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Iaia N, Noviello C, Muscaritoli M, Costelli P. Inflammation in cancer cachexia: still the central tenet or just another player? Am J Physiol Cell Physiol 2025; 328:C1837-C1852. [PMID: 40250836 DOI: 10.1152/ajpcell.00808.2024] [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: 11/06/2024] [Revised: 11/23/2024] [Accepted: 04/10/2025] [Indexed: 04/20/2025]
Abstract
Cancer cachexia, a multifactorial syndrome characterized by body weight loss, muscle, and adipose tissue wasting, affects patients with cancer. Over time, the definition of cachexia has been modified, including inflammation as one of the main causal factors. Evidence has suggested that a range of proinflammatory mediators may be involved in the regulation of intracellular signaling, resulting in enhanced resting energy expenditure, metabolic changes, and muscle atrophy, all of which are typical features of cachexia. Physiologically speaking, however, inflammation is a response aimed at facing potentially damaging events. Along this line, its induction in the cancer hosts could be an attempt to restore the physiological homeostasis. Interesting observations have shown that cytokines such as interleukins 4 and 6 could improve muscle wasting, supporting the view that the same mediator may exert pro- or anti-inflammatory activity depending on the immune cells involved as well as on the tissue metabolic demand. In conclusion, whether inflammation is crucial to the occurrence of cachexia or just one contributor among others, is still unclear. Indeed, while inflammation is a trigger of cachexia, the alterations of energy and protein metabolism and of the hormonal homeostasis occurring in cachexia likely act as inflammatory stimuli on their own. Whether the causative role prevails over the compensatory one likely depends on the tumor type and stage, patient lifestyle, the presence of comorbidities, and the response to anticancer treatments paving the way to a holistic, personalized approach to cancer cachexia.
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Affiliation(s)
- Noemi Iaia
- Department of Clinical and Biological Sciences, University of Turin, Turin, Italy
- Department of Translational Medicine, University of Eastern Piedmont, Novara, Italy
| | - Chiara Noviello
- Department of Clinical and Biological Sciences, University of Turin, Turin, Italy
- Department of Translational Medicine, University of Eastern Piedmont, Novara, Italy
| | | | - Paola Costelli
- Department of Clinical and Biological Sciences, University of Turin, Turin, Italy
- Department of Translational Medicine, University of Eastern Piedmont, Novara, Italy
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2
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Liu H, Liu X, Tian F, Chen Y, Li J, Wang X, Qiu W, Wang X, Ma C, Ge W. PRMT3-Mediated H4R3me2a Promotes Primary Age-Related Tauopathy by Driving Tau Hyperphosphorylation in Neuron. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2025:e2506044. [PMID: 40344412 DOI: 10.1002/advs.202506044] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/03/2025] [Indexed: 05/11/2025]
Abstract
Primary age-related tauopathy (PART) and Alzheimer's disease (AD) both exhibit 3R/4R hyperphosphorylated tau-positive neurofibrillary tangles (NFTs) within the hippocampal-entorhinal system. Notably, PART patients show a higher degree of tau hyperphosphorylation in the entorhinal cortex (EC) than AD, yet the molecular mechanisms driving Aβ-independent tau hyperphosphorylation in PART remain poorly understood. Herein, through transcriptomic profiling of postmortem EC tissues and in vitro and in vivo functional validation, the present study identifies protein arginine methyltransferase 3 (PRMT3) as a critical driver of tau hyperphosphorylation. Mechanistically, PRMT3-mediated tau hyperphosphorylation is dependent on asymmetric dimethylation of histone H4 at arginine 3 (H4R3me2a), which upregulates miR-448. Elevated miR-448 specifically targets and suppresses IGF1R, leading to downstream GSK3β activation and subsequent tau hyperphosphorylation through PI3K/AKT/GSK3β signaling. Treatment with SGC707, a selective PRMT3 inhibitor, effectively reduces tau hyperphosphorylation and demonstrates therapeutic promise for PART and potentially other tauopathies. Collectively, this study defines the PRMT3/H4R3me2a/miR-448 axis as a critical regulatory pathway in tau hyperphosphorylation within PART, underscoring the potential of PRMT3 inhibition as a targeted therapeutic strategy for tauopathies.
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Affiliation(s)
- Haotian Liu
- Department of Immunology, State Key Laboratory of Complex, Severe, and Rare Diseases, Institute of Basic Medical Sciences Chinese Academy of Medical Sciences, School of Basic Medicine Peking Union Medical College, Beijing, 100005, China
- Department of Human Anatomy, Histology and Embryology, Neuroscience Center, National Human Brain Bank for Development and Function, Institute of Basic Medical Sciences Chinese Academy of Medical Sciences, School of Basic Medicine Peking Union Medical College, Beijing, 100005, China
| | - Xinnan Liu
- Department of Human Anatomy, Histology and Embryology, Neuroscience Center, National Human Brain Bank for Development and Function, Institute of Basic Medical Sciences Chinese Academy of Medical Sciences, School of Basic Medicine Peking Union Medical College, Beijing, 100005, China
| | - Fengyuan Tian
- Department of Immunology, State Key Laboratory of Complex, Severe, and Rare Diseases, Institute of Basic Medical Sciences Chinese Academy of Medical Sciences, School of Basic Medicine Peking Union Medical College, Beijing, 100005, China
| | - Yashuang Chen
- Department of Immunology, State Key Laboratory of Complex, Severe, and Rare Diseases, Institute of Basic Medical Sciences Chinese Academy of Medical Sciences, School of Basic Medicine Peking Union Medical College, Beijing, 100005, China
| | - Jingying Li
- Department of Immunology, State Key Laboratory of Complex, Severe, and Rare Diseases, Institute of Basic Medical Sciences Chinese Academy of Medical Sciences, School of Basic Medicine Peking Union Medical College, Beijing, 100005, China
| | - Xue Wang
- Department of Human Anatomy, Histology and Embryology, Neuroscience Center, National Human Brain Bank for Development and Function, Institute of Basic Medical Sciences Chinese Academy of Medical Sciences, School of Basic Medicine Peking Union Medical College, Beijing, 100005, China
| | - Wenying Qiu
- Department of Human Anatomy, Histology and Embryology, Neuroscience Center, National Human Brain Bank for Development and Function, Institute of Basic Medical Sciences Chinese Academy of Medical Sciences, School of Basic Medicine Peking Union Medical College, Beijing, 100005, China
| | - Xia Wang
- Department of Immunology, State Key Laboratory of Complex, Severe, and Rare Diseases, Institute of Basic Medical Sciences Chinese Academy of Medical Sciences, School of Basic Medicine Peking Union Medical College, Beijing, 100005, China
| | - Chao Ma
- Department of Human Anatomy, Histology and Embryology, Neuroscience Center, National Human Brain Bank for Development and Function, Institute of Basic Medical Sciences Chinese Academy of Medical Sciences, School of Basic Medicine Peking Union Medical College, Beijing, 100005, China
| | - Wei Ge
- Department of Immunology, State Key Laboratory of Complex, Severe, and Rare Diseases, Institute of Basic Medical Sciences Chinese Academy of Medical Sciences, School of Basic Medicine Peking Union Medical College, Beijing, 100005, China
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Ma Z, Lyu X, Qin N, Liu H, Zhang M, Lai Y, Dong B, Lu P. Coactivator-associated arginine methyltransferase 1: A versatile player in cell differentiation and development. Genes Dis 2023; 10:2383-2392. [PMID: 37554200 PMCID: PMC10404874 DOI: 10.1016/j.gendis.2022.05.021] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2022] [Revised: 04/19/2022] [Accepted: 05/11/2022] [Indexed: 11/26/2022] Open
Abstract
Protein arginine methylation is a common post-translational modification involved in the regulation of various cellular functions. Coactivator-associated arginine methyltransferase 1 (CARM1) is a protein arginine methyltransferase that asymmetrically dimethylates histone H3 and non-histone proteins to regulate gene transcription. CARM1 has been found to play important roles in cell differentiation and development, cell cycle progression, autophagy, metabolism, pre-mRNA splicing and transportation, and DNA replication. In this review, we describe the molecular characteristics of CARM1 and summarize its roles in the regulation of cell differentiation and development in mammals.
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Affiliation(s)
- Zhongrui Ma
- Medical Research Center, The First Affiliated Hospital of Shandong First Medical University, Jinan, Shandong 250014, China
- Department of Immunology, Medical Science and Technology Innovation Center, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan, Shandong 250117, China
| | - Xinxing Lyu
- Medical Research Center, The First Affiliated Hospital of Shandong First Medical University, Jinan, Shandong 250014, China
- Department of Biochemistry and Molecular Biology, School of Basic Medicine, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan, Shandong 250117, China
| | - Ning Qin
- Department of Biochemistry and Molecular Biology, School of Basic Medicine, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan, Shandong 250117, China
| | - Haoyu Liu
- Department of Biochemistry and Molecular Biology, School of Basic Medicine, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan, Shandong 250117, China
| | - Mengrui Zhang
- Department of Biochemistry and Molecular Biology, School of Basic Medicine, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan, Shandong 250117, China
| | - Yongchao Lai
- Medical Research Center, The First Affiliated Hospital of Shandong First Medical University, Jinan, Shandong 250014, China
| | - Bo Dong
- Department of Cardiology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong 250021, China
| | - Peiyuan Lu
- Medical Research Center, The First Affiliated Hospital of Shandong First Medical University, Jinan, Shandong 250014, China
- Department of Immunology, Medical Science and Technology Innovation Center, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan, Shandong 250117, China
- Department of Biochemistry and Molecular Biology, School of Basic Medicine, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan, Shandong 250117, China
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Coding and Noncoding Genes Involved in Atrophy and Compensatory Muscle Growth in Nile Tilapia. Cells 2022; 11:cells11162504. [PMID: 36010581 PMCID: PMC9406742 DOI: 10.3390/cells11162504] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2022] [Accepted: 08/03/2022] [Indexed: 11/16/2022] Open
Abstract
Improvements in growth-related traits reduce fish time and production costs to reach market size. Feed deprivation and refeeding cycles have been introduced to maximize aquaculture profits through compensatory growth. However, the molecular compensatory growth signature is still uncertain in Nile tilapia. In this study, fish were subjected to two weeks of fasting followed by two weeks of refeeding. The growth curve in refed tilapia was suggestive of a partial compensatory response. Transcriptome profiling of starved and refed fish was conducted to identify genes regulating muscle atrophy and compensatory growth. Pairwise comparisons revealed 5009 and 478 differentially expressed (differential) transcripts during muscle atrophy and recovery, respectively. Muscle atrophy appears to be mediated by the ubiquitin-proteasome and autophagy/lysosome systems. Autophagy-related 2A, F-box and WD repeat domain containing 7, F-box only protein 32, miR-137, and miR-153 showed exceptional high expression suggesting them as master regulators of muscle atrophy. On the other hand, the muscle compensatory growth response appears to be mediated by the continuous stimulation of muscle hypertrophy which exceeded normal levels found in control fish. For instance, genes promoting ribosome biogenesis or enhancing the efficiency of translational machinery were upregulated in compensatory muscle growth. Additionally, myogenic microRNAs (e.g., miR-1 and miR-206), and hypertrophy-associated microRNAs (e.g., miR-27a-3p, miR-29c, and miR-29c) were reciprocally expressed to favor hypertrophy during muscle recovery. Overall, the present study provided insights into the molecular mechanisms regulating muscle mass in fish. The study pinpoints extensive growth-related gene networks that could be used to inform breeding programs and also serve as valuable genomic resources for future mechanistic studies.
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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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Ravel-Chapuis A, Haghandish A, Daneshvar N, Jasmin BJ, Côté J. A novel CARM1-HuR axis involved in muscle differentiation and plasticity misregulated in spinal muscular atrophy. Hum Mol Genet 2021; 31:1453-1470. [PMID: 34791230 DOI: 10.1093/hmg/ddab333] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2021] [Revised: 10/19/2021] [Accepted: 10/19/2021] [Indexed: 11/14/2022] Open
Abstract
Spinal muscular atrophy (SMA) is characterized by the loss of alpha motor neurons in the spinal cord and a progressive muscle weakness and atrophy. SMA is caused by loss-of-function mutations and/or deletions in the survival of motor neuron (SMN) gene. The role of SMN in motor neurons has been extensively studied, but its function and the consequences of its loss in muscle has also emerged as a key aspect of SMA pathology. In this study, we explore the molecular mechanisms involved in muscle defects in SMA. First, we show in C2C12 myoblasts, that arginine methylation by CARM1 controls myogenic differentiation. More specifically, the methylation of HuR on K217 regulates HuR levels and subcellular localization during myogenic differentiation, and the formation of myotubes. Furthermore, we demonstrate that SMN and HuR interact in C2C12 myoblasts. Interestingly, the SMA-causing E134K point mutation within the SMN Tudor domain, and CARM1 depletion, modulate the SMN-HuR interaction. In addition, using the Smn2B/- mouse model, we report that CARM1 levels are markedly increased in SMA muscles and that HuR fails to properly respond to muscle denervation, thereby affecting the regulation of its mRNA targets. Altogether, our results show a novel CARM1-HuR axis in the regulation of muscle differentiation and plasticity as well as in the aberrant regulation of this axis caused by the absence of SMN in SMA muscle. With the recent developments of therapeutics targeting motor neurons, this study further indicates the need for more global therapeutic approaches for SMA.
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Affiliation(s)
- Aymeric Ravel-Chapuis
- Department of Cellular and Molecular Medicine, Faculty of Medicine, University of Ottawa, Ottawa, ON K1H 8M5, Canada
- Eric Poulin Centre for Neuromuscular Disease, Faculty of Medicine, University of Ottawa, Ottawa, ON K1H 8M5, Canada
| | - Amir Haghandish
- Department of Cellular and Molecular Medicine, Faculty of Medicine, University of Ottawa, Ottawa, ON K1H 8M5, Canada
- Eric Poulin Centre for Neuromuscular Disease, Faculty of Medicine, University of Ottawa, Ottawa, ON K1H 8M5, Canada
| | - Nasibeh Daneshvar
- Department of Cellular and Molecular Medicine, Faculty of Medicine, University of Ottawa, Ottawa, ON K1H 8M5, Canada
- Eric Poulin Centre for Neuromuscular Disease, Faculty of Medicine, University of Ottawa, Ottawa, ON K1H 8M5, Canada
| | - Bernard J Jasmin
- Department of Cellular and Molecular Medicine, Faculty of Medicine, University of Ottawa, Ottawa, ON K1H 8M5, Canada
- Eric Poulin Centre for Neuromuscular Disease, Faculty of Medicine, University of Ottawa, Ottawa, ON K1H 8M5, Canada
| | - Jocelyn Côté
- Department of Cellular and Molecular Medicine, Faculty of Medicine, University of Ottawa, Ottawa, ON K1H 8M5, Canada
- Eric Poulin Centre for Neuromuscular Disease, Faculty of Medicine, University of Ottawa, Ottawa, ON K1H 8M5, Canada
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PRMT1 activates myogenin transcription via MyoD arginine methylation at R121. BIOCHIMICA ET BIOPHYSICA ACTA-GENE REGULATORY MECHANISMS 2019; 1862:194442. [DOI: 10.1016/j.bbagrm.2019.194442] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/15/2019] [Revised: 09/28/2019] [Accepted: 10/04/2019] [Indexed: 11/23/2022]
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Asymmetrical methyltransferase PRMT3 regulates human mesenchymal stem cell osteogenesis via miR-3648. Cell Death Dis 2019; 10:581. [PMID: 31378783 PMCID: PMC6680051 DOI: 10.1038/s41419-019-1815-7] [Citation(s) in RCA: 32] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2019] [Revised: 07/03/2019] [Accepted: 07/12/2019] [Indexed: 12/15/2022]
Abstract
Histone arginine methylation, which is catalyzed by protein arginine methyltransferases (PRMTs), plays a key regulatory role in various biological processes. Several PRMTs are involved in skeletal development; however, their role in the osteogenic differentiation of mesenchymal stem cells (MSCs) is not completely clear. In this study, we aimed to elucidate the function of PRMT3, a type-I PRMT that catalyzes the formation of ω-mono- or asymmetric dimethyl arginine, in MSCs osteogenesis. We found that PRMT3 promoted MSCs osteogenic commitment and bone remodeling. PRMT3 activated the expression of miR-3648 by enhancing histone H4 arginine 3 asymmetric dimethylation (H4R3me2a) levels at promoter region of the gene. Overexpression of miR-3648 rescued impaired osteogenesis in PRMT3-deficient cells. Moreover, administration of Prmt3 shRNA or a chemical inhibitor of PRMT3 (SGC707) caused an osteopenia phenotype in mice. These results indicate that PRMT3 is a potential therapeutic target for the treatment of bone regeneration and osteopenia disorders.
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Jin J, Martin M, Hartley AV, Lu T. PRMTs and miRNAs: functional cooperation in cancer and beyond. Cell Cycle 2019; 18:1676-1686. [PMID: 31234694 DOI: 10.1080/15384101.2019.1629791] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022] Open
Abstract
Epigenetic modulators play pivotal roles in directing gene expression for the maintenance of normal cellular functions. However, when these modulators are aberrantly regulated, this can result in a variety of disease states, including cancer. One class of epigenetic regulators, protein arginine methyltransferases (PRMTs), have been shown to play critical roles in disease through methylation of arginine residues (R) on histone or non-histone proteins. Quite different from PRMTs, microRNAs (miRNAs) belong to the family of modulators known as noncoding RNAs (ncRNA) that act to regulate gene expression via RNA-mediated gene silencing. Importantly, miRNAs are frequently dysregulated and contribute to the progression of cancer and other conditions, including neurological and cardiovascular diseases. Recently, numerous studies have shown that miRNAs and other epigenetic enzymes can co-regulate each other. This review highlights multiple nodes of interaction between miRNAs and PRMTs and also discusses how this interplay might open up promising opportunities for drug development for the treatment of cancer and other diseases.
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Affiliation(s)
- Jiamin Jin
- a College of Life Science , Northeast Forestry University , Harbin , China.,b Department of Pharmacology and Toxicology , Indiana University School of Medicine , Indianapolis , IN , USA
| | - Matthew Martin
- b Department of Pharmacology and Toxicology , Indiana University School of Medicine , Indianapolis , IN , USA
| | - Antja-Voy Hartley
- b Department of Pharmacology and Toxicology , Indiana University School of Medicine , Indianapolis , IN , USA
| | - Tao Lu
- b Department of Pharmacology and Toxicology , Indiana University School of Medicine , Indianapolis , IN , USA.,c Department of Biochemistry and Molecular Biology , Indiana University School of Medicine , Indianapolis , IN , USA.,d Department of Medical and Molecular Genetics , Indiana University School of Medicine , Indianapolis , IN , USA
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Wang CD, Guo XF, Wong TCB, Wang H, Qi XF, Cai DQ, Deng Y, Zhao H. Developmental expression of three prmt genes in Xenopus. Zool Res 2019; 40:102-107. [PMID: 30127333 PMCID: PMC6378560 DOI: 10.24272/j.issn.2095-8137.2018.064] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2018] [Accepted: 06/15/2018] [Indexed: 11/23/2022] Open
Abstract
Protein arginine methyltransferases (PRMTs) are involved in many cellular processes via the arginine methylation of histone or non-histone proteins. We examined the expression patterns of prmt4, prmt7, and prmt9 during embryogenesis in Xenopus using whole-mount in situ hybridization and quantitative reverse transcription polymerase chain reaction (RT-PCR). Xenopus prmt4 and prmt7 were expressed in the neural crest, brain, and spinal cord, and also detected in the eye, branchial arches, and heart at the tailbud stage. Specific prmt9 signals were not detected in Xenopus embryos until the late tailbud stage when weak expression was observed in the branchial arches. Quantitative RT-PCR indicated that the expressions of prmt4 and prmt7 were up-regulated during the neurula stage, whereas prmt9 maintained its low expression until the late tailbud stage, consistent with the whole-mount in situ hybridization results. Thus, the developmental expression patterns of these three prmt genes in Xenopus embryos provide a basis for further functional study of such genes.
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Affiliation(s)
- Cheng-Dong Wang
- Key Laboratory for Regenerative Medicine, Ministry of Education, School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong SAR, China
| | - Xiao-Fang Guo
- Key Laboratory for Regenerative Medicine of Ministry of Education, Jinan University, Guangzhou Guangdong 510632, China
- Department of Developmental & Regenerative Biology, College of Life Science and Technology, Jinan University, Guangzhou Guangdong 510632, China
| | - Thomas Chi Bun Wong
- Key Laboratory for Regenerative Medicine, Ministry of Education, School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong SAR, China
| | - Hui Wang
- Key Laboratory for Regenerative Medicine, Ministry of Education, School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong SAR, China
| | - Xu-Feng Qi
- Key Laboratory for Regenerative Medicine of Ministry of Education, Jinan University, Guangzhou Guangdong 510632, China
- Department of Developmental & Regenerative Biology, College of Life Science and Technology, Jinan University, Guangzhou Guangdong 510632, China
| | - Dong-Qing Cai
- Key Laboratory for Regenerative Medicine of Ministry of Education, Jinan University, Guangzhou Guangdong 510632, China
- Department of Developmental & Regenerative Biology, College of Life Science and Technology, Jinan University, Guangzhou Guangdong 510632, China
| | - Yi Deng
- Guangdong Provincial Key Laboratory of Cell Microenvironment, Department of Biology, South University of Science and Technology of China, Shenzhen Guangdong 518055, China
| | - Hui Zhao
- Key Laboratory for Regenerative Medicine, Ministry of Education, School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong SAR, China; E-mail:
- Kunming Institute of Zoology, Chinese Academy of Sciences-The Chinese University of Hong Kong Joint Laboratory of Bioresources and Molecular Research of Common Diseases, Hong Kong SAR, China
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Yang Q, Yang Y, Zhou N, Tang K, Lau WB, Lau B, Wang W, Xu L, Yang Z, Huang S, Wang X, Yi T, Zhao X, Wei Y, Wang H, Zhao L, Zhou S. Epigenetics in ovarian cancer: premise, properties, and perspectives. Mol Cancer 2018; 17:109. [PMID: 30064416 PMCID: PMC6069741 DOI: 10.1186/s12943-018-0855-4] [Citation(s) in RCA: 87] [Impact Index Per Article: 12.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2017] [Accepted: 07/11/2018] [Indexed: 01/04/2023] Open
Abstract
Malignant ovarian tumors bear the highest mortality rate among all gynecological cancers. Both late tumor diagnosis and tolerance to available chemical therapy increase patient mortality. Therefore, it is both urgent and important to identify biomarkers facilitating early identification and novel agents preventing recurrence. Accumulating evidence demonstrates that epigenetic aberrations (particularly histone modifications) are crucial in tumor initiation and development. Histone acetylation and methylation are respectively regulated by acetyltransferases-deacetylases and methyltransferases-demethylases, both of which are implicated in ovarian cancer pathogenesis. In this review, we summarize the most recent discoveries pertaining to ovarian cancer development arising from the imbalance of histone acetylation and methylation, and provide insight into novel therapeutic interventions for the treatment of ovarian carcinoma.
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Affiliation(s)
- Qilian Yang
- Department of Obstetrics and Gynecology, Key Laboratory of Birth Defects and Related Diseases of Women and Children of MOE and State Key Laboratory of Biotherapy, West China Second University Hospital, Sichuan University and Collaborative Innovation Center, Chengdu, 610041, People's Republic of China
| | - Yuqing Yang
- Nanchang University, Nanchang, People's Republic of China
| | - Nianxin Zhou
- Department of Obstetrics and Gynecology, Key Laboratory of Birth Defects and Related Diseases of Women and Children of MOE and State Key Laboratory of Biotherapy, West China Second University Hospital, Sichuan University and Collaborative Innovation Center, Chengdu, 610041, People's Republic of China
| | - Kexin Tang
- Sichuan Normal University Affiliated Middle School, Chengdu, People's Republic of China
| | - Wayne Bond Lau
- Department of Emergency Medicine, Thomas Jefferson University Hospital, Philadelphia, USA
| | - Bonnie Lau
- Department of Surgery, Emergency Medicine, Kaiser Santa Clara Medical Center, Affiliate of Stanford University, Stanford, USA
| | - Wei Wang
- Department of Biomedical Sciences, City University of Hong Kong, Kowloon Tong, Hong Kong, China
| | - Lian Xu
- Department of Pathology, West China Second University Hospital, Sichuan University, Chengdu, People's Republic of China
| | - Zhengnan Yang
- Department of Obstetrics and Gynecology, Key Laboratory of Birth Defects and Related Diseases of Women and Children of MOE and State Key Laboratory of Biotherapy, West China Second University Hospital, Sichuan University and Collaborative Innovation Center, Chengdu, 610041, People's Republic of China
| | - Shuang Huang
- Department of Obstetrics and Gynecology, Key Laboratory of Birth Defects and Related Diseases of Women and Children of MOE and State Key Laboratory of Biotherapy, West China Second University Hospital, Sichuan University and Collaborative Innovation Center, Chengdu, 610041, People's Republic of China
| | - Xin Wang
- Department of Biomedical Sciences, City University of Hong Kong, Kowloon Tong, Hong Kong, China
| | - Tao Yi
- Department of Obstetrics and Gynecology, Key Laboratory of Birth Defects and Related Diseases of Women and Children of MOE and State Key Laboratory of Biotherapy, West China Second University Hospital, Sichuan University and Collaborative Innovation Center, Chengdu, 610041, People's Republic of China
| | - Xia Zhao
- Department of Obstetrics and Gynecology, Key Laboratory of Birth Defects and Related Diseases of Women and Children of MOE and State Key Laboratory of Biotherapy, West China Second University Hospital, Sichuan University and Collaborative Innovation Center, Chengdu, 610041, People's Republic of China
| | - Yuquan Wei
- Department of Obstetrics and Gynecology, Key Laboratory of Birth Defects and Related Diseases of Women and Children of MOE and State Key Laboratory of Biotherapy, West China Second University Hospital, Sichuan University and Collaborative Innovation Center, Chengdu, 610041, People's Republic of China
| | - Hongjing Wang
- Department of Obstetrics and Gynecology, Key Laboratory of Birth Defects and Related Diseases of Women and Children of MOE and State Key Laboratory of Biotherapy, West China Second University Hospital, Sichuan University and Collaborative Innovation Center, Chengdu, 610041, People's Republic of China.
| | - Linjie Zhao
- Department of Obstetrics and Gynecology, Key Laboratory of Birth Defects and Related Diseases of Women and Children of MOE and State Key Laboratory of Biotherapy, West China Second University Hospital, Sichuan University and Collaborative Innovation Center, Chengdu, 610041, People's Republic of China.
| | - Shengtao Zhou
- Department of Obstetrics and Gynecology, Key Laboratory of Birth Defects and Related Diseases of Women and Children of MOE and State Key Laboratory of Biotherapy, West China Second University Hospital, Sichuan University and Collaborative Innovation Center, Chengdu, 610041, People's Republic of China.
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12
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Jiang H, Zhu Y, Zhou Z, Xu J, Jin S, Xu K, Zhang H, Sun Q, Wang J, Xu J. PRMT5 promotes cell proliferation by inhibiting BTG2 expression via the ERK signaling pathway in hepatocellular carcinoma. Cancer Med 2018; 7:869-882. [PMID: 29441724 PMCID: PMC5852340 DOI: 10.1002/cam4.1360] [Citation(s) in RCA: 45] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2017] [Revised: 10/23/2017] [Accepted: 01/04/2018] [Indexed: 12/12/2022] Open
Abstract
Increasing evidence suggests that PRMT5, a protein arginine methyltransferase, has roles in cell growth regulation and cancer development. However, the role of PRMT5 in hepatocellular carcinoma (HCC) progression remains unclear. Here, we showed that PRMT5 expression was frequently upregulated in HCC tissues, and its expression was inversely correlated with overall survival in HCC patients. PRMT5 knockdown markedly inhibited in vitro HCC proliferation and in vivo tumorigenesis. We revealed that the mechanism of PRMT5‐induced proliferation was partially mediated by BTG downregulation, leading to cell cycle arrest during the G1 phase in HCC cells. Ectopic BTG2 overexpression decreased HCC growth, caused cell cycle arrest at the G1 phase, and downregulated Cyclin D1 and Cyclin E1 protein expression. Furthermore, we found that PRMT5‐induced ERK phosphorylation regulated BTG2 expression in HCC cells, whereas pretreatment with a selective ERK1/2 inhibitor (PD184352) significantly reversed the effect of PRMT5 on BTG2 expression. Our results indicated that PRMT5 promotes HCC proliferation by downregulating BTG2 expression via the ERK pathway.
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Affiliation(s)
- Hai Jiang
- Guangdong Province Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Research Center of Medicine, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, 510120, China.,Department of Hepatobiliary Surgery, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, 510120, China
| | - Yue Zhu
- Guangdong Province Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Research Center of Medicine, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, 510120, China.,Department of Vascular and Thyroid Surgery, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, 510120, China
| | - Zhenyu Zhou
- Guangdong Province Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Research Center of Medicine, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, 510120, China.,Department of Hepatobiliary Surgery, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, 510120, China
| | - Junyang Xu
- Department of Neurology, Forth Affiliated Hospital, Guangzhou Medical University, Guangzhou, 510000, China
| | - Shaowen Jin
- Guangdong Province Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Research Center of Medicine, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, 510120, China.,Department of Hepatobiliary Surgery, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, 510120, China
| | - Kang Xu
- Guangdong Province Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Research Center of Medicine, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, 510120, China.,Department of Hepatobiliary Surgery, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, 510120, China
| | - Heyun Zhang
- Guangdong Province Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Research Center of Medicine, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, 510120, China.,Department of Hepatobiliary Surgery, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, 510120, China
| | - Qing Sun
- Guangdong Province Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Research Center of Medicine, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, 510120, China.,Department of Pathology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, 510120, China
| | - Jie Wang
- Guangdong Province Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Research Center of Medicine, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, 510120, China.,Department of Hepatobiliary Surgery, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, 510120, China
| | - Junyao Xu
- Guangdong Province Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Research Center of Medicine, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, 510120, China.,Department of Hepatobiliary Surgery, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, 510120, China
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13
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Protein arginine methyltransferase expression and activity during myogenesis. Biosci Rep 2018; 38:BSR20171533. [PMID: 29208765 PMCID: PMC6435512 DOI: 10.1042/bsr20171533] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2017] [Revised: 11/30/2017] [Accepted: 12/04/2017] [Indexed: 01/24/2023] Open
Abstract
Despite the emerging importance of protein arginine methyltransferases (PRMTs) in regulating skeletal muscle plasticity, PRMT biology during muscle development is complex and not completely understood. Therefore, our purpose was to investigate PRMT1, -4, and -5 expression and function in skeletal muscle cells during the phenotypic remodeling elicited by myogenesis. C2C12 muscle cell maturation, assessed during the myoblast (MB) stage, and during days 1, 3, 5, and 7 of differentiation, was employed as an in vitro model of myogenesis. We observed PRMT-specific patterns of expression and activity during myogenesis. PRMT4 and -5 gene expression was unchanged, while PRMT1 mRNA and protein content were significantly induced. Cellular monomethylarginines (MMAs) and symmetric dimethylarginines (SDMAs), indicative of global and type II PRMT activities, respectively, remained steady during development, while type I PRMT activity indicator asymmetric dimethylarginines (ADMAs) increased through myogenesis. Histone 4 arginine 3 (H4R3) and H3R17 contents were elevated coincident with the myonuclear accumulation of PRMT1 and -4. Collectively, this suggests that PRMTs are methyl donors throughout myogenesis and demonstrate specificity for their protein targets. Cells were then treated with TC-E 5003 (TC-E), a selective inhibitor of PRMT1 in order to specifically examine the enzymes role during myogenic differentiation. TC-E treated cells exhibited decrements in muscle differentiation, which were consistent with attenuated mitochondrial biogenesis and respiratory function. In summary, the present study increases our understanding of PRMT1, -4, and -5 biology during the plasticity of skeletal muscle development. Our results provide evidence for a role of PRMT1, via a mitochondrially mediated mechanism, in driving the muscle differentiation program.
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14
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Stouth DW, vanLieshout TL, Shen NY, Ljubicic V. Regulation of Skeletal Muscle Plasticity by Protein Arginine Methyltransferases and Their Potential Roles in Neuromuscular Disorders. Front Physiol 2017; 8:870. [PMID: 29163212 PMCID: PMC5674940 DOI: 10.3389/fphys.2017.00870] [Citation(s) in RCA: 29] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2017] [Accepted: 10/17/2017] [Indexed: 12/31/2022] Open
Abstract
Protein arginine methyltransferases (PRMTs) are a family of enzymes that catalyze the methylation of arginine residues on target proteins, thereby mediating a diverse set of intracellular functions that are indispensable for survival. Indeed, full-body knockouts of specific PRMTs are lethal and PRMT dysregulation has been implicated in the most prevalent chronic disorders, such as cancers and cardiovascular disease (CVD). PRMTs are now emerging as important mediators of skeletal muscle phenotype and plasticity. Since their first description in muscle in 2002, a number of studies employing wide varieties of experimental models support the hypothesis that PRMTs regulate multiple aspects of skeletal muscle biology, including development and regeneration, glucose metabolism, as well as oxidative metabolism. Furthermore, investigations in non-muscle cell types strongly suggest that proteins, such as peroxisome proliferator-activated receptor-γ coactivator-1α, E2F transcription factor 1, receptor interacting protein 140, and the tumor suppressor protein p53, are putative downstream targets of PRMTs that regulate muscle phenotype determination and remodeling. Recent studies demonstrating that PRMT function is dysregulated in Duchenne muscular dystrophy (DMD), spinal muscular atrophy (SMA), and amyotrophic lateral sclerosis (ALS) suggests that altering PRMT expression and/or activity may have therapeutic value for neuromuscular disorders (NMDs). This review summarizes our understanding of PRMT biology in skeletal muscle, and identifies uncharted areas that warrant further investigation in this rapidly expanding field of research.
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Affiliation(s)
- Derek W Stouth
- Department of Kinesiology, McMaster University, Hamilton, ON, Canada
| | | | - Nicole Y Shen
- Department of Kinesiology, McMaster University, Hamilton, ON, Canada
| | - Vladimir Ljubicic
- Department of Kinesiology, McMaster University, Hamilton, ON, Canada
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15
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Temporal regulation of chromatin during myoblast differentiation. Semin Cell Dev Biol 2017; 72:77-86. [PMID: 29079444 DOI: 10.1016/j.semcdb.2017.10.022] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2017] [Revised: 10/06/2017] [Accepted: 10/22/2017] [Indexed: 11/23/2022]
Abstract
The commitment to and execution of differentiation programmes involves a significant change in gene expression in the precursor cell to facilitate development of the mature cell type. In addition to being regulated by lineage-determining and auxiliary transcription factors that drive these changes, the structural status of the chromatin has a considerable impact on the transcriptional competence of differentiation-specific genes, which is clearly demonstrated by the large number of cofactors and the extraordinary complex mechanisms by which these genes become activated. The terminal differentiation of myoblasts to myotubes and mature skeletal muscle is an excellent system to illustrate these points. The MyoD family of closely related, lineage-determining transcription factors directs, largely through targeting to chromatin, a cascade of cooperating transcription factors and enzymes that incorporate or remove variant histones, post-translationally modify histones, and alter nucleosome structure and positioning via energy released by ATP hydrolysis. The coordinated action of these transcription factors and enzymes prevents expression of differentiation-specific genes in myoblasts and facilitates the transition of these genes from transcriptionally repressed to activated during the differentiation process. Regulation is achieved in both a temporal as well as spatial manner, as at least some of these factors and enzymes affect local chromatin structure at myogenic gene regulatory sequences as well as higher-order genome organization. Here we discuss the transition of genes that promote myoblast differentiation from the silenced to the activated state with an emphasis on the changes that occur to individual histones and the chromatin structure present at these loci.
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16
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Bianchi M, Renzini A, Adamo S, Moresi V. Coordinated Actions of MicroRNAs with other Epigenetic Factors Regulate Skeletal Muscle Development and Adaptation. Int J Mol Sci 2017; 18:E840. [PMID: 28420141 PMCID: PMC5412424 DOI: 10.3390/ijms18040840] [Citation(s) in RCA: 55] [Impact Index Per Article: 6.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2017] [Revised: 04/04/2017] [Accepted: 04/13/2017] [Indexed: 01/01/2023] Open
Abstract
Epigenetics plays a pivotal role in regulating gene expression in development, in response to cellular stress or in disease states, in virtually all cell types. MicroRNAs (miRNAs) are short, non-coding RNA molecules that mediate RNA silencing and regulate gene expression. miRNAs were discovered in 1993 and have been extensively studied ever since. They can be expressed in a tissue-specific manner and play a crucial role in tissue development and many biological processes. miRNAs are responsible for changes in the cell epigenome because of their ability to modulate gene expression post-transcriptionally. Recently, numerous studies have shown that miRNAs and other epigenetic factors can regulate each other or cooperate in regulating several biological processes. On the one hand, the expression of some miRNAs is silenced by DNA methylation, and histone modifications have been demonstrated to modulate miRNA expression in many cell types or disease states. On the other hand, miRNAs can directly target epigenetic factors, such as DNA methyltransferases or histone deacetylases, thus regulating chromatin structure. Moreover, several studies have reported coordinated actions between miRNAs and other epigenetic mechanisms to reinforce the regulation of gene expression. This paper reviews multiple interactions between miRNAs and epigenetic factors in skeletal muscle development and in response to stimuli or disease.
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Affiliation(s)
- Marzia Bianchi
- DAHFMO Unit of Histology and Medical Embryology, Interuniversity Institute of Myology, Sapienza University of Rome, Via Antonio Scarpa 14, 00161 Rome, Italy.
| | - Alessandra Renzini
- DAHFMO Unit of Histology and Medical Embryology, Interuniversity Institute of Myology, Sapienza University of Rome, Via Antonio Scarpa 14, 00161 Rome, Italy.
| | - Sergio Adamo
- DAHFMO Unit of Histology and Medical Embryology, Interuniversity Institute of Myology, Sapienza University of Rome, Via Antonio Scarpa 14, 00161 Rome, Italy.
| | - Viviana Moresi
- DAHFMO Unit of Histology and Medical Embryology, Interuniversity Institute of Myology, Sapienza University of Rome, Via Antonio Scarpa 14, 00161 Rome, Italy.
- Laboratory of Cardiovascular Endocrinology, IRCCS San Raffaele Pisana, 00166 Rome, Italy.
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17
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Xie M, Dart DA, Owen S, Wen X, Ji J, Jiang W. Insights into roles of the miR-1, -133 and -206 family in gastric cancer (Review). Oncol Rep 2016; 36:1191-8. [PMID: 27349337 DOI: 10.3892/or.2016.4908] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2015] [Accepted: 01/27/2016] [Indexed: 11/06/2022] Open
Abstract
Gastric cancer (GC) remains the third most common cause of cancer deaths worldwide and carries a high rate of metastatic risk contributing to the main cause of treatment failure. An accumulation of data has resulted in a better understanding of the molecular network of GC, however, gaps still exist between the unique bio-resources and clinical application. MicroRNAs are an important part of non-coding RNAs and behave as major regulators of tumour biology, alongside their well-known roles as intrinsic factors of gene expression in cellular processes, via their post-transcriptional regulation of components of signalling pathways in a coordinated manner. Deregulation of the miR-1, -133 and -206 family plays a key role in tumorigenesis, progression, invasion and metastasis. This review aims to provide a summary of recent findings on the miR-1, -133 and -206 family in GC and how this knowledge might be exploited for the development of future miRNA-based therapies for the treatment of GC.
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Affiliation(s)
- Meng Xie
- Department of Gastrointestinal Translational Research, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital and Institute, Haidian, Beijing 100142, P.R. China
| | - Dafydd Alwyn Dart
- Cardiff China Medical Research Collaborative, Cardiff University School of Medicine, Cardiff, CF14 4XN, UK
| | - Sioned Owen
- Cardiff China Medical Research Collaborative, Cardiff University School of Medicine, Cardiff, CF14 4XN, UK
| | - Xianzi Wen
- Department of Gastrointestinal Translational Research, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital and Institute, Haidian, Beijing 100142, P.R. China
| | - Jiafu Ji
- Department of Gastrointestinal Translational Research, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital and Institute, Haidian, Beijing 100142, P.R. China
| | - Wenguo Jiang
- Cardiff China Medical Research Collaborative, Cardiff University School of Medicine, Cardiff, CF14 4XN, UK
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18
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Cheng N, Guo M, Chang P, Zhang X, Zhang R, Qi C, Zhong X, Zhou Q, Zhao H. Expression of mep50 in adult and embryos of medaka fish (Oryzias latipes). FISH PHYSIOLOGY AND BIOCHEMISTRY 2016; 42:1053-1061. [PMID: 26749004 DOI: 10.1007/s10695-016-0196-4] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/30/2015] [Accepted: 01/03/2016] [Indexed: 06/05/2023]
Abstract
Protein arginine methylation is important for gene regulation and biological processes. Methylosome protein 50 (Mep50) is identified as a partner of protein arginine methyltransferase 5 (Prmt5), a major enzyme capable of symmetric dimethylation, in mammals and Xenopus. The isolation and characterization of medaka mep50 were reported in this paper. Medaka Mep50 is a homolog of human MEP50 with six WD40 domains. Medaka mep50 was ubiquitously expressed in the adult tissues and had maternal origin with continuous and dynamical expression during embryonic development detected by RT-PCR and in situ hybridization. A strong interaction of medaka Mep50 and Prmt5 was shown by yeast two hybridization. The expression pattern of mep50 is similar to that of prmt5 in medaka. The results suggested that medaka Mep50 could be a partner of Prmt5 and might play major roles in a variety of tissues in medaka.
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Affiliation(s)
- Nana Cheng
- Hubei Key Laboratory of Genetic Regulation and Integrative Biology, School of Life Sciences, Central China Normal University, Wuhan, 430079, China
| | - Maomao Guo
- Hubei Key Laboratory of Genetic Regulation and Integrative Biology, School of Life Sciences, Central China Normal University, Wuhan, 430079, China
| | - Pei Chang
- Hubei Key Laboratory of Genetic Regulation and Integrative Biology, School of Life Sciences, Central China Normal University, Wuhan, 430079, China
| | - Xueyan Zhang
- Hubei Key Laboratory of Genetic Regulation and Integrative Biology, School of Life Sciences, Central China Normal University, Wuhan, 430079, China
| | - Runshuai Zhang
- Hubei Key Laboratory of Genetic Regulation and Integrative Biology, School of Life Sciences, Central China Normal University, Wuhan, 430079, China
| | - Chao Qi
- Hubei Key Laboratory of Genetic Regulation and Integrative Biology, School of Life Sciences, Central China Normal University, Wuhan, 430079, China
| | - Xueping Zhong
- Hubei Key Laboratory of Genetic Regulation and Integrative Biology, School of Life Sciences, Central China Normal University, Wuhan, 430079, China
| | - Qingchun Zhou
- Hubei Key Laboratory of Genetic Regulation and Integrative Biology, School of Life Sciences, Central China Normal University, Wuhan, 430079, China
| | - Haobin Zhao
- Hubei Key Laboratory of Genetic Regulation and Integrative Biology, School of Life Sciences, Central China Normal University, Wuhan, 430079, China.
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19
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Sakaguchi N, Maeda K. Germinal Center B-Cell-Associated Nuclear Protein (GANP) Involved in RNA Metabolism for B Cell Maturation. Adv Immunol 2016; 131:135-86. [PMID: 27235683 DOI: 10.1016/bs.ai.2016.02.003] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Germinal center B-cell-associated nuclear protein (GANP) is upregulated in germinal center B cells against T-cell-dependent antigens in mice and humans. In mice, GANP depletion in B cells impairs antibody affinity maturation. Conversely, its transgenic overexpression augments the generation of high-affinity antigen-specific B cells. GANP associates with AID in the cytoplasm, shepherds AID into the nucleus, and augments its access to the rearranged immunoglobulin (Ig) variable (V) region of the genome in B cells, thereby precipitating the somatic hypermutation of V region genes. GANP is also upregulated in human CD4(+) T cells and is associated with APOBEC3G (A3G). GANP interacts with A3G and escorts it to the virion cores to potentiate its antiretroviral activity by inactivating HIV-1 genomic cDNA. Thus, GANP is characterized as a cofactor associated with AID/APOBEC cytidine deaminase family molecules in generating diversity of the IgV region of the genome and genetic alterations of exogenously introduced viral targets. GANP, encoded by human chromosome 21, as well as its mouse equivalent on chromosome 10, contains a region homologous to Saccharomyces Sac3 that was characterized as a component of the transcription/export 2 (TREX-2) complex and was predicted to be involved in RNA export and metabolism in mammalian cells. The metabolism of RNA during its maturation, from the transcription site at the chromosome within the nucleus to the cytoplasmic translation apparatus, needs to be elaborated with regard to acquired and innate immunity. In this review, we summarize the current knowledge on GANP as a component of TREX-2 in mammalian cells.
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Affiliation(s)
- N Sakaguchi
- WPI Immunology Frontier Research Center (IFReC), Osaka University, Suita, Osaka, Japan; Tokyo Metropolitan Institute of Medical Science, Tokyo, Japan.
| | - K Maeda
- WPI Immunology Frontier Research Center (IFReC), Osaka University, Suita, Osaka, Japan; Laboratory of Host Defense, Research Institute for Microbial Diseases, Osaka University, Suita, Japan
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20
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Mitchelson KR, Qin WY. Roles of the canonical myomiRs miR-1, -133 and -206 in cell development and disease. World J Biol Chem 2015; 6:162-208. [PMID: 26322174 PMCID: PMC4549760 DOI: 10.4331/wjbc.v6.i3.162] [Citation(s) in RCA: 121] [Impact Index Per Article: 12.1] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/11/2014] [Revised: 03/13/2015] [Accepted: 05/28/2015] [Indexed: 02/05/2023] Open
Abstract
MicroRNAs are small non-coding RNAs that participate in different biological processes, providing subtle combinational regulation of cellular pathways, often by regulating components of signalling pathways. Aberrant expression of miRNAs is an important factor in the development and progression of disease. The canonical myomiRs (miR-1, -133 and -206) are central to the development and health of mammalian skeletal and cardiac muscles, but new findings show they have regulatory roles in the development of other mammalian non-muscle tissues, including nerve, brain structures, adipose and some specialised immunological cells. Moreover, the deregulation of myomiR expression is associated with a variety of different cancers, where typically they have tumor suppressor functions, although examples of an oncogenic role illustrate their diverse function in different cell environments. This review examines the involvement of the related myomiRs at the crossroads between cell development/tissue regeneration/tissue inflammation responses, and cancer development.
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21
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Stopa N, Krebs JE, Shechter D. The PRMT5 arginine methyltransferase: many roles in development, cancer and beyond. Cell Mol Life Sci 2015; 72:2041-59. [PMID: 25662273 PMCID: PMC4430368 DOI: 10.1007/s00018-015-1847-9] [Citation(s) in RCA: 374] [Impact Index Per Article: 37.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2014] [Revised: 01/10/2015] [Accepted: 01/29/2015] [Indexed: 10/24/2022]
Abstract
Post-translational arginine methylation is responsible for regulation of many biological processes. The protein arginine methyltransferase 5 (PRMT5, also known as Hsl7, Jbp1, Skb1, Capsuleen, or Dart5) is the major enzyme responsible for mono- and symmetric dimethylation of arginine. An expanding literature demonstrates its critical biological function in a wide range of cellular processes. Histone and other protein methylation by PRMT5 regulate genome organization, transcription, stem cells, primordial germ cells, differentiation, the cell cycle, and spliceosome assembly. Metazoan PRMT5 is found in complex with the WD-repeat protein MEP50 (also known as Wdr77, androgen receptor coactivator p44, or Valois). PRMT5 also directly associates with a range of other protein factors, including pICln, Menin, CoPR5 and RioK1 that may alter its subcellular localization and protein substrate selection. Protein substrate and PRMT5-MEP50 post-translation modifications induce crosstalk to regulate PRMT5 activity. Crystal structures of C. elegans PRMT5 and human and frog PRMT5-MEP50 complexes provide substantial insight into the mechanisms of substrate recognition and procession to dimethylation. Enzymological studies of PRMT5 have uncovered compelling insights essential for future development of specific PRMT5 inhibitors. In addition, newly accumulating evidence implicates PRMT5 and MEP50 expression levels and their methyltransferase activity in cancer tumorigenesis, and, significantly, as markers of poor clinical outcome, marking them as potential oncogenes. Here, we review the substantial new literature on PRMT5 and its partners to highlight the significance of understanding this essential enzyme in health and disease.
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Affiliation(s)
- Nicole Stopa
- Department of Biological Sciences, University of Alaska Anchorage, 3211 Providence Drive, Anchorage, AK 99508, USA
| | - Jocelyn E. Krebs
- Department of Biological Sciences, University of Alaska Anchorage, 3211 Providence Drive, Anchorage, AK 99508, USA
| | - David Shechter
- Department of Biochemistry, Albert Einstein College of Medicine of Yeshiva University, 1300 Morris Park Avenue, Bronx, NY 10461, USA
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22
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Brancaccio A, Palacios D. Chromatin signaling in muscle stem cells: interpreting the regenerative microenvironment. Front Aging Neurosci 2015; 7:36. [PMID: 25904863 PMCID: PMC4387924 DOI: 10.3389/fnagi.2015.00036] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2015] [Accepted: 03/04/2015] [Indexed: 12/12/2022] Open
Abstract
Muscle regeneration in the adult occurs in response to damage at expenses of a population of adult stem cells, the satellite cells. Upon injury, either physical or genetic, signals released within the satellite cell niche lead to the commitment, expansion and differentiation of the pool of muscle progenitors to repair damaged muscle. To achieve this goal satellite cells undergo a dramatic transcriptional reprogramming to coordinately activate and repress specific subset of genes. Although the epigenetics of muscle regeneration has been extensively discussed, less emphasis has been put on how extra-cellular cues are translated into the specific chromatin reorganization necessary for progression through the myogenic program. In this review we will focus on how satellite cells sense the regenerative microenvironment in physiological and pathological circumstances, paying particular attention to the mechanism through which the external stimuli are transduced to the nucleus to modulate chromatin structure and gene expression. We will discuss the pathways involved and how alterations in this chromatin signaling may contribute to satellite cells dysfunction during aging and disease.
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Affiliation(s)
- Arianna Brancaccio
- Laboratory of Epigenetics and Signaling, IRCCS Fondazione Santa Lucia Rome, Italy
| | - Daniela Palacios
- Laboratory of Epigenetics and Signaling, IRCCS Fondazione Santa Lucia Rome, Italy
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23
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Hernando CE, Sanchez SE, Mancini E, Yanovsky MJ. Genome wide comparative analysis of the effects of PRMT5 and PRMT4/CARM1 arginine methyltransferases on the Arabidopsis thaliana transcriptome. BMC Genomics 2015; 16:192. [PMID: 25880665 PMCID: PMC4381356 DOI: 10.1186/s12864-015-1399-2] [Citation(s) in RCA: 36] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2014] [Accepted: 02/24/2015] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Methylation at arginine residues (R) is an important post-translational modification that regulates a myriad of essential cellular processes in eukaryotes, such as transcriptional regulation, RNA processing, signal transduction and DNA repair. Arginine methylation is catalyzed by a family of enzymes known as protein arginine methyltransferases (PRMTs). PRMTs are classified as Type I or Type II, depending on the position of the methyl group on the guanidine of the methylated arginine. Previous reports have linked symmetric R methylation to transcriptional repression, while asymmetric R methylation is generally associated with transcriptional activation. However, global studies supporting this conclusion are not available. RESULTS Here we compared side by side the physiological and molecular roles of the best characterized plant PRMTs, the Type II PRMT5 and the Type I PRMT4, also known as CARM1 in mammals. We found that prmt5 and prmt4a;4b mutants showed similar alterations in flowering time, photomorphogenic responses and salt stress tolerance, while only prmt5 mutants exhibited alterations in circadian rhythms. An RNA-seq analysis revealed that expression and splicing of many differentially regulated genes was similarly enhanced or repressed by PRMT5 and PRMT4s. Furthermore, PRMT5 and PRMT4s co-regulated the expression and splicing of key regulatory genes associated with transcription, RNA processing, responses to light, flowering, and abiotic stress tolerance, being candidates to mediate the physiological alterations observed in the mutants. CONCLUSIONS Our global analysis indicates that two of the most important Type I and Type II arginine methyltransferases, PRTM4 and PRMT5, have mostly overlapping as well as specific, but not opposite, roles in the global regulation of gene expression in plants.
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Affiliation(s)
- Carlos E Hernando
- Fundación Instituto Leloir, Instituto de Investigaciones Bioquímicas de Buenos Aires-Consejo Nacional de Investigaciones Científicas y Técnicas de Argentina, Buenos Aires, Argentina.
| | - Sabrina E Sanchez
- Fundación Instituto Leloir, Instituto de Investigaciones Bioquímicas de Buenos Aires-Consejo Nacional de Investigaciones Científicas y Técnicas de Argentina, Buenos Aires, Argentina. .,Molecular and Computational Biology Section, University of Southern California, Los Angeles, CA, 90089, USA.
| | - Estefanía Mancini
- Fundación Instituto Leloir, Instituto de Investigaciones Bioquímicas de Buenos Aires-Consejo Nacional de Investigaciones Científicas y Técnicas de Argentina, Buenos Aires, Argentina.
| | - Marcelo J Yanovsky
- Fundación Instituto Leloir, Instituto de Investigaciones Bioquímicas de Buenos Aires-Consejo Nacional de Investigaciones Científicas y Técnicas de Argentina, Buenos Aires, Argentina.
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Yang F, Wang J, Ren HY, Jin J, Wang AL, Sun LL, Diao KX, Wang EH, Mi XY. Proliferative role of TRAF4 in breast cancer by upregulating PRMT5 nuclear expression. Tumour Biol 2015; 36:5901-11. [PMID: 25704480 DOI: 10.1007/s13277-015-3262-0] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2015] [Accepted: 02/13/2015] [Indexed: 11/25/2022] Open
Abstract
In this study, we examined protein arginine methyltransferase 5 (PRMT5) and tumor necrosis factor receptor-associated 4 (TRAF4) expression in breast cancer to find the interaction mechanism between the two. We examined TRAF4 and PRMT5 expression by immunohistochemistry and found that their expression is positively correlated in breast cancer. Besides, PRMT5 expression was significantly associated with histological type and tumor size (p < 0.05). PRMT5 nuclear expression was significantly associated with HER2 expression (p < 0.05). PRMT5 and TRAF4 were both overexpressed in breast cancer tissues and cells, and we found that PRMT5 binds to the zinc finger structures in TRAF4 by coimmunoprecipitation and Western blotting. We also tested the potential regulatory effect between TRAF4 and PRMT5. TRAF4 upregulated PRMT5 expression, which occurred predominantly in the nucleus, on which TRAF4 promotion of cell proliferation in breast cancer is mainly dependent. PRMT5 may play an important role in activation of the NF-κB signaling pathway.
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Affiliation(s)
- Fan Yang
- Department of Pathology, First Affiliated Hospital and College of Basic Medical Sciences, China Medical University, Shenyang, 110001, China
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25
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Morettin A, Baldwin RM, Cote J. Arginine methyltransferases as novel therapeutic targets for breast cancer. Mutagenesis 2015; 30:177-89. [DOI: 10.1093/mutage/geu039] [Citation(s) in RCA: 37] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022] Open
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Selvi BR, Swaminathan A, Maheshwari U, Nagabhushana A, Mishra RK, Kundu TK. CARM1 regulates astroglial lineage through transcriptional regulation of Nanog and posttranscriptional regulation by miR92a. Mol Biol Cell 2014; 26:316-26. [PMID: 25392304 PMCID: PMC4294678 DOI: 10.1091/mbc.e14-01-0019] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/11/2022] Open
Abstract
Coactivator-associated arginine methyltransferase (CARM1/PRMT4)-mediated transcriptional coactivation and arginine methylation is known to regulate various tissue-specific differentiation events. Although CARM1 is expressed in the neural crest region in early development, coinciding with early neuronal progenitor specification, the role of CARM1 in any neuronal developmental pathways has been unexplored. Using a specific small-molecule inhibitor of CARM1-mediated H3R17 methylation in human embryonic stem cell line, we find that H3R17 methylation contributes to the maintenance of the astroglial cell population. A network of regulation was observed on the miR92a promoter by which H3R17-responsive Nanog bound to the miR92a promoter decreased upon inhibition, resulting in an abnormal gene expression program influencing the glial lineage. This was also true in zebrafish, in which, with the help of CARM1 inhibitor and CARM1 morpholinos, we show that inhibition of H3R17 methylation results in defective glial cell morphology and a sensory defect in a subpopulation. A gain-of-function strategy in which mCARM1 was introduced in the morpholino-treated embryos exhibited recovery of the sensory defect phenotype. This study thus establishes the functional cooperation between arginine methylation and microRNA expression in the neuronal developmental process, with potential implications in sensory development pathways.
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Affiliation(s)
- B Ruthrotha Selvi
- Transcription and Disease Laboratory, Molecular Biology and Genetics Unit, Jawaharlal Nehru Centre for Advanced Scientific Research, Bangalore 560 064, India
| | - Amrutha Swaminathan
- Transcription and Disease Laboratory, Molecular Biology and Genetics Unit, Jawaharlal Nehru Centre for Advanced Scientific Research, Bangalore 560 064, India
| | - Uma Maheshwari
- Centre for Cellular and Molecular Biology, Hyderabad 500 007, India
| | | | - Rakesh K Mishra
- Centre for Cellular and Molecular Biology, Hyderabad 500 007, India
| | - Tapas K Kundu
- Transcription and Disease Laboratory, Molecular Biology and Genetics Unit, Jawaharlal Nehru Centre for Advanced Scientific Research, Bangalore 560 064, India
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Ibrahim R, Matsubara D, Osman W, Morikawa T, Goto A, Morita S, Ishikawa S, Aburatani H, Takai D, Nakajima J, Fukayama M, Niki T, Murakami Y. Expression of PRMT5 in lung adenocarcinoma and its significance in epithelial-mesenchymal transition. Hum Pathol 2014; 45:1397-405. [PMID: 24775604 DOI: 10.1016/j.humpath.2014.02.013] [Citation(s) in RCA: 62] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/05/2013] [Revised: 01/16/2014] [Accepted: 02/12/2014] [Indexed: 10/25/2022]
Abstract
Although protein arginine methyltransferase 5 (PRMT5) has been implicated in various cancers, its expression pattern in lung adenocarcinoma cell lines and tissues has not been elucidated enough. In this study, microarray analysis of 40 non-small-cell lung carcinoma cell lines showed that PRMT5 was a candidate histone methyltransferase gene that correlated with epithelial-mesenchymal transition. Immunocytochemical analysis of these cell lines indicated that the expression of PRMT5 was localized to the cytoplasm of E-cadherin-low and vimentin-high cell lines, whereas it was predominant in the nucleus and faint in the cytoplasm of E-cadherin-high and vimentin-low cell lines. Immunohistochemical analysis of lung adenocarcinoma cases (n = 130) revealed that the expression of PRMT5 was high in the cytoplasm of 47 cases (36%) and the nuclei of 34 cases (26%). The marked cytoplasmic expression of PRMT5 was frequently observed in high-grade subtypes (1 of 17 low grade, 21 of 81 intermediate grade, and 25 of 32 high grade; P < .0001) such as solid adenocarcinoma with the low expression of thyroid transcription factor 1 (the master regulator of lung) and low expression of cytokeratin 7 and E-cadherin (2 markers for bronchial epithelial differentiation), whereas the high nuclear expression of PRMT5 was frequently noted in adenocarcinoma in situ, a low-grade subtype (6 of 17 low grade, 25 of 81 intermediate grade, and 3 of 32 high grade; P = .0444). The cytoplasmic expression of PRMT5 correlated with a poor prognosis (P = .0089). We herein highlighted the importance of PRMT5 expression, especially its cytoplasmic expression, in the process of epithelial-mesenchymal transition and loss of the bronchial epithelial phenotype of lung adenocarcinoma.
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Affiliation(s)
- Reem Ibrahim
- Molecular Pathology Laboratory, Institute of Medical Science, the University of Tokyo, Tokyo, Japan
| | - Daisuke Matsubara
- Molecular Pathology Laboratory, Institute of Medical Science, the University of Tokyo, Tokyo, Japan; Department of Integrative Pathology, Jichi Medical University, Tochigi, Japan.
| | - Wael Osman
- Molecular Pathology Laboratory, Institute of Medical Science, the University of Tokyo, Tokyo, Japan
| | - Teppei Morikawa
- Human Pathology Department, Graduate School of Medicine, the University of Tokyo, Tokyo, Japan
| | - Akiteru Goto
- Department of Cellular and Organ Pathology, Akita University Graduate School of Medicine, Akita, Japan
| | - Shigeki Morita
- Human Pathology Department, Graduate School of Medicine, the University of Tokyo, Tokyo, Japan
| | - Shumpei Ishikawa
- Human Pathology Department, Graduate School of Medicine, the University of Tokyo, Tokyo, Japan
| | - Hiroyuki Aburatani
- Division of Genome Science, Research Center for Advanced Science and Technology, the University of Tokyo, Tokyo, Japan
| | - Daiya Takai
- Department of Clinical Laboratory, the University of Tokyo, Tokyo, Japan
| | - Jun Nakajima
- Department of Thoracic Surgery, the University of Tokyo, Tokyo, Japan
| | - Masashi Fukayama
- Human Pathology Department, Graduate School of Medicine, the University of Tokyo, Tokyo, Japan
| | - Toshiro Niki
- Department of Integrative Pathology, Jichi Medical University, Tochigi, Japan
| | - Yoshinori Murakami
- Molecular Pathology Laboratory, Institute of Medical Science, the University of Tokyo, Tokyo, Japan
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Bao X, Zhao S, Liu T, Liu Y, Liu Y, Yang X. Overexpression of PRMT5 promotes tumor cell growth and is associated with poor disease prognosis in epithelial ovarian cancer. J Histochem Cytochem 2013; 61:206-17. [PMID: 23292799 DOI: 10.1369/0022155413475452] [Citation(s) in RCA: 103] [Impact Index Per Article: 8.6] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022] Open
Abstract
PRMT5 has been reported to be involved in the processes of tumor progression at various steps. The aim of this study was to examine the role of PRMT5 in epithelial ovarian cancer (EOC). In this study, PRMT5 and Ki-67 expression were examined by immunohistochemistry (IHC) in cohorts of normal, benign, and cancerous ovarian tissues. PRMT5 overexpression was observed in 83.1% (98/118) of EOCs, and it was significantly associated with serous type, poor differentiation, advanced tumor stage, lymph node invasion, presence of residual tumor, and high expression of Ki-67 (p<0.05, respectively). Moreover, overexpression of PRMT5 was an independent prognostic marker for decreased overall survival and progression-free survival in univariate survival analysis and multivariate Cox regression analysis. In ovarian cancer cell lines A2780 and SKOV3, PRMT5 knockdown by siRNA inhibited cell growth/proliferation and induced apoptosis via upregulation of E2F-1. These results suggest that overexpression of PRMT5 correlates with an aggressive malignant phenotype and may constitute a novel prognostic factor for EOC. Thus, PRMT5 may represent a clinically effective new target for therapy of ovarian cancer.
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Affiliation(s)
- Xiangxiang Bao
- Department of Gynecology, Qilu Hospital, Shandong University, Jinan, China
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29
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Abstract
There are nine protein arginine methyltransferases (PRMTs) encoded in mammalian genomes, the protein products of which catalyse three types of arginine methylation--monomethylation and two types of dimethylation. Protein arginine methylation is an abundant modification that has been implicated in signal transduction, gene transcription, DNA repair and mRNA splicing, among others. Studies have only recently linked this modification to carcinogenesis and metastasis. Sequencing studies have not generally found alterations to the PRMTs; however, overexpression of these enzymes is often associated with various cancers, which might make some of them viable targets for therapeutic strategies.
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Affiliation(s)
- Yanzhong Yang
- Department of Molecular Carcinogenesis, The University of Texas MD Anderson Cancer Center, 1808 Park Road 1C, P.O. BOX 389, Smithville, Texas 78957, USA
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30
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CARM1/PRMT4 is necessary for the glycogen gene expression programme in skeletal muscle cells. Biochem J 2012; 444:323-31. [PMID: 22428544 DOI: 10.1042/bj20112033] [Citation(s) in RCA: 39] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022]
Abstract
CARM1 (co-activator-associated arginine methyltransferase 1)/PRMT4 (protein arginine methyltransferase 4), functions as a co-activator for transcription factors that are regulators of muscle fibre type and oxidative metabolism, including PGC (peroxisome-proliferator-activated receptor γ co-activator)-1α and MEF2 (myocyte enhancer factor 2). We observed significantly higher Prmt4 mRNA expression in comparison with Prmt1-Prmt6 mRNA expression in mouse muscle (in vitro and in vivo). Transfection of Prmt4 siRNA (small interfering RNA) into mouse skeletal muscle C2C12 cells attenuated PRMT4 mRNA and protein expression. We subsequently performed additional qPCR (quantitative PCR) analysis (in the context of metabolism) to examine the effect of Prmt4 siRNA expression on >200 critical genes that control (and are involved in) lipid, glucose and energy homoeostasis, and circadian rhythm. This analysis revealed a strikingly specific metabolic expression footprint, and revealed that PRMT4 is necessary for the expression of genes involved in glycogen metabolism in skeletal muscle cells. Prmt4 siRNA expression selectively suppressed the mRNAs encoding Gys1 (glycogen synthase 1), Pgam2 (muscle phosphoglycerate mutase 2) and Pygm (muscle glycogen phosphorylase). Significantly, PGAM, PYGM and GYS1 deficiency in humans causes glycogen storage diseases type X, type V/McArdle's disease and type 0 respectively. Attenuation of PRMT4 was also associated with decreased expression of the mRNAs encoding AMPK (AMP-activated protein kinase) α2/γ3 (Prkaa2 and Prkag3) and p38 MAPK (mitogen-activated protein kinase), previously implicated in Wolff-Parkinson-White syndrome and Pompe Disease (glycogen storage disease type II). Furthermore, stable transfection of two PRMT4-site-specific (methyltransferase deficient) mutants (CARM1/PRMT4 VLD and CARM1E267Q) significantly repressed the expression of Gys1, Pgam2 and AMPKγ3. Finally, in concordance, we observed increased and decreased glycogen levels in PRMT4 (native)- and VLD (methylation deficient mutant)-transfected skeletal muscle cells respectively. This demonstrated that PRMT4 expression and the associated methyltransferase activity is necessary for the gene expression programme involved in glycogen metabolism and human glycogen storage diseases.
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LeBlanc SE, Konda S, Wu Q, Hu YJ, Oslowski CM, Sif S, Imbalzano AN. Protein arginine methyltransferase 5 (Prmt5) promotes gene expression of peroxisome proliferator-activated receptor γ2 (PPARγ2) and its target genes during adipogenesis. Mol Endocrinol 2012; 26:583-97. [PMID: 22361822 DOI: 10.1210/me.2011-1162] [Citation(s) in RCA: 52] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/19/2022] Open
Abstract
Regulation of adipose tissue formation by adipogenic-regulatory proteins has long been a topic of interest given the ever-increasing health concerns of obesity and type 2 diabetes in the general population. Differentiation of precursor cells into adipocytes involves a complex network of cofactors that facilitate the functions of transcriptional regulators from the CCATT/enhancer binding protein, and the peroxisome proliferator-activated receptor (PPAR) families. Many of these cofactors are enzymes that modulate the structure of chromatin by altering histone-DNA contacts in an ATP-dependent manner or by posttranslationally modifying the histone proteins. Here we report that inhibition of protein arginine methyltransferase 5 (Prmt5) expression in multiple cell culture models for adipogenesis prevented the activation of adipogenic genes. In contrast, overexpression of Prmt5 enhanced adipogenic gene expression and differentiation. Chromatin immunoprecipitation experiments indicated that Prmt5 binds to and dimethylates histones at adipogenic promoters. Furthermore, the presence of Prmt5 promoted the binding of ATP-dependent chromatin-remodeling enzymes and was required for the binding of PPARγ2 at PPARγ2-regulated promoters. The data indicate that Prmt5 acts as a coactivator for the activation of adipogenic gene expression and promotes adipogenic differentiation.
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Affiliation(s)
- Scott E LeBlanc
- Department of Cell Biology, University of Massachusetts Medical School, 55 Lake Avenue North, Worcester, Massachusetts 01655, USA
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Batut J, Duboé C, Vandel L. The methyltransferases PRMT4/CARM1 and PRMT5 control differentially myogenesis in zebrafish. PLoS One 2011; 6:e25427. [PMID: 22016767 PMCID: PMC3189919 DOI: 10.1371/journal.pone.0025427] [Citation(s) in RCA: 34] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2011] [Accepted: 09/05/2011] [Indexed: 12/31/2022] Open
Abstract
In vertebrates, skeletal myogenesis involves the sequential activation of myogenic factors to lead ultimately to the differentiation into slow and fast muscle fibers. How transcriptional co-regulators such as arginine methyltransferases PRMT4/CARM1 and PRMT5 control myogenesis in vivo remains poorly understood. Loss-of-function experiments using morpholinos against PRMT4/CARM1 and PRMT5 combined with in situ hybridization, quantitative polymerase chain reaction, as well as immunohistochemistry indicate a positive, but differential, role of these enzymes during myogenesis in vivo. While PRMT5 regulates myod, myf5 and myogenin expression and thereby slow and fast fiber formation, PRMT4/CARM1 regulates myogenin expression, fast fiber formation and does not affect slow fiber formation. However, our results show that PRMT4/CARM1 is required for proper slow myosin heavy chain localization. Altogether, our results reveal a combinatorial role of PRMT4/CARM1 and PRMT5 for proper myogenesis in zebrafish.
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Affiliation(s)
- Julie Batut
- Université de Toulouse-Paul Sabatier, Centre de Biologie du Développement, Toulouse, France
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Versatility of PRMT5-induced methylation in growth control and development. Trends Biochem Sci 2011; 36:633-41. [PMID: 21975038 DOI: 10.1016/j.tibs.2011.09.001] [Citation(s) in RCA: 218] [Impact Index Per Article: 15.6] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2011] [Revised: 09/06/2011] [Accepted: 09/07/2011] [Indexed: 01/03/2023]
Abstract
Arginine methylation governs important cellular processes that impact growth and proliferation, as well as differentiation and development. Through their ability to catalyze symmetric or asymmetric methylation of histone and non-histone proteins, members of the protein arginine methyltransferase (PRMT) family regulate chromatin structure and expression of a wide spectrum of target genes. Unlike other PRMTs, PRMT5 works in concert with a variety of cellular proteins including ATP-dependent chromatin remodelers and co-repressors to induce epigenetic silencing. Recent work also implicates PRMT5 in the control of growth-promoting and pro-survival pathways, which demonstrates its versatility as an enzyme involved in both epigenetic regulation of anti-cancer target genes and organelle biogenesis. These studies not only provide insight into the molecular mechanisms by which PRMT5 contributes to growth control, but also justify therapeutic targeting of PRMT5.
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Ljubicic V, Khogali S, Renaud JM, Jasmin BJ. Chronic AMPK stimulation attenuates adaptive signaling in dystrophic skeletal muscle. Am J Physiol Cell Physiol 2011; 302:C110-21. [PMID: 21940670 DOI: 10.1152/ajpcell.00183.2011] [Citation(s) in RCA: 41] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
In the present study, we evaluated how a pharmacologically induced phenotype shift in dystrophic skeletal muscle would affect subsequent intracellular signaling in response to a complementary, adaptive physiological stimulus. mdx mice were treated with the AMP-activated protein kinase (AMPK) activator 5-aminoimidazole-4-carboxamide-1-β-D-ribofuranoside (AICAR; 500 mg·kg(-1)·day(-1)) for 30 days, and then one-half of the animals were subjected to a bout of treadmill running to induce acute AMPK and p38 MAPK signaling. The mRNA levels of phenotypic modifiers, including peroxisome proliferator-activated receptor-δ (PPARδ), PPARγ coactivator-1α (PGC-1α), receptor interacting protein 140 (RIP 140), and silent information regulator two ortholog 1 (SIRT1) were assessed in skeletal muscle, as well as the expression of the protein arginine methyltransferase genes PRMT1 and CARM1. We found unique AMPK and p38 phosphorylation and expression signatures between dystrophic and healthy muscle. In dystrophic skeletal muscle, treadmill running induced PPARδ, PGC-1α, and SIRT1 mRNAs, three molecules that promote the slow, oxidative myogenic program. In the mdx animals that received the chronic AICAR treatment, running-elicited AMPK and p38 phosphorylation was attenuated compared with vehicle-treated mice. Similarly, acute stress-evoked expression of PPARδ, PGC-1α, and SIRT1 was also blunted by chronic pharmacological AMPK stimulation. Skeletal muscle PRMT1 and CARM1 protein contents were higher in mdx mice compared with wild-type littermates. The acute running-evoked induction of PRMT1 and CARM1 mRNAs was also attenuated by the AICAR treatment. Our data demonstrate that prior pharmacological conditioning is a salient determinant in how dystrophic muscle adapts to subsequent complementary, acute physiological stress stimuli. These results provide insight into possible therapeutic applications of synthetic agonists in neuromuscular diseases, such as during chronic administration to Duchenne muscular dystrophy patients.
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Affiliation(s)
- Vladimir Ljubicic
- Department of Cellular and Molecular Medicine, Faculty of Medicine, and Center for Neuromuscular Disease, University of Ottawa, Ottawa, Ontario, Canada.
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