Zhang T, Kim EJ, Jiang M, Wang K, Wang J, Chen S, Zhang N, Wu H, Li F, Dela Seña CC, Zeng H, Vivcharuk V, Niu X, Zheng W, Lee JP, Chen Y, Barsyte D, Szewczyk M, Hajian T, Ibáñez G, Dong A, Dombrovski L, Zhang Z, Deng H, Min J, Arrowsmith CH, Mazutis L, Shi L, Vedadi M, Brown PJ, Xiang J, Qin LX, Xu W, Luo M. A chemical probe of CARM1 alters epigenetic plasticity against breast cancer cell invasion. eLife 2019; 8:47110. [PMID: 31657716 PMCID: PMC6917500 DOI: 10.7554/elife.47110] [Citation(s) in RCA: 33] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2019] [Accepted: 10/27/2019] [Indexed: 12/21/2022] Open
Abstract
CARM1 is a cancer-relevant protein arginine methyltransferase that regulates many aspects of transcription. Its pharmacological inhibition is a promising anti-cancer strategy. Here SKI-73 (6a in this work) is presented as a CARM1 chemical probe with pro-drug properties. SKI-73 (6a) can rapidly penetrate cell membranes and then be processed into active inhibitors, which are retained intracellularly with 10-fold enrichment for several days. These compounds were characterized for their potency, selectivity, modes of action, and on-target engagement. SKI-73 (6a) recapitulates the effect of CARM1 knockout against breast cancer cell invasion. Single-cell RNA-seq analysis revealed that the SKI-73(6a)-associated reduction of invasiveness acts by altering epigenetic plasticity and suppressing the invasion-prone subpopulation. Interestingly, SKI-73 (6a) and CARM1 knockout alter the epigenetic plasticity with remarkable difference, suggesting distinct modes of action for small-molecule and genetic perturbations. We therefore discovered a CARM1-addiction mechanism of cancer metastasis and developed a chemical probe to target this process. Drugs that are small molecules have the potential to block the individual proteins that drive the spread of cancer, but their design is a challenge. This is because they need to get inside the cell and find their target without binding to other proteins on the way. However, small molecule drugs often have an electric charge, which makes it hard for them to cross the cell membrane. Additionally, most proteins are not completely unique, making it harder for the drugs to find the correct target. CARM1 is a protein that plays a role in the spread of breast cancer cells, and scientists are currently looking for a small molecule that will inhibit its action. The group of enzymes that CARM1 belongs to act by taking a small chemical group, called a methyl group, from a molecule called SAM, and transferring it to proteins that switch genes on and off. In the case of CARM1, this changes cell behavior by turning on genes involved in cell movement. Genetically modifying cells so they will not produce any CARM1 stops the spread of breast cancer cells, but developing a drug with the same effects has proved difficult. Existing drugs that can inhibit CARM1 in a test tube struggle to get inside cells and to distinguish between CARM1 and its related enzymes. Now, Cai et al. have modified and tested a CARM1 inhibitor to address these problems, and find out how these small molecules work. At its core, the inhibitor has a structure very similar to a SAM molecule, so it can fit into the SAM binding pocket of CARM1 and its related enzymes. To stop the inhibitor from binding to other proteins, Cai et al. made small changes to its structure until it only interacted with CARM1.Then, to get the inhibitor inside breast cancer cells, Cai et al. cloaked its charged area with a chemical shield, allowing it to cross the cell membrane. Inside the cell, the chemical shield broke away, allowing the inhibitor to attach to CARM1. Analysis of cells showed that this inhibition only affected the cancer cells most likely to spread. Blocking CARM1 switched off genes involved in cell movement and stopped cancer cells from travelling through 3D gels. This work is a step towards making a drug that can block CARM1 in cancer cells, but there is still further work to be done. The next stages will be to test whether the new inhibitor works in other types of cancer cells, in living animals, and in human patient samples.
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Affiliation(s)
- Xiao-Chuan Cai
- Chemical Biology Program, Memorial Sloan Kettering Cancer Center, New York, United States
| | - Tuo Zhang
- Genomics Resources Core Facility, Weill Cornell Medical College, Cornell University, New York, United States
| | - Eui-Jun Kim
- McArdle Laboratory for Cancer Research, University of Wisconsin-Madison, Madison, United States
| | - Ming Jiang
- Chemical Biology Program, Memorial Sloan Kettering Cancer Center, New York, United States.,Program of Pharmacology, Weill Cornell Medical College of Cornell University, New York, United States
| | - Ke Wang
- Chemical Biology Program, Memorial Sloan Kettering Cancer Center, New York, United States
| | - Junyi Wang
- Chemical Biology Program, Memorial Sloan Kettering Cancer Center, New York, United States
| | - Shi Chen
- Chemical Biology Program, Memorial Sloan Kettering Cancer Center, New York, United States.,Tri-Institutional PhD Program in Chemical Biology, Memorial Sloan Kettering Cancer Center, New York, United States
| | - Nawei Zhang
- Chemical Biology Program, Memorial Sloan Kettering Cancer Center, New York, United States.,Department of Obstetrics and Gynecology, Chaoyang Hospital, Affiliation Hospital of Capital Medical University, Beijing, China
| | - Hong Wu
- Structural Genomics Consortium, University of Toronto, Toronto, Canada
| | - Fengling Li
- Structural Genomics Consortium, University of Toronto, Toronto, Canada
| | - Carlo C Dela Seña
- Structural Genomics Consortium, University of Toronto, Toronto, Canada
| | - Hong Zeng
- Structural Genomics Consortium, University of Toronto, Toronto, Canada
| | - Victor Vivcharuk
- Department of Physiology and Biophysics, Weill Cornell Medical College of Cornell University, New York, United States
| | - Xiang Niu
- Computational and Systems Biology Program, Memorial Sloan Kettering Cancer Center, New York, United States.,Tri-Institutional PhD Program in Computational Biology and Medicine, Memorial Sloan Kettering Cancer Center, New York, United States
| | - Weihong Zheng
- Chemical Biology Program, Memorial Sloan Kettering Cancer Center, New York, United States
| | - Jonghan P Lee
- Chemical Biology Program, Memorial Sloan Kettering Cancer Center, New York, United States.,Tri-Institutional PhD Program in Chemical Biology, Memorial Sloan Kettering Cancer Center, New York, United States
| | - Yuling Chen
- Center for Synthetic and Systematic Biology, School of Life Sciences, Tsinghua University, Beijing, China
| | - Dalia Barsyte
- Structural Genomics Consortium, University of Toronto, Toronto, Canada
| | - Magda Szewczyk
- Structural Genomics Consortium, University of Toronto, Toronto, Canada
| | - Taraneh Hajian
- Structural Genomics Consortium, University of Toronto, Toronto, Canada
| | - Glorymar Ibáñez
- Chemical Biology Program, Memorial Sloan Kettering Cancer Center, New York, United States
| | - Aiping Dong
- Structural Genomics Consortium, University of Toronto, Toronto, Canada
| | | | - Zhenyu Zhang
- Department of Obstetrics and Gynecology, Chaoyang Hospital, Affiliation Hospital of Capital Medical University, Beijing, China
| | - Haiteng Deng
- Structural Genomics Consortium, University of Toronto, Toronto, Canada.,Center for Synthetic and Systematic Biology, School of Life Sciences, Tsinghua University, Beijing, China
| | - Jinrong Min
- Structural Genomics Consortium, University of Toronto, Toronto, Canada.,Department of Physiology, University of Toronto, Toronto, Canada
| | - Cheryl H Arrowsmith
- Structural Genomics Consortium, University of Toronto, Toronto, Canada.,Princess Margaret Cancer Centre, Department of Medical Biophysics, University of Toronto, Toronto, Canada
| | - Linas Mazutis
- Computational and Systems Biology Program, Memorial Sloan Kettering Cancer Center, New York, United States
| | - Lei Shi
- Department of Physiology and Biophysics, Weill Cornell Medical College of Cornell University, New York, United States
| | - Masoud Vedadi
- Structural Genomics Consortium, University of Toronto, Toronto, Canada.,Department of Pharmacology and Toxicology, University of Toronto, Toronto, Canada
| | - Peter J Brown
- Structural Genomics Consortium, University of Toronto, Toronto, Canada
| | - Jenny Xiang
- Genomics Resources Core Facility, Weill Cornell Medical College, Cornell University, New York, United States
| | - Li-Xuan Qin
- Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, United States
| | - Wei Xu
- McArdle Laboratory for Cancer Research, University of Wisconsin-Madison, Madison, United States
| | - Minkui Luo
- Chemical Biology Program, Memorial Sloan Kettering Cancer Center, New York, United States.,Program of Pharmacology, Weill Cornell Medical College of Cornell University, New York, United States
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23
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Tewary SK, Zheng YG, Ho MC. Protein arginine methyltransferases: insights into the enzyme structure and mechanism at the atomic level. Cell Mol Life Sci 2019; 76:2917-2932. [PMID: 31123777 PMCID: PMC6741777 DOI: 10.1007/s00018-019-03145-x] [Citation(s) in RCA: 86] [Impact Index Per Article: 14.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2019] [Accepted: 05/10/2019] [Indexed: 02/06/2023]
Abstract
Protein arginine methyltransferases (PRMTs) catalyze the methyl transfer to the arginine residues of protein substrates and are classified into three major types based on the final form of the methylated arginine. Recent studies have shown a strong correlation between PRMT expression level and the prognosis of cancer patients. Currently, crystal structures of eight PRMT members have been determined. Kinetic and structural studies have shown that all PRMTs share similar, but unique catalytic and substrate recognition mechanism. In this review, we discuss the structural similarities and differences of different PRMT members, focusing on their overall structure, S-adenosyl-L-methionine-binding pocket, substrate arginine recognition and catalytic mechanisms. Since PRMTs are valuable targets for drug discovery, we also rationally classify the known PRMT inhibitors into five classes and discuss their mechanisms of action at the atomic level.
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Affiliation(s)
| | - Y George Zheng
- College of Pharmacy, University of Georgia, Athens, GA, 30602, USA
| | - Meng-Chiao Ho
- Institute of Biological Chemistry, Academia Sinica, Taipei, 115, Taiwan.
- Institute of Biochemical Sciences, National Taiwan University, Taipei, 106, Taiwan.
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24
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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: 19] [Impact Index Per Article: 3.2] [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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25
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PTEN arginine methylation by PRMT6 suppresses PI3K-AKT signaling and modulates pre-mRNA splicing. Proc Natl Acad Sci U S A 2019; 116:6868-6877. [PMID: 30886105 DOI: 10.1073/pnas.1811028116] [Citation(s) in RCA: 61] [Impact Index Per Article: 10.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
Arginine methylation is a ubiquitous posttranslational modification that regulates critical cellular processes including signal transduction and pre-mRNA splicing. Here, we report that the tumor-suppressor PTEN is methylated by protein arginine methyltransferase 6 (PRMT6). Mass-spectrometry analysis reveals that PTEN is dimethylated at arginine 159 (R159). We found that PTEN is mutated at R159 in cancers, and the PTEN mutant R159K loses its capability to inhibit the PI3K-AKT cascade. Furthermore, PRMT6 is physically associated with PTEN, promotes asymmetrical dimethylation of PTEN, and regulates the PI3K-AKT cascade through PTEN R159 methylation. In addition, using transcriptome analyses, we found that PTEN R159 methylation is involved in modulation of pre-mRNA alternative splicing. Our results demonstrate that PTEN is functionally regulated by arginine methylation. We propose that PTEN arginine methylation modulates pre-mRNA alternative splicing and influences diverse physiologic processes.
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26
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Meng H, Ma R, Fitzgerald MC. Chemical Denaturation and Protein Precipitation Approach for Discovery and Quantitation of Protein–Drug Interactions. Anal Chem 2018; 90:9249-9255. [DOI: 10.1021/acs.analchem.8b01772] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/01/2023]
Affiliation(s)
- He Meng
- Department of Chemistry, Duke University, Durham, North Carolina 27708, United States
| | - Renze Ma
- Department of Chemistry, Duke University, Durham, North Carolina 27708, United States
| | - Michael C. Fitzgerald
- Department of Chemistry, Duke University, Durham, North Carolina 27708, United States
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27
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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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28
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Brown JI, Koopmans T, van Strien J, Martin NI, Frankel A. Kinetic Analysis of PRMT1 Reveals Multifactorial Processivity and a Sequential Ordered Mechanism. Chembiochem 2017; 19:85-99. [PMID: 29112789 DOI: 10.1002/cbic.201700521] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2017] [Indexed: 01/13/2023]
Abstract
Arginine methylation is a prevalent post-translational modification in eukaryotic cells. Two significant debates exist within the field: do these enzymes dimethylate their substrates in a processive or distributive manner, and do these enzymes operate using a random or sequential method of bisubstrate binding? We revealed that human protein arginine N-methyltransferase 1 (PRMT1) enzyme kinetics are dependent on substrate sequence. Further, peptides containing an Nη-hydroxyarginine generally demonstrated substrate inhibition and had improved KM values, which evoked a possible role in inhibitor design. We also revealed that the perceived degree of enzyme processivity is a function of both cofactor and enzyme concentration, suggesting that previous conclusions about PRMT sequential methyl transfer mechanisms require reassessment. Finally, we demonstrated a sequential ordered Bi-Bi kinetic mechanism for PRMT1, based on steady-state kinetic analysis. Together, our data indicate a PRMT1 mechanism of action and processivity that might also extend to other functionally and structurally conserved PRMTs.
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Affiliation(s)
- Jennifer I Brown
- Faculty of Pharmaceutical Sciences, University of British Columbia, 2405 Wesbrook Mall, Vancouver, BC, V6T 1Z3, Canada
| | - Timo Koopmans
- Department of Chemical Biology and Drug Discovery, Utrecht Institute for Pharmaceutical Sciences, University of Utrecht, 3584 CG, Utrecht, The Netherlands
| | - Jolinde van Strien
- Leiden Institute for Chemistry, Gorlaeus Laboratories, Einsteinweg 55, 2333CC, Leiden, The Netherlands
| | - Nathaniel I Martin
- Department of Chemical Biology and Drug Discovery, Utrecht Institute for Pharmaceutical Sciences, University of Utrecht, 3584 CG, Utrecht, The Netherlands
| | - Adam Frankel
- Faculty of Pharmaceutical Sciences, University of British Columbia, 2405 Wesbrook Mall, Vancouver, BC, V6T 1Z3, Canada
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29
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Abstract
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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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