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1
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Bonomi RE, Riordan W, Gelovani JG. The Structures, Functions, and Roles of Class III HDACs (Sirtuins) in Neuropsychiatric Diseases. Cells 2024; 13:1644. [PMID: 39404407 PMCID: PMC11476333 DOI: 10.3390/cells13191644] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2024] [Revised: 09/29/2024] [Accepted: 09/30/2024] [Indexed: 10/19/2024] Open
Abstract
Over the past two decades, epigenetic regulation has become a rapidly growing and influential field in biology and medicine. One key mechanism involves the acetylation and deacetylation of lysine residues on histone core proteins and other critical proteins that regulate gene expression and cellular signaling. Although histone deacetylases (HDACs) have received significant attention, the roles of individual HDAC isoforms in the pathogenesis of psychiatric diseases still require further research. This is particularly true with regard to the sirtuins, class III HDACs. Sirtuins have unique functional activity and significant roles in normal neurophysiology, as well as in the mechanisms of addiction, mood disorders, and other neuropsychiatric abnormalities. This review aims to elucidate the differences in catalytic structure and function of the seven sirtuins as they relate to psychiatry.
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Affiliation(s)
- Robin E. Bonomi
- Department of Psychiatry, Yale University, New Haven, CT 06511, USA;
| | - William Riordan
- Department of Psychiatry, Yale University, New Haven, CT 06511, USA;
| | - Juri G. Gelovani
- College of Medicine and Health Sciences, Office of the Provost, United Arab Emirates University, Al Ain P.O. Box 15551, United Arab Emirates;
- Department of Biomedical Engineering, College of Engineering and School of Medicine, Wayne State University, Detroit, MI 48201, USA
- Department of Radiology, Division of Nuclear Medicine, Siriraj Hospital, Mahidol University, Bangkok 10700, Thailand
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2
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Villar-Pazos S, Thomas L, Yang Y, Chen K, Lyles JB, Deitch BJ, Ochaba J, Ling K, Powers B, Gingras S, Kordasiewicz HB, Grubisha MJ, Huang YH, Thomas G. Neural deficits in a mouse model of PACS1 syndrome are corrected with PACS1- or HDAC6-targeting therapy. Nat Commun 2023; 14:6547. [PMID: 37848409 PMCID: PMC10582149 DOI: 10.1038/s41467-023-42176-8] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2023] [Accepted: 09/29/2023] [Indexed: 10/19/2023] Open
Abstract
PACS1 syndrome is a neurodevelopmental disorder (NDD) caused by a recurrent de novo missense mutation in PACS1 (p.Arg203Trp (PACS1R203W)). The mechanism by which PACS1R203W causes PACS1 syndrome is unknown, and no curative treatment is available. Here, we use patient cells and PACS1 syndrome mice to show that PACS1 (or PACS-1) is an HDAC6 effector and that the R203W substitution increases the PACS1/HDAC6 interaction, aberrantly potentiating deacetylase activity. Consequently, PACS1R203W reduces acetylation of α-tubulin and cortactin, causing the Golgi ribbon in hippocampal neurons and patient-derived neural progenitor cells (NPCs) to fragment and overpopulate dendrites, increasing their arborization. The dendrites, however, are beset with varicosities, diminished spine density, and fewer functional synapses, characteristic of NDDs. Treatment of PACS1 syndrome mice or patient NPCs with PACS1- or HDAC6-targeting antisense oligonucleotides, or HDAC6 inhibitors, restores neuronal structure and synaptic transmission in prefrontal cortex, suggesting that targeting PACS1R203W/HDAC6 may be an effective therapy for PACS1 syndrome.
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Affiliation(s)
- Sabrina Villar-Pazos
- Department of Microbiology and Molecular Genetics, University of Pittsburgh School of Medicine, Pittsburgh, PA, 15219, USA
- Institute of Molecular Biotechnology of the Austrian Academy of Sciences (IMBA), Vienna Biocenter Campus (VBC), Vienna, Austria
| | - Laurel Thomas
- Department of Microbiology and Molecular Genetics, University of Pittsburgh School of Medicine, Pittsburgh, PA, 15219, USA
| | - Yunhan Yang
- Department of Microbiology and Molecular Genetics, University of Pittsburgh School of Medicine, Pittsburgh, PA, 15219, USA
| | - Kun Chen
- Department of Microbiology and Molecular Genetics, University of Pittsburgh School of Medicine, Pittsburgh, PA, 15219, USA
- Department of Anesthesiology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Jenea B Lyles
- Department of Microbiology and Molecular Genetics, University of Pittsburgh School of Medicine, Pittsburgh, PA, 15219, USA
| | - Bradley J Deitch
- Department of Microbiology and Molecular Genetics, University of Pittsburgh School of Medicine, Pittsburgh, PA, 15219, USA
| | | | - Karen Ling
- Ionis Pharmaceuticals, Carlsbad, CA, USA
| | | | - Sebastien Gingras
- Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
| | | | - Melanie J Grubisha
- Department of Psychiatry, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
- Translational Neuroscience Program, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
| | - Yanhua H Huang
- Department of Psychiatry, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
- Translational Neuroscience Program, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
| | - Gary Thomas
- Department of Microbiology and Molecular Genetics, University of Pittsburgh School of Medicine, Pittsburgh, PA, 15219, USA.
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3
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Naren P, Samim KS, Tryphena KP, Vora LK, Srivastava S, Singh SB, Khatri DK. Microtubule acetylation dyshomeostasis in Parkinson's disease. Transl Neurodegener 2023; 12:20. [PMID: 37150812 PMCID: PMC10165769 DOI: 10.1186/s40035-023-00354-0] [Citation(s) in RCA: 20] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2022] [Accepted: 04/06/2023] [Indexed: 05/09/2023] Open
Abstract
The inter-neuronal communication occurring in extensively branched neuronal cells is achieved primarily through the microtubule (MT)-mediated axonal transport system. This mechanistically regulated system delivers cargos (proteins, mRNAs and organelles such as mitochondria) back and forth from the soma to the synapse. Motor proteins like kinesins and dynein mechanistically regulate polarized anterograde (from the soma to the synapse) and retrograde (from the synapse to the soma) commute of the cargos, respectively. Proficient axonal transport of such cargos is achieved by altering the microtubule stability via post-translational modifications (PTMs) of α- and β-tubulin heterodimers, core components constructing the MTs. Occurring within the lumen of MTs, K40 acetylation of α-tubulin via α-tubulin acetyl transferase and its subsequent deacetylation by HDAC6 and SIRT2 are widely scrutinized PTMs that make the MTs highly flexible, which in turn promotes their lifespan. The movement of various motor proteins, including kinesin-1 (responsible for axonal mitochondrial commute), is enhanced by this PTM, and dyshomeostasis of neuronal MT acetylation has been observed in a variety of neurodegenerative conditions, including Alzheimer's disease and Parkinson's disease (PD). PD is the second most common neurodegenerative condition and is closely associated with impaired MT dynamics and deregulated tubulin acetylation levels. Although the relationship between status of MT acetylation and progression of PD pathogenesis has become a chicken-and-egg question, our review aims to provide insights into the MT-mediated axonal commute of mitochondria and dyshomeostasis of MT acetylation in PD. The enzymatic regulators of MT acetylation along with their synthetic modulators have also been briefly explored. Moving towards a tubulin-based therapy that enhances MT acetylation could serve as a disease-modifying treatment in neurological conditions that lack it.
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Affiliation(s)
- Padmashri Naren
- Molecular and Cellular Neuroscience Lab, Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research (NIPER), Hyderabad, Telangana, 500037, India
| | - Khan Sabiya Samim
- Molecular and Cellular Neuroscience Lab, Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research (NIPER), Hyderabad, Telangana, 500037, India
| | - Kamatham Pushpa Tryphena
- Molecular and Cellular Neuroscience Lab, Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research (NIPER), Hyderabad, Telangana, 500037, India
| | - Lalitkumar K Vora
- School of Pharmacy, Queen's University Belfast, 97 Lisburn Road, Belfast, BT9 7BL, UK.
| | - Saurabh Srivastava
- Department of Pharmaceutics, National Institute of Pharmaceutical Education and Research (NIPER), Hyderabad, Telangana, 500037, India.
| | - Shashi Bala Singh
- Molecular and Cellular Neuroscience Lab, Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research (NIPER), Hyderabad, Telangana, 500037, India
| | - Dharmendra Kumar Khatri
- Molecular and Cellular Neuroscience Lab, Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research (NIPER), Hyderabad, Telangana, 500037, India.
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4
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Kabir F, Atkinson R, Cook AL, Phipps AJ, King AE. The role of altered protein acetylation in neurodegenerative disease. Front Aging Neurosci 2023; 14:1025473. [PMID: 36688174 PMCID: PMC9845957 DOI: 10.3389/fnagi.2022.1025473] [Citation(s) in RCA: 16] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2022] [Accepted: 11/03/2022] [Indexed: 01/06/2023] Open
Abstract
Acetylation is a key post-translational modification (PTM) involved in the regulation of both histone and non-histone proteins. It controls cellular processes such as DNA transcription, RNA modifications, proteostasis, aging, autophagy, regulation of cytoskeletal structures, and metabolism. Acetylation is essential to maintain neuronal plasticity and therefore essential for memory and learning. Homeostasis of acetylation is maintained through the activities of histone acetyltransferases (HAT) and histone deacetylase (HDAC) enzymes, with alterations to these tightly regulated processes reported in several neurodegenerative diseases including Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), and amyotrophic lateral sclerosis (ALS). Both hyperacetylation and hypoacetylation can impair neuronal physiological homeostasis and increase the accumulation of pathophysiological proteins such as tau, α-synuclein, and Huntingtin protein implicated in AD, PD, and HD, respectively. Additionally, dysregulation of acetylation is linked to impaired axonal transport, a key pathological mechanism in ALS. This review article will discuss the physiological roles of protein acetylation and examine the current literature that describes altered protein acetylation in neurodegenerative disorders.
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5
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Xue M, Feng T, Chen Z, Yan Y, Chen Z, Dai J. Protein Acetylation Going Viral: Implications in Antiviral Immunity and Viral Infection. Int J Mol Sci 2022; 23:11308. [PMID: 36232610 PMCID: PMC9570087 DOI: 10.3390/ijms231911308] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2022] [Revised: 09/10/2022] [Accepted: 09/21/2022] [Indexed: 11/16/2022] Open
Abstract
During viral infection, both host and viral proteins undergo post-translational modifications (PTMs), including phosphorylation, ubiquitination, methylation, and acetylation, which play critical roles in viral replication, pathogenesis, and host antiviral responses. Protein acetylation is one of the most important PTMs and is catalyzed by a series of acetyltransferases that divert acetyl groups from acetylated molecules to specific amino acid residues of substrates, affecting chromatin structure, transcription, and signal transduction, thereby participating in the cell cycle as well as in metabolic and other cellular processes. Acetylation of host and viral proteins has emerging roles in the processes of virus adsorption, invasion, synthesis, assembly, and release as well as in host antiviral responses. Methods to study protein acetylation have been gradually optimized in recent decades, providing new opportunities to investigate acetylation during viral infection. This review summarizes the classification of protein acetylation and the standard methods used to map this modification, with an emphasis on viral and host protein acetylation during viral infection.
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Affiliation(s)
- Minfei Xue
- Department of Respiratory Medicine, Children’s Hospital of Soochow University, Soochow University, Suzhou 215025, China
- Jiangsu Key Laboratory of Infection and Immunity, Institute of Biology and Medical Sciences, Soochow University, Suzhou 215123, China
| | - Tingting Feng
- Jiangsu Key Laboratory of Infection and Immunity, Institute of Biology and Medical Sciences, Soochow University, Suzhou 215123, China
| | - Zhiqiang Chen
- Jiangsu Key Laboratory of Infection and Immunity, Institute of Biology and Medical Sciences, Soochow University, Suzhou 215123, China
| | - Yongdong Yan
- Department of Respiratory Medicine, Children’s Hospital of Soochow University, Soochow University, Suzhou 215025, China
| | - Zhengrong Chen
- Department of Respiratory Medicine, Children’s Hospital of Soochow University, Soochow University, Suzhou 215025, China
| | - Jianfeng Dai
- Jiangsu Key Laboratory of Infection and Immunity, Institute of Biology and Medical Sciences, Soochow University, Suzhou 215123, China
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6
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Bonomi RE, Girgenti M, Krystal JH, Cosgrove KP. A Role for Histone Deacetylases in the Biology and Treatment of Post-Traumatic Stress Disorder: What Do We Know and Where Do We Go from Here? Complex Psychiatry 2022; 8:13-27. [PMID: 36545044 PMCID: PMC9669946 DOI: 10.1159/000524079] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2021] [Accepted: 03/04/2022] [Indexed: 12/24/2022] Open
Abstract
Post-traumatic stress disorder is a prevalent disorder within the USA and worldwide with a yearly diagnosis rate of 2-4% and affecting women more than men. One of the primary methods for study of this stress disorder relies on animal models as there are few noninvasive methods and few replicated peripheral biomarkers for use in humans. One area of active research in psychiatric neuroscience is the field of epigenetics - how the chemical modifications of the genetic code regulate behavior. The dynamic changes in histone acetylation and deacetylation in the brain are not fully reflected by the study of peripheral biomarker. In this review, we aim to examine the role of histone acetylation and deacetylation in memory formation and fear memory learning. The studies discussed here focus largely on the role of histone deacetylases (HDACs) in animal models of trauma and fear response. Many studies used HDAC inhibitors to elucidate the effects after inhibition of these enzymes after trauma or stress. These studies of memory processing and cued fear extinction in animal can often shed light on human disorders of cued fear responses and memory dysregulation after stress or trauma such as in PTSD. These results provide strong evidence for a role of these enzymes in PTSD in humans. The few clinical studies that exist with HDAC inhibitors also suggest a fundamental role of these enzymes in the neurobiology of the stress response. Further study of these enzymes in both clinical and pre-clinical settings may help elucidate the neurobiology of stress-related pathology like PTSD and provide a foundation for novel therapy to treat these disorders.
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Affiliation(s)
- Robin E. Bonomi
- Department of Psychiatry, Yale University, New Haven, Connecticut, USA
- *Robin E. Bonomi,
| | - Matthew Girgenti
- Department of Psychiatry, Yale University, New Haven, Connecticut, USA
- National Center for PTSD, US Department of Veterans Affairs, West Haven, Connecticut, USA
| | - John H. Krystal
- Department of Psychiatry, Yale University, New Haven, Connecticut, USA
- National Center for PTSD, US Department of Veterans Affairs, West Haven, Connecticut, USA
| | - Kelly P. Cosgrove
- Department of Psychiatry, Yale University, New Haven, Connecticut, USA
- **Kelly P. Cosgrove,
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Yan J, Zhang P, Tan J, Li M, Xu X, Shao X, Fang F, Zou Z, Zhou Y, Tian B. Cdk5 phosphorylation-induced SIRT2 nuclear translocation promotes the death of dopaminergic neurons in Parkinson's disease. NPJ Parkinsons Dis 2022; 8:46. [PMID: 35443760 PMCID: PMC9021196 DOI: 10.1038/s41531-022-00311-0] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2021] [Accepted: 03/28/2022] [Indexed: 12/17/2022] Open
Abstract
NAD-dependent protein deacetylase Sirtuin 2 (SIRT2), which regulates several cellular pathways by deacetylating multiple substrates, has been extensively studied in the context of Parkinson’s disease (PD). Although several studies based on the MPTP model of PD show that SIRT2 deletion can protect against dopaminergic neuron loss, the precise mechanisms of SIRT2-mediated neuronal death have largely remained unknown. Here, we show that SIRT2 knockout can effectively ameliorate anomalous behavioral phenotypes in transgenic mouse models of PD. Importantly, in both cellular and animal models of PD, it was observed that SIRT2 translocates from the cytoplasm to the nucleus. Further, the nuclear translocation of SIRT2 promotes neuronal death. Moreover, the cyclin-dependent kinase 5 (Cdk5)-mediated phosphorylation of SIRT2 at the Ser331 and Ser335 sites appears to be necessary for such nuclear translocation. Taken together, the results provide insights into the mechanisms involved in the regulation of neuronal death during PD progression via the Cdk5-dependent nuclear–cytoplasmic shuttling of SIRT2.
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Affiliation(s)
- Jianguo Yan
- Department of Physiology, Faculty of Basic Medical Science, Guilin Medical University, 1 Zhiyuan Road, Guilin, Guangxi Province, 541199, P. R. China.,Guangxi Key Laboratory of Brain and Cognitive Neuroscience, Guilin Medical University, 1 Zhiyuan Road, Guilin, Guangxi Province, 541199, P. R. China
| | - Pei Zhang
- Department of Neurobiology, Tongji Medical School, Huazhong University of Science and Technology, 13 Hangkong Road, Wuhan, Hubei Province, 430030, P. R. China
| | - Jie Tan
- Guangxi Key Laboratory of Brain and Cognitive Neuroscience, Guilin Medical University, 1 Zhiyuan Road, Guilin, Guangxi Province, 541199, P. R. China
| | - Mao Li
- Department of Physiology, Faculty of Basic Medical Science, Guilin Medical University, 1 Zhiyuan Road, Guilin, Guangxi Province, 541199, P. R. China.,Guangxi Key Laboratory of Brain and Cognitive Neuroscience, Guilin Medical University, 1 Zhiyuan Road, Guilin, Guangxi Province, 541199, P. R. China
| | - Xingfeng Xu
- Department of Physiology, Faculty of Basic Medical Science, Guilin Medical University, 1 Zhiyuan Road, Guilin, Guangxi Province, 541199, P. R. China.,Guangxi Key Laboratory of Brain and Cognitive Neuroscience, Guilin Medical University, 1 Zhiyuan Road, Guilin, Guangxi Province, 541199, P. R. China
| | - Xiaoyun Shao
- Guangxi Key Laboratory of Brain and Cognitive Neuroscience, Guilin Medical University, 1 Zhiyuan Road, Guilin, Guangxi Province, 541199, P. R. China
| | - Fang Fang
- Guangxi Key Laboratory of Brain and Cognitive Neuroscience, Guilin Medical University, 1 Zhiyuan Road, Guilin, Guangxi Province, 541199, P. R. China
| | - Zhenyou Zou
- Guangxi Key Laboratory of Brain and Cognitive Neuroscience, Guilin Medical University, 1 Zhiyuan Road, Guilin, Guangxi Province, 541199, P. R. China
| | - Yali Zhou
- Guangxi Key Laboratory of Brain and Cognitive Neuroscience, Guilin Medical University, 1 Zhiyuan Road, Guilin, Guangxi Province, 541199, P. R. China. .,Department of Microbiology, Faculty of Basic Medical Science, Guilin Medical University, 1 Zhiyuan Road, Guilin, Guangxi Province, 541199, P. R. China.
| | - Bo Tian
- Department of Neurobiology, Tongji Medical School, Huazhong University of Science and Technology, 13 Hangkong Road, Wuhan, Hubei Province, 430030, P. R. China.
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Barone S, Cassese E, Alfano AI, Brindisi M, Summa V. Chasing a Breath of Fresh Air in Cystic Fibrosis (CF): Therapeutic Potential of Selective HDAC6 Inhibitors to Tackle Multiple Pathways in CF Pathophysiology. J Med Chem 2022; 65:3080-3097. [PMID: 35148101 PMCID: PMC8883472 DOI: 10.1021/acs.jmedchem.1c02067] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/22/2023]
Abstract
![]()
Compelling new support
has been provided for histone deacetylase
isoform 6 (HDAC6) as a common thread in the generation of the dysregulated
proinflammatory and fibrotic phenotype in cystic fibrosis (CF). HDAC6
also plays a crucial role in bacterial clearance or killing as a direct
consequence of its effects on CF immune responses. Inhibiting HDAC6
functions thus eventually represents an innovative and effective strategy
to tackle multiple aspects of CF-associated lung disease. In this
Perspective, we not only showcase the latest evidence linking HDAC(6)
activity and expression with CF phenotype but also track the new dawn
of HDAC(6) modulators in CF and explore potentialities and future
perspectives in the field.
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Affiliation(s)
- Simona Barone
- Department of Pharmacy, Department of Excellence 2018-2022, School of Medicine and Surgery, University of Naples "Federico II", Via D. Montesano 49, I-80131 Naples, Italy
| | - Emilia Cassese
- Department of Pharmacy, Department of Excellence 2018-2022, School of Medicine and Surgery, University of Naples "Federico II", Via D. Montesano 49, I-80131 Naples, Italy
| | - Antonella Ilenia Alfano
- Department of Pharmacy, Department of Excellence 2018-2022, School of Medicine and Surgery, University of Naples "Federico II", Via D. Montesano 49, I-80131 Naples, Italy
| | - Margherita Brindisi
- Department of Pharmacy, Department of Excellence 2018-2022, School of Medicine and Surgery, University of Naples "Federico II", Via D. Montesano 49, I-80131 Naples, Italy
| | - Vincenzo Summa
- Department of Pharmacy, Department of Excellence 2018-2022, School of Medicine and Surgery, University of Naples "Federico II", Via D. Montesano 49, I-80131 Naples, Italy
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Ghazy E, Abdelsalam M, Robaa D, Pierce RJ, Sippl W. Histone Deacetylase (HDAC) Inhibitors for the Treatment of Schistosomiasis. Pharmaceuticals (Basel) 2022; 15:ph15010080. [PMID: 35056137 PMCID: PMC8779837 DOI: 10.3390/ph15010080] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2021] [Revised: 01/06/2022] [Accepted: 01/08/2022] [Indexed: 12/18/2022] Open
Abstract
Schistosomiasis is a major neglected parasitic disease that affects more than 240 million people worldwide and for which the control strategy consists of mass treatment with the only available drug, praziquantel. Schistosomes display morphologically distinct stages during their life cycle and the transformations between stages are controlled by epigenetic mechanisms. The targeting of epigenetic actors might therefore represent the parasites’ Achilles’ heel. Specifically, histone deacetylases have been recently characterized as drug targets for the treatment of schistosomiasis. This review focuses on the recent development of inhibitors for schistosome histone deacetylases. In particular, advances in the development of inhibitors of Schistosoma mansoni histone deacetylase 8 have indicated that targeting this enzyme is a promising approach for the treatment of this infection.
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Affiliation(s)
- Ehab Ghazy
- Department of Medicinal Chemistry, Institute of Pharmacy, Martin-Luther-University of Halle-Wittenberg, 06120 Halle (Saale), Germany; (E.G.); (M.A.); (D.R.)
- Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Alexandria University, Alexandria 21521, Egypt
| | - Mohamed Abdelsalam
- Department of Medicinal Chemistry, Institute of Pharmacy, Martin-Luther-University of Halle-Wittenberg, 06120 Halle (Saale), Germany; (E.G.); (M.A.); (D.R.)
- Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Alexandria University, Alexandria 21521, Egypt
| | - Dina Robaa
- Department of Medicinal Chemistry, Institute of Pharmacy, Martin-Luther-University of Halle-Wittenberg, 06120 Halle (Saale), Germany; (E.G.); (M.A.); (D.R.)
| | - Raymond J. Pierce
- Centre d’Infection et d’Immunité de Lille, U1019—UMR9017—CIIL, Institute Pasteur de Lille, CNRS, Inserm, CHU Lille, Univ. Lille, F-59000 Lille, France;
| | - Wolfgang Sippl
- Department of Medicinal Chemistry, Institute of Pharmacy, Martin-Luther-University of Halle-Wittenberg, 06120 Halle (Saale), Germany; (E.G.); (M.A.); (D.R.)
- Correspondence:
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10
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Jiang LP, Yu XH, Chen JZ, Hu M, Zhang YK, Lin HL, Tang WY, He PP, Ouyang XP. Histone Deacetylase 3: A Potential Therapeutic Target for Atherosclerosis. Aging Dis 2022; 13:773-786. [PMID: 35656103 PMCID: PMC9116907 DOI: 10.14336/ad.2021.1116] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2021] [Accepted: 11/16/2021] [Indexed: 11/17/2022] Open
Abstract
Atherosclerosis, the pathological basis of most cardiovascular disease, is characterized by plaque formation in the intima. Secondary lesions include intraplaque hemorrhage, plaque rupture, and local thrombosis. Vascular endothelial function impairment and smooth muscle cell migration lead to vascular dysfunction, which is conducive to the formation of macrophage-derived foam cells and aggravates inflammatory response and lipid accumulation that cause atherosclerosis. Histone deacetylase (HDAC) is an epigenetic modifying enzyme closely related to chromatin structure and gene transcriptional regulation. Emerging studies have demonstrated that the Class I member HDAC3 of the HDAC super family has cell-specific functions in atherosclerosis, including 1) maintenance of endothelial integrity and functions, 2) regulation of vascular smooth muscle cell proliferation and migration, 3) modulation of macrophage phenotype, and 4) influence on foam cell formation. Although several studies have shown that HDAC3 may be a promising therapeutic target, only a few HDAC3-selective inhibitors have been thoroughly researched and reported. Here, we specifically summarize the impact of HDAC3 and its inhibitors on vascular function, inflammation, lipid accumulation, and plaque stability in the development of atherosclerosis with the hopes of opening up new opportunities for the treatment of cardiovascular diseases.
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Affiliation(s)
- Li-Ping Jiang
- Department of Physiology, Institute of Neuroscience Research, Hengyang Key Laboratory of Neurodegeneration and Cognitive Impairment, Hunan Province Cooperative Innovation Center for Molecular Target New Drug Study, Hengyang Medical School, University of South China, Hunan, China.
| | - Xiao-Hua Yu
- Institute of Clinical Medicine, the Second Affiliated Hospital of Hainan Medical University, Haikou, China.
| | - Jin-Zhi Chen
- Department of Physiology, Institute of Neuroscience Research, Hengyang Key Laboratory of Neurodegeneration and Cognitive Impairment, Hunan Province Cooperative Innovation Center for Molecular Target New Drug Study, Hengyang Medical School, University of South China, Hunan, China.
| | - Mi Hu
- Department of Physiology, Institute of Neuroscience Research, Hengyang Key Laboratory of Neurodegeneration and Cognitive Impairment, Hunan Province Cooperative Innovation Center for Molecular Target New Drug Study, Hengyang Medical School, University of South China, Hunan, China.
| | - Yang-Kai Zhang
- Department of Physiology, Institute of Neuroscience Research, Hengyang Key Laboratory of Neurodegeneration and Cognitive Impairment, Hunan Province Cooperative Innovation Center for Molecular Target New Drug Study, Hengyang Medical School, University of South China, Hunan, China.
| | - Hui-Ling Lin
- Department of Physiology, Institute of Neuroscience Research, Hengyang Key Laboratory of Neurodegeneration and Cognitive Impairment, Hunan Province Cooperative Innovation Center for Molecular Target New Drug Study, Hengyang Medical School, University of South China, Hunan, China.
| | - Wan-Ying Tang
- Department of Physiology, Institute of Neuroscience Research, Hengyang Key Laboratory of Neurodegeneration and Cognitive Impairment, Hunan Province Cooperative Innovation Center for Molecular Target New Drug Study, Hengyang Medical School, University of South China, Hunan, China.
| | - Ping-Ping He
- School of Nursing, University of South China, Hunan, China
- Correspondence should be addressed to: Dr. Ping-Ping He, School of Nursing, University of South China, Hunan, China. and Dr. Xin-Ping Ouyang, Department of Physiology, University of South China, Hunan, China. .
| | - Xin-Ping Ouyang
- Department of Physiology, Institute of Neuroscience Research, Hengyang Key Laboratory of Neurodegeneration and Cognitive Impairment, Hunan Province Cooperative Innovation Center for Molecular Target New Drug Study, Hengyang Medical School, University of South China, Hunan, China.
- Correspondence should be addressed to: Dr. Ping-Ping He, School of Nursing, University of South China, Hunan, China. and Dr. Xin-Ping Ouyang, Department of Physiology, University of South China, Hunan, China. .
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11
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Ojiro R, Watanabe Y, Okano H, Takahashi Y, Takashima K, Tang Q, Ozawa S, Saito F, Akahori Y, Jin M, Yoshida T, Shibutani M. Gene expression profiles of multiple brain regions in rats differ between developmental and postpubertal exposure to valproic acid. J Appl Toxicol 2021; 42:864-882. [PMID: 34779009 DOI: 10.1002/jat.4263] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2021] [Revised: 10/06/2021] [Accepted: 10/19/2021] [Indexed: 11/05/2022]
Abstract
We have previously reported that the valproic acid (VPA)-induced disruption pattern of hippocampal adult neurogenesis differs between developmental and 28-day postpubertal exposure. In the present study, we performed brain region-specific global gene expression profiling to compare the profiles of VPA-induced neurotoxicity between developmental and postpubertal exposure. Offspring exposed to VPA at 0, 667, and 2000 parts per million (ppm) via maternal drinking water from gestational day 6 until weaning (postnatal day 21) were examined, along with male rats orally administered VPA at 0, 200, and 900 mg/kg body weight for 28 days starting at 5 weeks old. Four brain regions-the hippocampal dentate gyrus, corpus callosum, cerebral cortex, and cerebellar vermis-were subjected to expression microarray analysis. Profiled data suggested a region-specific pattern of effects after developmental VPA exposure, and a common pattern of effects among brain regions after postpubertal VPA exposure. Developmental VPA exposure typically led to the altered expression of genes related to nervous system development (Msx1, Xcl1, Foxj1, Prdm16, C3, and Kif11) in the hippocampus, and those related to nervous system development (Neurod1) and gliogenesis (Notch1 and Sox9) in the corpus callosum. Postpubertal VPA exposure led to the altered expression of genes related to neuronal differentiation and projection (Cd47, Cyr61, Dbi, Adamts1, and Btg2) in multiple brain regions. These findings suggested that neurotoxic patterns of VPA might be different between developmental and postpubertal exposure, which was consistent with our previous study. Of note, the hippocampal dentate gyrus might be a sensitive target of developmental neurotoxicants after puberty.
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Affiliation(s)
- Ryota Ojiro
- Laboratory of Veterinary Pathology, Division of Animal Life Science, Institute of Agriculture, Tokyo University of Agriculture and Technology, Fuchu-shi, Tokyo, Japan.,Cooperative Division of Veterinary Sciences, Graduate School of Agriculture, Tokyo University of Agriculture and Technology, Fuchu-shi, Tokyo, Japan
| | - Yousuke Watanabe
- Laboratory of Veterinary Pathology, Division of Animal Life Science, Institute of Agriculture, Tokyo University of Agriculture and Technology, Fuchu-shi, Tokyo, Japan
| | - Hiromu Okano
- Laboratory of Veterinary Pathology, Division of Animal Life Science, Institute of Agriculture, Tokyo University of Agriculture and Technology, Fuchu-shi, Tokyo, Japan.,Cooperative Division of Veterinary Sciences, Graduate School of Agriculture, Tokyo University of Agriculture and Technology, Fuchu-shi, Tokyo, Japan
| | - Yasunori Takahashi
- Laboratory of Veterinary Pathology, Division of Animal Life Science, Institute of Agriculture, Tokyo University of Agriculture and Technology, Fuchu-shi, Tokyo, Japan.,Cooperative Division of Veterinary Sciences, Graduate School of Agriculture, Tokyo University of Agriculture and Technology, Fuchu-shi, Tokyo, Japan
| | - Kazumi Takashima
- Laboratory of Veterinary Pathology, Division of Animal Life Science, Institute of Agriculture, Tokyo University of Agriculture and Technology, Fuchu-shi, Tokyo, Japan.,Cooperative Division of Veterinary Sciences, Graduate School of Agriculture, Tokyo University of Agriculture and Technology, Fuchu-shi, Tokyo, Japan
| | - Qian Tang
- Laboratory of Veterinary Pathology, Division of Animal Life Science, Institute of Agriculture, Tokyo University of Agriculture and Technology, Fuchu-shi, Tokyo, Japan.,Cooperative Division of Veterinary Sciences, Graduate School of Agriculture, Tokyo University of Agriculture and Technology, Fuchu-shi, Tokyo, Japan
| | - Shunsuke Ozawa
- Laboratory of Veterinary Pathology, Division of Animal Life Science, Institute of Agriculture, Tokyo University of Agriculture and Technology, Fuchu-shi, Tokyo, Japan.,Cooperative Division of Veterinary Sciences, Graduate School of Agriculture, Tokyo University of Agriculture and Technology, Fuchu-shi, Tokyo, Japan
| | - Fumiyo Saito
- Chemicals Assessment and Research Center, Chemicals Evaluation and Research Institute, Japan, Bunkyo-ku, Tokyo, Japan.,Department of Toxicology, Faculty of Veterinary Medicine, Okayama University of Science, Imabari-shi, Ehime, Japan
| | - Yumi Akahori
- Chemicals Assessment and Research Center, Chemicals Evaluation and Research Institute, Japan, Bunkyo-ku, Tokyo, Japan
| | - Meilan Jin
- Laboratory of Veterinary Pathology, College of Veterinary Medicine, Southwest University, Chongqing, China
| | - Toshinori Yoshida
- Laboratory of Veterinary Pathology, Division of Animal Life Science, Institute of Agriculture, Tokyo University of Agriculture and Technology, Fuchu-shi, Tokyo, Japan.,Cooperative Division of Veterinary Sciences, Graduate School of Agriculture, Tokyo University of Agriculture and Technology, Fuchu-shi, Tokyo, Japan
| | - Makoto Shibutani
- Laboratory of Veterinary Pathology, Division of Animal Life Science, Institute of Agriculture, Tokyo University of Agriculture and Technology, Fuchu-shi, Tokyo, Japan.,Cooperative Division of Veterinary Sciences, Graduate School of Agriculture, Tokyo University of Agriculture and Technology, Fuchu-shi, Tokyo, Japan.,Institute of Global Innovation Research, Tokyo University of Agriculture and Technology, Fuchu-shi, Tokyo, Japan
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12
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Yadav A, Huang TC, Chen SH, Ramasamy TS, Hsueh YY, Lin SP, Lu FI, Liu YH, Wu CC. Sodium phenylbutyrate inhibits Schwann cell inflammation via HDAC and NFκB to promote axonal regeneration and remyelination. J Neuroinflammation 2021; 18:238. [PMID: 34656124 PMCID: PMC8520633 DOI: 10.1186/s12974-021-02273-1] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2021] [Accepted: 09/08/2021] [Indexed: 11/24/2022] Open
Abstract
Background Epigenetic regulation by histone deacetylases (HDACs) in Schwann cells (SCs) after injury facilitates them to undergo de- and redifferentiation processes necessary to support various stages of nerve repair. Although de-differentiation activates the synthesis and secretion of inflammatory cytokines by SCs to initiate an immune response during nerve repair, changes in either the timing or duration of prolonged inflammation mediated by SCs can affect later processes associated with repair and regeneration. Limited studies have investigated the regulatory processes through which HDACs in SCs control inflammatory cytokines to provide a favorable environment for peripheral nerve regeneration. Methods We employed the HDAC inhibitor (HDACi) sodium phenylbutyrate (PBA) to address this question in an in vitro RT4 SC inflammation model and an in vivo sciatic nerve transection injury model to examine the effects of HDAC inhibition on the expression of pro-inflammatory cytokines. Furthermore, we assessed the outcomes of suppression of extended inflammation on the regenerative potential of nerves by assessing axonal regeneration, remyelination, and reinnervation. Results Significant reductions in lipopolysaccharide (LPS)-induced pro-inflammatory cytokine (tumor necrosis factor-α [TNFα]) expression and secretion were observed in vitro following PBA treatment. PBA treatment also affected the transient changes in nuclear factor κB (NFκB)-p65 phosphorylation and translocation in response to LPS induction in RT4 SCs. Similarly, PBA mediated long-term suppressive effects on HDAC3 expression and activity. PBA administration resulted in marked inhibition of pro-inflammatory cytokine secretion at the site of transection injury when compared with that in the hydrogel control group at 6-week post-injury. A conducive microenvironment for axonal regrowth and remyelination was generated by increasing expression levels of protein gene product 9.5 (PGP9.5) and myelin basic protein (MBP) in regenerating nerve tissues. PBA administration increased the relative gastrocnemius muscle weight percentage and maintained the intactness of muscle bundles when compared with those in the hydrogel control group. Conclusions Suppressing the lengthened state of inflammation using PBA treatment favors axonal regrowth and remyelination following nerve transection injury. PBA treatment also regulates pro-inflammatory cytokine expression by inhibiting the transcriptional activation of NFκB-p65 and HDAC3 in SCs in vitro. Supplementary Information The online version contains supplementary material available at 10.1186/s12974-021-02273-1.
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Affiliation(s)
- Anjali Yadav
- Taiwan International Graduate Program in Interdisciplinary Neuroscience, Academia Sinica, Taipei, Taiwan.,Institute of Clinical Medicine, College of Medicine, National Cheng Kung University, Tainan, Taiwan.,Department of Cell Biology and Anatomy, College of Medicine, National Cheng Kung University, Tainan, Taiwan
| | - Tzu-Chieh Huang
- Department of Cell Biology and Anatomy, College of Medicine, National Cheng Kung University, Tainan, Taiwan.,Institute of Basic Medical Sciences, College of Medicine, National Cheng Kung University, Tainan, Taiwan.,International Center for Wound Repair and Regeneration, National Cheng Kung University, Tainan, Taiwan
| | - Szu-Han Chen
- Institute of Clinical Medicine, College of Medicine, National Cheng Kung University, Tainan, Taiwan.,International Center for Wound Repair and Regeneration, National Cheng Kung University, Tainan, Taiwan.,Division of Plastic and Reconstructive Surgery, Department of Surgery, College of Medicine, National Cheng Kung University Hospital, National Cheng Kung University, Tainan, Taiwan
| | - Thamil Selvee Ramasamy
- Stem Cell Biology Laboratory, Department of Molecular Medicine, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia
| | - Yuan-Yu Hsueh
- Institute of Clinical Medicine, College of Medicine, National Cheng Kung University, Tainan, Taiwan.,International Center for Wound Repair and Regeneration, National Cheng Kung University, Tainan, Taiwan.,Division of Plastic and Reconstructive Surgery, Department of Surgery, College of Medicine, National Cheng Kung University Hospital, National Cheng Kung University, Tainan, Taiwan
| | - Shau-Ping Lin
- Institute of Biotechnology, College of Bio-Resources and Agriculture, National Taiwan University, Taipei, Taiwan
| | - Fu-I Lu
- Department of Biotechnology and Bioindustry Sciences, College of Bioscience and Biotechnology, National Cheng Kung University, Tainan, Taiwan
| | - Ya-Hsin Liu
- Department of Life Sciences, College of Bioscience and Biotechnology, National Cheng Kung University, Tainan, Taiwan
| | - Chia-Ching Wu
- Department of Cell Biology and Anatomy, College of Medicine, National Cheng Kung University, Tainan, Taiwan. .,Institute of Basic Medical Sciences, College of Medicine, National Cheng Kung University, Tainan, Taiwan. .,International Center for Wound Repair and Regeneration, National Cheng Kung University, Tainan, Taiwan. .,Department of Biomedical Engineering, National Cheng Kung University, Tainan, Taiwan.
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13
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Linciano P, Pinzi L, Belluti S, Chianese U, Benedetti R, Moi D, Altucci L, Franchini S, Imbriano C, Sorbi C, Rastelli G. Inhibitors of histone deacetylase 6 based on a novel 3-hydroxy-isoxazole zinc binding group. J Enzyme Inhib Med Chem 2021; 36:2080-2086. [PMID: 34583596 PMCID: PMC8480759 DOI: 10.1080/14756366.2021.1981306] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/23/2022] Open
Abstract
Histone deacetylase 6 (HDAC6) is an established drug target for cancer treatment. Inhibitors of HDAC6 based on a hydroxamic acid zinc binding group (ZBG) are often associated with undesirable side effects. Herein, we describe the identification of HDAC6 inhibitors based on a completely new 3-hydroxy-isoxazole ZBG. A series of derivatives decorated with different aromatic or heteroaromatic linkers, and various cap groups were synthesised and biologically tested. In vitro tests demonstrated that some compounds are able to inhibit HDAC6 with good potency, the best candidate reaching an IC50 of 700 nM. Such good potency obtained with a completely new ZBG make these compounds particularly attractive. The effect of the most active inhibitors on the acetylation levels of histone H3 and α- tubulin and their anti-proliferative activity of DU145 cells were also investigated. Docking studies were performed to evaluate the binding mode of these new derivatives and discuss structure-activity relationships.
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Affiliation(s)
- Pasquale Linciano
- Department of Life Sciences, University of Modena and Reggio Emilia, Modena, Italy
| | - Luca Pinzi
- Department of Life Sciences, University of Modena and Reggio Emilia, Modena, Italy
| | - Silvia Belluti
- Department of Life Sciences, University of Modena and Reggio Emilia, Modena, Italy
| | - Ugo Chianese
- Department of Precision Medicine, University of Campania "Luigi Vanvitelli", Naples, Italy
| | - Rosaria Benedetti
- Department of Precision Medicine, University of Campania "Luigi Vanvitelli", Naples, Italy
| | - Davide Moi
- Department of Life Sciences, University of Modena and Reggio Emilia, Modena, Italy
| | - Lucia Altucci
- Department of Precision Medicine, University of Campania "Luigi Vanvitelli", Naples, Italy.,Biogem Institute of Molecular and Genetic Biology, Ariano Irpino, Italy
| | - Silvia Franchini
- Department of Life Sciences, University of Modena and Reggio Emilia, Modena, Italy
| | - Carol Imbriano
- Department of Life Sciences, University of Modena and Reggio Emilia, Modena, Italy
| | - Claudia Sorbi
- Department of Life Sciences, University of Modena and Reggio Emilia, Modena, Italy
| | - Giulio Rastelli
- Department of Life Sciences, University of Modena and Reggio Emilia, Modena, Italy
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14
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Gu LF, Chen JQ, Lin QY, Yang YZ. Roles of mitochondrial unfolded protein response in mammalian stem cells. World J Stem Cells 2021; 13:737-752. [PMID: 34367475 PMCID: PMC8316864 DOI: 10.4252/wjsc.v13.i7.737] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/07/2021] [Revised: 05/13/2021] [Accepted: 06/15/2021] [Indexed: 02/06/2023] Open
Abstract
The mitochondrial unfolded protein response (UPRmt) is an evolutionarily conserved adaptive mechanism for improving cell survival under mitochondrial stress. Under physiological and pathological conditions, the UPRmt is the key to maintaining intracellular homeostasis and proteostasis. Important roles of the UPRmt have been demonstrated in a variety of cell types and in cell development, metabolism, and immune processes. UPRmt dysfunction leads to a variety of pathologies, including cancer, inflammation, neurodegenerative disease, metabolic disease, and immune disease. Stem cells have a special ability to self-renew and differentiate into a variety of somatic cells and have been shown to exist in a variety of tissues. These cells are involved in development, tissue renewal, and some disease processes. Although the roles and regulatory mechanisms of the UPRmt in somatic cells have been widely reported, the roles of the UPRmt in stem cells are not fully understood. The roles and functions of the UPRmt depend on stem cell type. Therefore, this paper summarizes the potential significance of the UPRmt in embryonic stem cells, tissue stem cells, tumor stem cells, and induced pluripotent stem cells. The purpose of this review is to provide new insights into stem cell differentiation and tumor pathogenesis.
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Affiliation(s)
- Li-Fang Gu
- Key Laboratory of Fertility Preservation and Maintenance, Ministry of Education, Key Laboratory of Reproduction and Genetics in Ningxia, Department of Histology and Embryology, School of Basic Medicine, Ningxia Medical University, Yinchuan 750004, Ningxia Hui Autonomous Region, China
| | - Jia-Qi Chen
- Key Laboratory of Fertility Preservation and Maintenance, Ministry of Education, Key Laboratory of Reproduction and Genetics in Ningxia, Department of Histology and Embryology, School of Basic Medicine, Ningxia Medical University, Yinchuan 750004, Ningxia Hui Autonomous Region, China
| | - Qing-Yin Lin
- Key Laboratory of Fertility Preservation and Maintenance, Ministry of Education, Key Laboratory of Reproduction and Genetics in Ningxia, Department of Histology and Embryology, School of Basic Medicine, Ningxia Medical University, Yinchuan 750004, Ningxia Hui Autonomous Region, China
| | - Yan-Zhou Yang
- Key Laboratory of Fertility Preservation and Maintenance, Ministry of Education, Key Laboratory of Reproduction and Genetics in Ningxia, Department of Histology and Embryology, School of Basic Medicine, Ningxia Medical University, Yinchuan 750001, Ningxia Hui Autonomous Region, China.
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15
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Balmik AA, Sonawane SK, Chinnathambi S. The extracellular HDAC6 ZnF UBP domain modulates the actin network and post-translational modifications of Tau. Cell Commun Signal 2021; 19:49. [PMID: 33933071 PMCID: PMC8088071 DOI: 10.1186/s12964-021-00736-9] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2020] [Accepted: 03/29/2021] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND Microtubule-associated protein Tau undergoes aggregation in Alzheimer`s disease (AD) and a group of other related diseases collectively known as Tauopathies. In AD, Tau forms aggregates, which are deposited intracellularly as neurofibrillary tangles. Histone deacetylase-6 (HDAC6) plays an important role in aggresome formation, where it recruits polyubiquitinated aggregates to the motor protein dynein. METHODS Here, we have studied the effects of HDAC6 ZnF UBP on Tau phosphorylation, ApoE localization, GSK-3β regulation and cytoskeletal organization in neuronal cells by immunocytochemical analysis. This analysis reveals that the cell exposure to the UBP-type zinc finger domain of HDAC6 (HDAC6 ZnF UBP) can modulate Tau phosphorylation and actin cytoskeleton organization. RESULTS HDAC6 ZnF UBP treatment to cells did not affect their viability and resulted in enhanced neurite extension and formation of structures similar to podosomes, lamellipodia and podonuts suggesting the role of this domain in actin re-organization. Also, HDAC6 ZnF UBP treatment caused increase in nuclear localization of ApoE and tubulin localization in microtubule organizing centre (MTOC). Therefore, our studies suggest the regulatory role of this domain in different aspects of neurodegenerative diseases. Upon HDAC6 ZnF UBP treatment, inactive phosphorylated form of GSK-3β increases without any change in total GSK-3β level. CONCLUSIONS HDAC6 ZnF UBP was found to be involved in cytoskeletal re-organization by modulating actin dynamics and tubulin localization. Overall, our study suggests that ZnF domain of HDAC6 performs various regulatory functions apart from its classical function in aggresome formation in protein misfolding diseases. Video abstract.
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Affiliation(s)
- Abhishek Ankur Balmik
- Neurobiology Group, Division of Biochemical Sciences, CSIR-National Chemical Laboratory (CSIR-NCL), Dr. Homi Bhabha Road, Pune, 411008, India.,Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, 201002, India
| | - Shweta Kishor Sonawane
- Neurobiology Group, Division of Biochemical Sciences, CSIR-National Chemical Laboratory (CSIR-NCL), Dr. Homi Bhabha Road, Pune, 411008, India.,Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, 201002, India
| | - Subashchandrabose Chinnathambi
- Neurobiology Group, Division of Biochemical Sciences, CSIR-National Chemical Laboratory (CSIR-NCL), Dr. Homi Bhabha Road, Pune, 411008, India. .,Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, 201002, India.
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16
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Song Y, Park SY, Wu Z, Liu KH, Seo YH. Hybrid inhibitors of DNA and HDACs remarkably enhance cytotoxicity in leukaemia cells. J Enzyme Inhib Med Chem 2021; 35:1069-1079. [PMID: 32314611 PMCID: PMC7191901 DOI: 10.1080/14756366.2020.1754812] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022] Open
Abstract
Chlorambucil is a nitrogen mustard-based DNA alkylating drug, which is widely used as a front-line treatment of chronic lymphocytic leukaemia (CLL). Despite its widespread application and success for the initial treatment of leukaemia, a majority of patients eventually develop acquired resistance to chlorambucil. In this regard, we have designed and synthesised a novel hybrid molecule, chloram-HDi that simultaneously impairs DNA and HDAC enzymes. Chloram-HDi efficiently inhibits the proliferation of HL-60 and U937 leukaemia cells with GI50 values of 1.24 µM and 1.75 µM, whereas chlorambucil exhibits GI50 values of 21.1 µM and 37.7 µM against HL-60 and U937 leukaemia cells, respectively. The mechanism behind its remarkably enhanced cytotoxicity is that chloram-HDi not only causes a significant DNA damage of leukaemia cells but also downregulates DNA repair protein, Rad52, resulting in the escalation of its DNA-damaging effect. Furthermore, chloram-HDi inhibits HDAC enzymes to induce the acetylation of α-tubulin and histone H3.
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Affiliation(s)
- Yoojin Song
- College of Pharmacy, Keimyung University, Daegu, Republic of Korea
| | - Sun You Park
- College of Pharmacy, Keimyung University, Daegu, Republic of Korea
| | - Zhexue Wu
- BK21 Plus KNU Multi-Omics based Creative Drug Research Team, College of Pharmacy and Research Institute of Pharmaceutical Sciences, Kyungpook National University, Daegu, South Korea
| | - Kwang-Hyeon Liu
- BK21 Plus KNU Multi-Omics based Creative Drug Research Team, College of Pharmacy and Research Institute of Pharmaceutical Sciences, Kyungpook National University, Daegu, South Korea
| | - Young Ho Seo
- College of Pharmacy, Keimyung University, Daegu, Republic of Korea
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17
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Sanaei M, Kavoosi F. Effect of Zebularine in Comparison to Trichostatin A on the Intrinsic and Extrinsic Apoptotic Pathway, Cell Viability, and Apoptosis in Hepatocellular Carcinoma SK-Hep 1, Human Colorectal Cancer SW620, and Human Pancreatic Cancer PaCa-44 Cell Lines. IRANIAN JOURNAL OF PHARMACEUTICAL RESEARCH : IJPR 2021; 20:310-323. [PMID: 34903991 PMCID: PMC8653687 DOI: 10.22037/ijpr.2021.115097.15196] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Abstract
Aberrant histone modifications or promoter region hypermethylation of tumor suppressor genes (TSGs) have been recognized as the important epigenetic molecular mechanism in cancer induction. The potential anticancer activities of histone deacetylase inhibitors (HDACIs) and DNA methyltransferase inhibitors (DNMTIs) have been investigated in recent years. The current study was assigned to investigate the effect of trichostatin A (HDACI) in comparison to zebularine (DNMTI) on the intrinsic pro-apoptotic (Bax, Bim, and Bak) and anti-apoptotic (Bcl-2, Mcl-1, and Bcl-xL) genes and extrinsic (DR4, DR5, FAS, FAS-L, and TRAIL genes) pathways, DNA methyltransferase 1, 3a, and 3b, histone deacetylase inhibitors 1, 2, and 3, cell viability, and apoptosis in hepatocellular carcinoma (HCC) SK-Hep 1, colorectal cancer SW620, and pancreatic cancer PaCa-44 cell lines. The SK-Hep 1, SW620, and PaCa-44 cells were cultured and treated with TSA and zebularine. To determine cell apoptosis, cell viability, and the relative gene expression level, flow cytometry assay, MTT assay, and qRT-PCR were done respectively. The result indicated that zebularine and TSA changed the expression level of the Bax, Bak, Bim Bcl-2, Bcl-xL, Mcl-1, DR4, DR5, FAS, FAS-L, TRAIL, DNA methyltransferase 1, 3a, and 3b, histone deacetylase inhibitors 1, 2, and 3 by which induced cell apoptosis and inhibit cell growth in all three cell lines. Concluding, TSA induced its role through both extrinsic and intrinsic apoptotic pathways in three cell lines, whereas, zebularine played its role via both pathways in the SK-Hep 1cell line, it had no significant effect on Bcl-2, Bcl-xL, and Mcl-1 gene expression in SW620 and PaCa-44 cell lines.
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18
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Kumar S, Attrish D, Srivastava A, Banerjee J, Tripathi M, Chandra PS, Dixit AB. Non-histone substrates of histone deacetylases as potential therapeutic targets in epilepsy. Expert Opin Ther Targets 2020; 25:75-85. [PMID: 33275850 DOI: 10.1080/14728222.2021.1860016] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Introduction: Epilepsy is a network-level neurological disorder characterized by unprovoked recurrent seizures and associated comorbidities. Aberrant activity and localization of histone deacetylases (HDACs) have been reported in epilepsy and HDAC inhibitors (HDACi) have been used for therapeutic purposes. Several non-histone targets of HDACs have been recognized whose reversible acetylation can modulate protein functions and can contribute to disease pathology. Areas covered: This review provides an overview of HDACs in epilepsy and reflects its action on non-histone substrates involved in the pathogenesis of epilepsy and explores the effectiveness of HDACi as anti-epileptic drugs (AEDs). It also covers the efforts undertaken to target the interaction of HDACs with their substrates. We have further discussed non-deacetylase activity possessed by specific HDACs that might be essential in unraveling the molecular mechanism underlying the disease. For this purpose, relevant literature from 1996 to 2020 was derived from PubMed. Expert opinion: The interaction of HDACs and their non-histone substrates can serve as a promising therapeutic target for epilepsy. Pan-HDACi offers limited benefits to the epileptic patients. Thus, identification of novel targets of HDACs contributing to the disease and designing inhibitors targeting these complexes would be more effective and holds a greater potential as an anti-epileptogenic therapy.
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Affiliation(s)
- Sonali Kumar
- Dr. B.R. Ambedkar Centre for Biomedical Research (ACBR), University of Delhi , New Delhi, India
| | - Diksha Attrish
- Dr. B.R. Ambedkar Centre for Biomedical Research (ACBR), University of Delhi , New Delhi, India
| | | | | | | | | | - Aparna Banerjee Dixit
- Dr. B.R. Ambedkar Centre for Biomedical Research (ACBR), University of Delhi , New Delhi, India
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19
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Cao Y, Liu T, Li Z, Yang J, Ma L, Mi X, Yang N, Qi A, Guo X, Wang A. Neurofilament degradation is involved in laparotomy-induced cognitive dysfunction in aged rats. Aging (Albany NY) 2020; 12:25643-25657. [PMID: 33232265 PMCID: PMC7803518 DOI: 10.18632/aging.104172] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2020] [Accepted: 09/19/2020] [Indexed: 12/04/2022]
Abstract
Excessive neuroinflammatory responses play important roles in the development of postoperative cognitive dysfunction (POCD). Neurofilaments (NFs) were essential to the structure of axon and nerve conduction; and the abnormal degradation of NFs were always accompanied with degenerative diseases, which were also characterized by excessive neuroinflammatory responses in brain. However, it is still unclear whether the NFs were involved in the POCD. In this study, the LC-MS/MS method was used to explore the neuroinflammatory response and NFs of POCD in aged rats. Moreover, trichostatin A (TSA), an inflammation-related drug, was selected to test whether it could improve the surgery-induced cognitive dysfunction, inflammatory responses and NFs. Evident cognitive dysfunction, excessive microglia activation, neuroinflammatory responses and upregulated NFs in hippocampus were observed in the POCD group. TSA pretreatment could significantly mitigate these changes. The KEGG analysis revealed that nine pathways were enriched in the TSA + surgery group (versus the surgery group). Among them, two signaling pathways were closely related with the changes of NFs proteins. In conclusion, surgery could impair the cognitive function and aggravate neuroinflammation and NFs. The TSA could significantly improve these changes which might be related to the activation of the “focal adhesion” and “ECM-receptor interaction” pathways.
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Affiliation(s)
- Yiyun Cao
- Department of Anesthesiology, Sixth People’s Hospital Affiliated to Shanghai Jiao Tong University, Shanghai 200233, China
| | - Taotao Liu
- Department of Anesthesiology, Peking University Third Hospital, Beijing 100191, China
| | - Zhengqian Li
- Department of Anesthesiology, Peking University Third Hospital, Beijing 100191, China
| | - Jiao Yang
- Department of Pharmacy, Sixth People’s Hospital East Campus Affiliated to Shanghai Jiao Tong University, Shanghai 200233, China
| | - Lijun Ma
- Department of Medical Imaging, North Minzu University, Yinchuan, Ningxia 750021, China
| | - Xinning Mi
- Department of Anesthesiology, Peking University Third Hospital, Beijing 100191, China
| | - Ning Yang
- Department of Anesthesiology, Peking University Third Hospital, Beijing 100191, China
| | - Aihua Qi
- Department of Anesthesiology, Sixth People’s Hospital Affiliated to Shanghai Jiao Tong University, Shanghai 200233, China
| | - Xiangyang Guo
- Department of Anesthesiology, Peking University Third Hospital, Beijing 100191, China
| | - Aizhong Wang
- Department of Anesthesiology, Sixth People’s Hospital Affiliated to Shanghai Jiao Tong University, Shanghai 200233, China
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20
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Tng J, Lim J, Wu KC, Lucke AJ, Xu W, Reid RC, Fairlie DP. Achiral Derivatives of Hydroxamate AR-42 Potently Inhibit Class I HDAC Enzymes and Cancer Cell Proliferation. J Med Chem 2020; 63:5956-5971. [DOI: 10.1021/acs.jmedchem.0c00230] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Affiliation(s)
- Jiahui Tng
- Division of Chemistry and Structural Biology, Institute for Molecular Bioscience, The University of Queensland, Brisbane, Queensland 4072, Australia
| | - Junxian Lim
- Division of Chemistry and Structural Biology, Institute for Molecular Bioscience, The University of Queensland, Brisbane, Queensland 4072, Australia
- Australian Research Council Centre of Excellence in Advanced Molecular Imaging, Institute for Molecular Bioscience, The University of Queensland, Brisbane, Queensland 4072, Australia
- Centre for Inflammation and Disease Research, Institute for Molecular Bioscience, The University of Queensland, Brisbane, Queensland 4072, Australia
| | - Kai-Chen Wu
- Division of Chemistry and Structural Biology, Institute for Molecular Bioscience, The University of Queensland, Brisbane, Queensland 4072, Australia
- Australian Research Council Centre of Excellence in Advanced Molecular Imaging, Institute for Molecular Bioscience, The University of Queensland, Brisbane, Queensland 4072, Australia
- Centre for Inflammation and Disease Research, Institute for Molecular Bioscience, The University of Queensland, Brisbane, Queensland 4072, Australia
| | - Andrew J. Lucke
- Division of Chemistry and Structural Biology, Institute for Molecular Bioscience, The University of Queensland, Brisbane, Queensland 4072, Australia
- Australian Research Council Centre of Excellence in Advanced Molecular Imaging, Institute for Molecular Bioscience, The University of Queensland, Brisbane, Queensland 4072, Australia
| | - Weijun Xu
- Division of Chemistry and Structural Biology, Institute for Molecular Bioscience, The University of Queensland, Brisbane, Queensland 4072, Australia
| | - Robert C. Reid
- Division of Chemistry and Structural Biology, Institute for Molecular Bioscience, The University of Queensland, Brisbane, Queensland 4072, Australia
- Australian Research Council Centre of Excellence in Advanced Molecular Imaging, Institute for Molecular Bioscience, The University of Queensland, Brisbane, Queensland 4072, Australia
- Centre for Inflammation and Disease Research, Institute for Molecular Bioscience, The University of Queensland, Brisbane, Queensland 4072, Australia
| | - David P. Fairlie
- Division of Chemistry and Structural Biology, Institute for Molecular Bioscience, The University of Queensland, Brisbane, Queensland 4072, Australia
- Australian Research Council Centre of Excellence in Advanced Molecular Imaging, Institute for Molecular Bioscience, The University of Queensland, Brisbane, Queensland 4072, Australia
- Centre for Inflammation and Disease Research, Institute for Molecular Bioscience, The University of Queensland, Brisbane, Queensland 4072, Australia
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Tago T, Toyohara J, Ishii K. Radiosynthesis and preliminary evaluation of an 18 F-labeled tubastatin A analog for PET imaging of histone deacetylase 6. J Labelled Comp Radiopharm 2020; 63:85-95. [PMID: 31881107 DOI: 10.1002/jlcr.3823] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2019] [Revised: 11/28/2019] [Accepted: 11/28/2019] [Indexed: 12/23/2022]
Abstract
Histone deacetylase 6 (HDAC6) is a unique member of the HDAC family because of its characteristics, namely, its cytoplasmic localization and ubiquitin binding. HDAC6 has been implicated in cancer metastasis and neurodegeneration. In the present study, we performed radiosynthesis and biological evaluation of a fluorine-18-labeled ligand [18 F]3, which is an analog of the HDAC6-selective inhibitor tubastatin A, for positron emission tomography (PET) imaging. [18 F]3 was synthesized by a two-step reaction composed of 18 F-fluorination and formation of a hydroxamic acid group. IC50 values of 3 against HDAC1 and HDAC6 activities were 996 nM and 33.1 nM, respectively. A biodistribution study in mice demonstrated low brain uptake of [18 F]3. Furthermore, bone radioactivity was stable at around 2% ID/g after injection, suggesting high tolerance to defluorination. Regarding metabolic stability, 70% of the compound was observed as the unchanged form at 30 minutes post injection in mouse plasma. A small animal PET study in mice showed that pretreatment with cyclosporine A had no effect on initial brain uptake of [18 F]3, suggesting low brain uptake of [18 F]3 was not caused by the P-glycoprotein-mediated efflux. While PET imaging using [18 F]3 has a limitation with respect to neurodegenerative diseases, further studies evaluating its utility for certain cancers are worth evaluating.
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Affiliation(s)
- Tetsuro Tago
- Research Team for Neuroimaging, Tokyo Metropolitan Institute of Gerontology, Tokyo, Japan
| | - Jun Toyohara
- Research Team for Neuroimaging, Tokyo Metropolitan Institute of Gerontology, Tokyo, Japan
| | - Kenji Ishii
- Research Team for Neuroimaging, Tokyo Metropolitan Institute of Gerontology, Tokyo, Japan
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Laws MT, Bonomi RE, Gelovani DJ, Llaniguez J, Lu X, Mangner T, Gelovani JG. Noninvasive quantification of SIRT1 expression-activity and pharmacologic inhibition in a rat model of intracerebral glioma using 2-[ 18F]BzAHA PET/CT/MRI. Neurooncol Adv 2020; 2:vdaa006. [PMID: 32118205 PMCID: PMC7034639 DOI: 10.1093/noajnl/vdaa006] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
Background Several studies demonstrated that glioblastoma multiforme progression and recurrence is linked to epigenetic regulatory mechanisms. Sirtuin 1 (SIRT1) plays an important role in glioma progression, invasion, and treatment response and is a potential therapeutic target. The aim of this study is to test the feasibility of 2-[18F]BzAHA for quantitative imaging of SIRT1 expression–activity and monitoring pharmacologic inhibition in a rat model of intracerebral glioma. Methods Sprague Dawley rats bearing 9L (N = 12) intracerebral gliomas were injected with 2-[18F]BzAHA (300–500 µCi/animal i.v.) and dynamic positron-emission tomography (PET) imaging was performed for 60 min. Then, SIRT1 expression in 9L tumors (N = 6) was studied by immunofluorescence microscopy (IF). Two days later, rats with 9L gliomas were treated either with SIRT1 specific inhibitor EX-527 (5 mg/kg, i.p.; N = 3) or with histone deacetylases class IIa specific inhibitor MC1568 (30 mg/kg, i.p.; N = 3) and 30 min later were injected i.v. with 2-[18F]BzAHA. PET-computerized tomography-magnetic resonance (PET/CT/MR) images acquired after EX-527 and MC1568 treatments were co-registered with baseline images. Results Standard uptake values (SUVs) of 2-[18F]BzAHA in 9L tumors measured at 20 min post-radiotracer administration were 1.11 ± 0.058 and had a tumor-to-brainstem SUV ratio of 2.73 ± 0.141. IF of 9L gliomas revealed heterogeneous upregulation of SIRT1, especially in hypoxic and peri-necrotic regions. Significant reduction in 2-[18F]BzAHA SUV and distribution volume in 9L tumors was observed after administration of EX-527, but not MC1568. Conclusions PET/CT/MRI with 2-[18F]BzAHA can facilitate studies to elucidate the roles of SIRT1 in gliomagenesis and progression, as well as to optimize therapeutic doses of novel SIRT1 inhibitors.
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Affiliation(s)
- Maxwell T Laws
- Department of Biomedical Engineering, College of Engineering and School of Medicine, Wayne State University, Detroit, Michigan, USA
| | - Robin E Bonomi
- Department of Biomedical Engineering, College of Engineering and School of Medicine, Wayne State University, Detroit, Michigan, USA
| | - David J Gelovani
- Department of Biomedical Engineering, College of Engineering and School of Medicine, Wayne State University, Detroit, Michigan, USA
| | - Jeremy Llaniguez
- Department of Biomedical Engineering, College of Engineering and School of Medicine, Wayne State University, Detroit, Michigan, USA
| | - Xin Lu
- Positron Emission Tomography Center, Wayne State University, Detroit, Michigan, USA
| | - Thomas Mangner
- Positron Emission Tomography Center, Wayne State University, Detroit, Michigan, USA
| | - Juri G Gelovani
- Department of Biomedical Engineering, College of Engineering and School of Medicine, Wayne State University, Detroit, Michigan, USA.,Department of Oncology, Wayne State University School of Medicine, Detroit, Michigan, USA.,Department of Neurosurgery, Wayne State University School of Medicine, Detroit, Michigan, USA.,Molecular Imaging Program, Karmanos Cancer Institute, Wayne State University School of Medicine, Detroit, Michigan, USA
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Sild M, Booij L. Histone deacetylase 4 (HDAC4): a new player in anorexia nervosa? Mol Psychiatry 2019; 24:1425-1434. [PMID: 30742020 DOI: 10.1038/s41380-019-0366-8] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/19/2018] [Revised: 12/20/2018] [Accepted: 01/23/2019] [Indexed: 12/26/2022]
Abstract
Anorexia nervosa (AN) and other eating disorders continue to constitute significant challenges for individual and public health. AN is thought to develop as a result of complex interactions between environmental triggers, psychological risk factors, sociocultural influences, and genetic vulnerability. Recent research developments have highlighted a novel potentially relevant component in the AN etiology-activity of the histone deacetylase 4 (HDAC4) gene that has emerged in several recent studies related to AN. HDAC4 is a member of the ubiquitously important family of epigenetic modifier enzymes called histone deacetylases and has been implicated in processes related to the formation and function of the central nervous system (CNS), bone, muscle, and metabolism. In a family affected by eating disorders, a missense mutation in HDAC4 (A786T) was found to segregate with the illness. The relevance of this mutation in eating-related behaviors was further confirmed with mouse models. Despite the fact that HDAC4 has not been identified as a significant signal in genome-wide association studies in AN, several studies have found significant or near-significant methylation differences in HDAC4 locus in peripheral tissues of actively ill AN patients in comparison with different control groups. Limitations of these studies include a lack of understanding of to what extent the changes in methylation are predictive of AN as such changes might also occur as a consequence of the disease. It remains to be determined how methylation in peripheral tissues correlates with that in the CNS and how different methylation patterns affect HDAC4 expression. The present review discusses the findings and potential roles of HDAC4 in AN. Its emerging roles in learning and neuroplasticity may be specific and relevant for the etiology of AN and potentially lead to novel therapeutic approaches.
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Affiliation(s)
- Mari Sild
- Department of Psychology, Concordia University, Montreal, QC, Canada.,CHU Sainte-Justine Hospital Research Center, Montreal, QC, Canada
| | - Linda Booij
- Department of Psychology, Concordia University, Montreal, QC, Canada. .,CHU Sainte-Justine Hospital Research Center, Montreal, QC, Canada. .,Department of Psychiatry, McGill University, Montreal, QC, Canada. .,Department of Psychiatry, University of Montreal, Montreal, QC, Canada.
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24
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Pan-HDAC Inhibitors Promote Tau Aggregation by Increasing the Level of Acetylated Tau. Int J Mol Sci 2019; 20:ijms20174283. [PMID: 31480543 PMCID: PMC6747090 DOI: 10.3390/ijms20174283] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2019] [Revised: 08/28/2019] [Accepted: 08/29/2019] [Indexed: 12/21/2022] Open
Abstract
Epigenetic remodeling via histone acetylation has become a popular therapeutic strategy to treat Alzheimer's disease (AD). In particular, histone deacetylase (HDAC) inhibitors including M344 and SAHA have been elucidated to be new drug candidates for AD, improving cognitive abilities impaired in AD mouse models. Although emerged as a promising target for AD, most of the HDAC inhibitors are poorly selective and could cause unwanted side effects. Here we show that tau is one of the cytosolic substrates of HDAC and the treatment of HDAC inhibitors such as Scriptaid, M344, BML281, and SAHA could increase the level of acetylated tau, resulting in the activation of tau pathology.
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Brindisi M, Saraswati AP, Brogi S, Gemma S, Butini S, Campiani G. Old but Gold: Tracking the New Guise of Histone Deacetylase 6 (HDAC6) Enzyme as a Biomarker and Therapeutic Target in Rare Diseases. J Med Chem 2019; 63:23-39. [PMID: 31415174 DOI: 10.1021/acs.jmedchem.9b00924] [Citation(s) in RCA: 77] [Impact Index Per Article: 12.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Epigenetic regulation orchestrates many cellular processes and greatly influences key disease mechanisms. Histone deacetylase (HDAC) enzymes play a crucial role either as biomarkers or therapeutic targets owing to their involvement in specific pathophysiological pathways. Beyond their well-characterized role as histone modifiers, HDACs also interact with several nonhistone substrates and their increased expression has been highlighted in specific diseases. The HDAC6 isoform, due to its unique cytoplasmic localization, modulates the acetylation status of tubulin, HSP90, TGF-β, and peroxiredoxins. HDAC6 also exerts noncatalytic activities through its interaction with ubiquitin. Both catalytic and noncatalytic functions of HDACs are being actively studied in the field of specific rare disorders beyond the well-established role in carcinogenesis. This Perspective outlines the application of HDAC(6) inhibitors in rare diseases, such as Rett syndrome, inherited retinal disorders, idiopathic pulmonary fibrosis, and Charcot-Marie-Tooth disease, highlighting their therapeutic potential as innovative and targeted disease-modifying agents.
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Affiliation(s)
- Margherita Brindisi
- Department of Pharmacy, Department of Excellence 2018-2022 , University of Naples Federico II , Via D. Montesano 49 , I-80131 Naples , Italy
| | - A Prasanth Saraswati
- Department of Biotechnology, Chemistry and Pharmacy, Department of Excellence 2018-2022 , University of Siena , via Aldo Moro 2 , 53100 , Siena , Italy
| | - Simone Brogi
- Department of Pharmacy , University of Pisa , via Bonanno 6 , 56126 , Pisa , Italy
| | - Sandra Gemma
- Department of Biotechnology, Chemistry and Pharmacy, Department of Excellence 2018-2022 , University of Siena , via Aldo Moro 2 , 53100 , Siena , Italy
| | - Stefania Butini
- Department of Biotechnology, Chemistry and Pharmacy, Department of Excellence 2018-2022 , University of Siena , via Aldo Moro 2 , 53100 , Siena , Italy
| | - Giuseppe Campiani
- Department of Biotechnology, Chemistry and Pharmacy, Department of Excellence 2018-2022 , University of Siena , via Aldo Moro 2 , 53100 , Siena , Italy
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A Novel Substrate Radiotracer for Molecular Imaging of SIRT2 Expression and Activity with Positron Emission Tomography. Mol Imaging Biol 2019; 20:594-604. [PMID: 29423902 PMCID: PMC6816246 DOI: 10.1007/s11307-017-1149-8] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/01/2023]
Abstract
PURPOSE The purpose of this study was to develop a SIRT2-specific substrate-type radiotracer for non-invasive PET imaging of epigenetic regulatory processes mediated by SIRT2 in normal and disease tissues. PROCEDURES A library of compounds containing tert-butyloxycarbonyl-lysine-aminomethylcoumarin backbone was derivatized with fluoroalkyl chains 3-16 carbons in length. SIRT2 most efficiently cleaved the myristoyl, followed by 12-fluorododecanoic and 10-fluorodecanoic groups (Kcat/Km 716.5 ± 72.8, 615.4 ± 50.5, 269.5 ± 52.1/s mol, respectively). Radiosynthesis of 12- [18F]fluorododecanoic aminohexanoicanilide (12-[18F]DDAHA) was achieved by nucleophilic radiofluorination of 12-iododecanoic-AHA precursor. RESULTS A significantly higher accumulation of 12-[18F]DDAHA was observed in MCF-7 and MDA-MB-435 cells in vitro as compared to U87, MiaPaCa, and MCF10A, which was consistent with levels of SIRT2 expression. Initial in vivo studies using 12-[18F]DDAHA conducted in a 9L glioma-bearing rats were discouraging, due to rapid defluorination of this radiotracer upon intravenous administration, as evidenced by significant accumulation of F-18 radioactivity in the skull and other bones, which confounded the interpretation of images of radiotracer accumulation within the tumor and other regions of the brain. CONCLUSIONS The next generation of SIRT2-specific radiotracers resistant to systemic defluorination should be developed using alternative sites of radiofluorination on the aliphatic chain of DDAHA. A SIRT2-selective radiotracer may provide information about SIRT2 expression and activity in tumors and normal organs and tissues, which may help to better understand the roles of SIRT2 in different diseases.
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Lascano S, Lopez M, Arimondo PB. Natural Products and Chemical Biology Tools: Alternatives to Target Epigenetic Mechanisms in Cancers. CHEM REC 2018; 18:1854-1876. [PMID: 30537358 DOI: 10.1002/tcr.201800133] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2018] [Revised: 11/05/2018] [Accepted: 11/05/2018] [Indexed: 12/21/2022]
Abstract
DNA methylation and histone acetylation are widely studied epigenetic modifications. They are involved in numerous pathologies such as cancer, neurological disease, inflammation, obesity, etc. Since the discovery of the epigenome, numerous compounds have been developed to reverse DNA methylation and histone acetylation aberrant profile in diseases. Among them several were inspired by Nature and have a great interest as therapeutic molecules. In the quest of finding new ways to target epigenetic mechanisms, the use of chemical tools is a powerful strategy to better understand epigenetic mechanisms in biological systems. In this review we will present natural products reported as DNMT or HDAC inhibitors for anticancer treatments. We will then discuss the use of chemical tools that have been used in order to explore the epigenome.
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Affiliation(s)
- Santiago Lascano
- Institut des Biomolécules Max Mousseron (IBMM), UMR 5247 CNRS-Université de Montpellier-ENSCM, 240 avenue du Prof. E. Jeanbrau, 34296, Montpellier cedex 5, France
| | - Marie Lopez
- Institut des Biomolécules Max Mousseron (IBMM), UMR 5247 CNRS-Université de Montpellier-ENSCM, 240 avenue du Prof. E. Jeanbrau, 34296, Montpellier cedex 5, France
| | - Paola B Arimondo
- Epigenetic Chemical Biology, Institut Pasteur, CNRS UMR3523, 28 rue du Docteur Roux, 75724, Paris cedex 15, France
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Abstract
Introduction: Epigenetic dysregulation drives or supports numerous human cancers. The chromatin landscape in cancer cells is often marked by abnormal histone post-translational modification (PTM) patterns and by aberrant assembly and recruitment of protein complexes to specific genomic loci. Mass spectrometry-based proteomic analyses can support the discovery and characterization of both phenomena. Areas covered: We broadly divide this literature into two parts: 'modification-centric' analyses that link histone PTMs to cancer biology; and 'complex-centric' analyses that examine protein-protein interactions that occur de novo as a result of oncogenic mutations. We also discuss proteomic studies of oncohistones. We highlight relevant examples, discuss limitations, and speculate about forthcoming innovations regarding each application. Expert commentary: 'Modification-centric' analyses have been used to further understanding of cancer's histone code and to identify associated therapeutic vulnerabilities. 'Complex-centric' analyses have likewise revealed insights into mechanisms of oncogenesis and suggested potential therapeutic targets, particularly in MLL-associated leukemia. Proteomic experiments have also supported some of the pioneering studies of oncohistone-mediated tumorigenesis. Additional applications of proteomics that may benefit cancer epigenetics research include middle-down and top-down histone PTM analysis, chromatin reader profiling, and genomic locus-specific protein identification. In the coming years, proteomic approaches will remain powerful ways to interrogate the biology of cancer.
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Affiliation(s)
- Dylan M Marchione
- a Epigenetics Institute, Department of Biochemistry and Biophysics, Perelman School of Medicine , University of Pennsylvania , Philadelphia , PA , USA
| | - Benjamin A Garcia
- a Epigenetics Institute, Department of Biochemistry and Biophysics, Perelman School of Medicine , University of Pennsylvania , Philadelphia , PA , USA
| | - John Wojcik
- b Department of Pathology and Laboratory Medicine, Perelman School of Medicine , University of Pennsylvania , Philadelphia , PA , USA
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Yuliana A, Jheng HF, Kawarasaki S, Nomura W, Takahashi H, Ara T, Kawada T, Goto T. β-adrenergic Receptor Stimulation Revealed a Novel Regulatory Pathway via Suppressing Histone Deacetylase 3 to Induce Uncoupling Protein 1 Expression in Mice Beige Adipocyte. Int J Mol Sci 2018; 19:ijms19082436. [PMID: 30126161 PMCID: PMC6121552 DOI: 10.3390/ijms19082436] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2018] [Revised: 08/14/2018] [Accepted: 08/15/2018] [Indexed: 12/21/2022] Open
Abstract
Browning of adipose tissue has been prescribed as a potential way to treat obesity, marked by the upregulation of uncoupling protein 1 (Ucp1). Several reports have suggested that histone deacetylase (HDAC) might regulate Ucp1 by remodelling chromatin structure, although the mechanism remains unclear. Herein, we investigate the effect of β-adrenergic receptor (β-AR) activation on the chromatin state of beige adipocyte. β-AR-stimulated Ucp1 expression via cold (in vivo) and isoproterenol (in vitro) resulted in acetylation of histone activation mark H3K27. H3K27 acetylation was also seen within Ucp1 promoter upon isoproterenol addition, favouring open chromatin for Ucp1 transcriptional activation. This result was found to be associated with the downregulation of class I HDAC mRNA, particularly Hdac3 and Hdac8. Further investigation showed that although HDAC8 activity decreased, Ucp1 expression was not altered when HDAC8 was activated or inhibited. In contrast, HDAC3 mRNA and protein levels were simultaneously downregulated upon isoproterenol addition, resulting in reduced recruitment of HDAC3 to the Ucp1 enhancer region, causing an increased H3K27 acetylation for Ucp1 upregulation. The importance of HDAC3 inhibition was confirmed through the enhanced Ucp1 expression when the cells were treated with HDAC3 inhibitor. This study highlights the novel mechanism of HDAC3-regulated Ucp1 expression during β-AR stimulation.
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Affiliation(s)
- Ana Yuliana
- Laboratory of Molecular Function of Food, Division of Food Science and Biotechnology, Graduate School of Agriculture, Kyoto University, Gokasho, Uji, Kyoto 611-0011, Japan.
| | - Huei-Fen Jheng
- Laboratory of Molecular Function of Food, Division of Food Science and Biotechnology, Graduate School of Agriculture, Kyoto University, Gokasho, Uji, Kyoto 611-0011, Japan.
| | - Satoko Kawarasaki
- Laboratory of Molecular Function of Food, Division of Food Science and Biotechnology, Graduate School of Agriculture, Kyoto University, Gokasho, Uji, Kyoto 611-0011, Japan.
| | - Wataru Nomura
- Laboratory of Molecular Function of Food, Division of Food Science and Biotechnology, Graduate School of Agriculture, Kyoto University, Gokasho, Uji, Kyoto 611-0011, Japan.
- Research Unit for Physiological Chemistry, the Center for the Promotion of Interdisciplinary Education and Research, Kyoto University, Kyoto 606-8501, Japan.
| | - Haruya Takahashi
- Laboratory of Molecular Function of Food, Division of Food Science and Biotechnology, Graduate School of Agriculture, Kyoto University, Gokasho, Uji, Kyoto 611-0011, Japan.
| | - Takeshi Ara
- Laboratory of Molecular Function of Food, Division of Food Science and Biotechnology, Graduate School of Agriculture, Kyoto University, Gokasho, Uji, Kyoto 611-0011, Japan.
| | - Teruo Kawada
- Laboratory of Molecular Function of Food, Division of Food Science and Biotechnology, Graduate School of Agriculture, Kyoto University, Gokasho, Uji, Kyoto 611-0011, Japan.
- Research Unit for Physiological Chemistry, the Center for the Promotion of Interdisciplinary Education and Research, Kyoto University, Kyoto 606-8501, Japan.
| | - Tsuyoshi Goto
- Laboratory of Molecular Function of Food, Division of Food Science and Biotechnology, Graduate School of Agriculture, Kyoto University, Gokasho, Uji, Kyoto 611-0011, Japan.
- Research Unit for Physiological Chemistry, the Center for the Promotion of Interdisciplinary Education and Research, Kyoto University, Kyoto 606-8501, Japan.
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The Therapeutic Strategy of HDAC6 Inhibitors in Lymphoproliferative Disease. Int J Mol Sci 2018; 19:ijms19082337. [PMID: 30096875 PMCID: PMC6121661 DOI: 10.3390/ijms19082337] [Citation(s) in RCA: 59] [Impact Index Per Article: 8.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2018] [Revised: 08/02/2018] [Accepted: 08/03/2018] [Indexed: 12/15/2022] Open
Abstract
Histone deacetylases (HDACs) are master regulators of chromatin remodeling, acting as epigenetic regulators of gene expression. In the last decade, inhibition of HDACs has become a target for specific epigenetic modifications related to cancer development. Overexpression of HDAC has been observed in several hematologic malignancies. Therefore, the observation that HDACs might play a role in various hematologic malignancies has brought to the development of HDAC inhibitors as potential antitumor agents. Recently, the class IIb, HDAC6, has emerged as one potential selective HDACi. This isoenzyme represents an important pharmacological target for selective inhibition. Its selectivity may reduce the toxicity related to the off-target effects of pan-HDAC inhibitors. HDAC6 has also been studied in cancer especially for its ability to coordinate a variety of cellular processes that are important for cancer pathogenesis. HDAC6 has been reported to be overexpressed in lymphoid cells and its inhibition has demonstrated activity in preclinical and clinical study of lymphoproliferative disease. Various studies of HDAC6 inhibitors alone and in combination with other agents provide strong scientific rationale for the evaluation of these new agents in the clinical setting of hematological malignancies. In this review, we describe the HDACs, their inhibitors, and the recent advances of HDAC6 inhibitors, their mechanisms of action and role in lymphoproliferative disorders.
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Programmed cell death 5 suppresses AKT-mediated cytoprotection of endothelium. Proc Natl Acad Sci U S A 2018; 115:4672-4677. [PMID: 29588416 DOI: 10.1073/pnas.1712918115] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022] Open
Abstract
Programmed cell death 5 (PDCD5) has been associated with human cancers as a regulator of cell death; however, the role of PDCD5 in the endothelium has not been revealed. Thus, we investigated whether PDCD5 regulates protein kinase B (PKB/AKT)-endothelial nitric oxide synthase (eNOS)-dependent signal transduction in the endothelium and affects atherosclerosis. Endothelial-specific PDCD5 knockout mice showed significantly reduced vascular remodeling compared with wild-type (WT) mice after partial carotid ligation. WT PDCD5 competitively inhibited interaction between histone deacetylase 3 (HDAC3) and AKT, but PDCD5L6R, an HDAC3-binding-deficient mutant, did not. Knockdown of PDCD5 accelerated HDAC3-AKT interaction, AKT and eNOS phosphorylation, and nitric oxide (NO) production in human umbilical vein endothelial cells. Moreover, we found that serum PDCD5 levels reflect endothelial NO production and are correlated with diabetes mellitus, high-density lipoprotein cholesterol, and coronary calcium in human samples obtained from the cardiovascular high-risk cohort. Therefore, we conclude that PDCD5 is associated with endothelial dysfunction and may be a novel therapeutic target in atherosclerosis.
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Jang BG, Choi B, Kim S, Lee JY, Kim MJ. Trichostatin A and Sirtinol Regulate the Expression and Nucleocytoplasmic Shuttling of Histone Deacetylases in All-Trans Retinoic Acid-Induced Differentiation of Neuroblastoma Cells. J Mol Neurosci 2018. [PMID: 29516351 DOI: 10.1007/s12031-018-1050-1] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Neuroblastoma cell differentiation is a valuable model for studying therapeutic methods in neuroblastoma and the mechanisms of neuronal differentiation. Here, we used trichostatin A (TSA) and sirtinol, which are inhibitors of cHDACs and sirtuins, respectively, to show that classical histone deacetylases (cHDACs) and sirtuins (silent mating type information regulation 2 homolog; SIRTs) affect all-trans retinoic acid (ATRA)-induced differentiation of neuroblastoma cells. After first determining neurite elongation and expression levels of tyrosine hydroxylase and high size neurofilament as useful differentiation markers, we observed that TSA increased neuroblastoma cell differentiation, while sirtinol had the antagonistic effect of decreasing it. The changes were also associated with the nucleocytoplasmic shuttling of cHDACs and sirtuins. ATRA significantly decreased the nuclear to cytoplasmic ratio of SIRT1 and SIRT2.1, while sirtinol inhibited that of SIRT1, and TSA increased that of SIRT1 and SIRT2.1 during early differentiation. Moreover, the effect of the sirtinol-related signal was located upstream for cHDACs and sirtuins total expression, and downstream for their subcellular localization compared with that for the TSA-related signal. These results provide a mechanistic understanding of differentiation in neuroblastoma cells and indicate that cHDACs and sirtuins are critical therapeutic targets for neuroblastoma.
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Affiliation(s)
- Bong-Geum Jang
- Institute of Epilepsy Research, College of Medicine, Hallym University, 1 Hallymdaehak-gil, Chuncheon, 24252, Gangwon-Do, South Korea
| | - Boyoung Choi
- Department of Anatomy and Neurobiology, College of Medicine, Hallym University, 1 Hallymdaehak-gil, Chuncheon, 25242, Gangwon-Do, South Korea
| | - Suyeon Kim
- Department of Anatomy and Neurobiology, College of Medicine, Hallym University, 1 Hallymdaehak-gil, Chuncheon, 25242, Gangwon-Do, South Korea
| | - Jae-Yong Lee
- Department of Biochemistry, College of Medicine, Hallym University, 1 Hallymdaehak-gil, Chuncheon, 24252, Gangwon-Do, South Korea
| | - Min-Ju Kim
- Institute of Epilepsy Research, College of Medicine, Hallym University, 1 Hallymdaehak-gil, Chuncheon, 24252, Gangwon-Do, South Korea.
- Department of Anatomy and Neurobiology, College of Medicine, Hallym University, 1 Hallymdaehak-gil, Chuncheon, 25242, Gangwon-Do, South Korea.
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Tago T, Toyohara J. Advances in the Development of PET Ligands Targeting Histone Deacetylases for the Assessment of Neurodegenerative Diseases. Molecules 2018; 23:E300. [PMID: 29385079 PMCID: PMC6017260 DOI: 10.3390/molecules23020300] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/01/2018] [Revised: 01/29/2018] [Accepted: 01/29/2018] [Indexed: 12/05/2022] Open
Abstract
Epigenetic alterations of gene expression have emerged as a key factor in several neurodegenerative diseases. In particular, inhibitors targeting histone deacetylases (HDACs), which are enzymes responsible for deacetylation of histones and other proteins, show therapeutic effects in animal neurodegenerative disease models. However, the details of the interaction between changes in HDAC levels in the brain and disease progression remain unknown. In this review, we focus on recent advances in development of radioligands for HDAC imaging in the brain with positron emission tomography (PET). We summarize the results of radiosynthesis and biological evaluation of the HDAC ligands to identify their successful results and challenges. Since 2006, several small molecules that are radiolabeled with a radioisotope such as carbon-11 or fluorine-18 have been developed and evaluated using various assays including in vitro HDAC binding assays and PET imaging in rodents and non-human primates. Although most compounds do not readily cross the blood-brain barrier, adamantane-conjugated radioligands tend to show good brain uptake. Until now, only one HDAC radioligand has been tested clinically in a brain PET study. Further PET imaging studies to clarify age-related and disease-related changes in HDACs in disease models and humans will increase our understanding of the roles of HDACs in neurodegenerative diseases.
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Affiliation(s)
- Tetsuro Tago
- Research Team for Neuroimaging, Tokyo Metropolitan Institute of Gerontology, 35-2 Sakae-cho, Itabashi-ku, Tokyo 173-0015, Japan.
| | - Jun Toyohara
- Research Team for Neuroimaging, Tokyo Metropolitan Institute of Gerontology, 35-2 Sakae-cho, Itabashi-ku, Tokyo 173-0015, Japan.
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Toro TB, Painter RG, Haynes RA, Glotser EY, Bratton MR, Bryant JR, Nichols KA, Matthew-Onabanjo AN, Matthew AN, Bratcher DR, Perry CD, Watt TJ. Purification of metal-dependent lysine deacetylases with consistently high activity. Protein Expr Purif 2018; 141:1-6. [PMID: 28843507 PMCID: PMC5624855 DOI: 10.1016/j.pep.2017.08.009] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2017] [Revised: 07/28/2017] [Accepted: 08/22/2017] [Indexed: 11/25/2022]
Abstract
Metal-dependent lysine deacetylases (KDACs) are involved in regulation of numerous biological and disease processes through control of post-translational acetylation. Characterization of KDAC activity and substrate identification is complicated by inconsistent activity of prepared enzyme and a range of multi-step purifications. We describe a simplified protocol based on two-step affinity chromatography. The purification method is appropriate for use regardless of expression host, and we demonstrate purification of several representative members of the KDAC family as well as a selection of mutated variants. The purified proteins are highly active and consistent across preparations.
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Affiliation(s)
- Tasha B Toro
- Department of Chemistry, Xavier University of Louisiana, 1 Drexel Dr., New Orleans, LA 70125-1098, USA.
| | - Richard G Painter
- Department of Chemistry, Xavier University of Louisiana, 1 Drexel Dr., New Orleans, LA 70125-1098, USA.
| | - Rashad A Haynes
- Department of Chemistry, Xavier University of Louisiana, 1 Drexel Dr., New Orleans, LA 70125-1098, USA.
| | - Elena Y Glotser
- Department of Chemistry, Xavier University of Louisiana, 1 Drexel Dr., New Orleans, LA 70125-1098, USA.
| | - Melyssa R Bratton
- Department of Chemistry, Xavier University of Louisiana, 1 Drexel Dr., New Orleans, LA 70125-1098, USA.
| | - Jenae R Bryant
- Department of Chemistry, Xavier University of Louisiana, 1 Drexel Dr., New Orleans, LA 70125-1098, USA.
| | - Kyara A Nichols
- Department of Chemistry, Xavier University of Louisiana, 1 Drexel Dr., New Orleans, LA 70125-1098, USA.
| | - Asia N Matthew-Onabanjo
- Department of Chemistry, Xavier University of Louisiana, 1 Drexel Dr., New Orleans, LA 70125-1098, USA.
| | - Ashley N Matthew
- Department of Chemistry, Xavier University of Louisiana, 1 Drexel Dr., New Orleans, LA 70125-1098, USA.
| | - Derek R Bratcher
- Department of Chemistry, Xavier University of Louisiana, 1 Drexel Dr., New Orleans, LA 70125-1098, USA.
| | - Chanel D Perry
- Department of Chemistry, Xavier University of Louisiana, 1 Drexel Dr., New Orleans, LA 70125-1098, USA.
| | - Terry J Watt
- Department of Chemistry, Xavier University of Louisiana, 1 Drexel Dr., New Orleans, LA 70125-1098, USA.
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35
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Toro TB, Edenfield SA, Hylton BJ, Watt TJ. Chelatable trace zinc causes low, irreproducible KDAC8 activity. Anal Biochem 2018; 540-541:9-14. [PMID: 29100752 PMCID: PMC5712482 DOI: 10.1016/j.ab.2017.10.024] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2017] [Revised: 10/09/2017] [Accepted: 10/29/2017] [Indexed: 12/25/2022]
Abstract
Acetylation is an important regulatory mechanism in cells, and emphasis is being placed on identifying substrates and small molecule modulators of this post-translational modification. However, the reported in vitro activity of the lysine deacetylase KDAC8 is inconsistent across experimental setups, even with the same substrate, complicating progress in the field. We detected trace levels of zinc, a known inhibitor of KDAC8 when present in excess, even in high-quality buffer reagents, at concentrations that are sufficient to significantly inhibit the enzyme under common reaction conditions. We hypothesized that trace zinc in solution could account for the observed variability in KDAC8 activity. We demonstrate that addition of chelators, including BSA, EDTA, and citrate, and/or the use of a phosphate-based buffer instead of the more common tris-based buffer, eliminates the inhibition from low levels of zinc as well as the dependence of specific activity on enzyme concentration. This results in high KDAC8 activity that is consistent across buffer systems, even using low concentrations of enzyme. We report conditions that are suitable for several assays to increase both enzyme activity and reproducibility. Our results have significant implications for approaches used to identify substrates and small molecule modulators of KDAC8 and interpretation of existing data.
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Affiliation(s)
- Tasha B Toro
- Department of Chemistry, Xavier University of Louisiana, 1 Drexel Dr., New Orleans, LA 70125-1098, USA.
| | - Samantha A Edenfield
- Department of Chemistry, Xavier University of Louisiana, 1 Drexel Dr., New Orleans, LA 70125-1098, USA.
| | - Brandon J Hylton
- Department of Chemistry, Xavier University of Louisiana, 1 Drexel Dr., New Orleans, LA 70125-1098, USA.
| | - Terry J Watt
- Department of Chemistry, Xavier University of Louisiana, 1 Drexel Dr., New Orleans, LA 70125-1098, USA.
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36
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Durham BS, Grigg R, Wood IC. Inhibition of histone deacetylase 1 or 2 reduces induced cytokine expression in microglia through a protein synthesis independent mechanism. J Neurochem 2017; 143:214-224. [PMID: 28796285 DOI: 10.1111/jnc.14144] [Citation(s) in RCA: 46] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2017] [Revised: 07/03/2017] [Accepted: 07/31/2017] [Indexed: 12/24/2022]
Abstract
Histone deacetylase (HDAC) inhibitors prevent neural cell death in in vivo models of cerebral ischaemia, brain injury and neurodegenerative disease. One mechanism by which HDAC inhibitors may do this is by suppressing the excessive inflammatory response of chronically activated microglia. However, the molecular mechanisms underlying this anti-inflammatory effect and the specific HDAC responsible are not fully understood. Recent data from in vivo rodent studies have shown that inhibition of class I HDACs suppresses neuroinflammation and is neuroprotective. In our study, we have identified that selective HDAC inhibition with inhibitors apicidin, MS-275 or MI-192, or specific knockdown of HDAC1 or 2 using siRNA, suppresses the expression of cytokines interleukin-6 (IL-6) and tumour necrosis factor-alpha (TNF-α) in BV-2 murine microglia activated with lipopolysaccharide (LPS). Furthermore, we found that in the absence of HDAC1, HDAC2 is up-regulated and these increased levels are compensatory, suggesting that these two HDACs have redundancy in regulating the inflammatory response of microglia. Investigating the possible underlying anti-inflammatory mechanisms suggests an increase in protein expression is not important. Taken together, this study supports the idea that inhibitors selective towards HDAC1 or HDAC2, may be therapeutically useful for targeting neuroinflammation in brain injuries and neurodegenerative disease.
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Affiliation(s)
| | - Ronald Grigg
- School of Chemistry, University of Leeds, Leeds, UK
| | - Ian C Wood
- School of Biomedical Sciences, University of Leeds, Leeds, UK
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37
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Age-related alterations in histone deacetylase expression in Purkinje neurons of ethanol-fed rats. Brain Res 2017; 1675:8-19. [PMID: 28855102 DOI: 10.1016/j.brainres.2017.08.026] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2017] [Revised: 08/23/2017] [Accepted: 08/25/2017] [Indexed: 12/11/2022]
Abstract
Ethanol and age-induced pathologies of the Purkinje neuron (PN) may result from histone deacetylases (HDACs), enzymes which repress transcription through coiling of the DNA. The purposes of this study were to investigate expression patterns of Class 1 and IIa HDACs in PN and the effects of aging and alcohol on the density of HDACs and histone acetylation in PN. Ninety, eight month old rats (30/diet) were fed a liquid ethanol, liquid control, or rat chow diet for 10, 20, or 40weeks (30/treatment duration). Double immunocytochemical labeling on tissue sections from these rats used antibodies against HDAC isoforms or acetylated histones, and calbindin, a marker for PN. Fluorescent intensities were also measured. Results showed a significant age but not an alcohol-related decrease in the densities of HDACs 2, 3, and 7. In contrast, there were age related-increases in the densities of phosphorylated form of HDAC (4, 5, 7) PN and in PN nuclei expressing HDAC 7. There were also a trend towards ethanol-induced inhibition of acetylation as the density of AH2b PN nuclei and AH3 and AH2b fluorescent intensity was significantly lower in the EF compared to the PF rats. This study presents unique data concerning which HDACs are commonly expressed in PN and indicates that aging rather than lengthy alcohol expression alters expression of the HDACs studied here. These results also suggest that lengthy ethanol consumption may inhibit histone deacetylation in PN.
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38
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Toro TB, Bryant JR, Watt TJ. Lysine Deacetylases Exhibit Distinct Changes in Activity Profiles Due to Fluorophore Conjugation of Substrates. Biochemistry 2017; 56:4549-4558. [PMID: 28749131 PMCID: PMC5937523 DOI: 10.1021/acs.biochem.7b00270] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
Lysine deacetylases (KDACs) are enzymes that reverse the post-translational modification of lysine acetylation. Thousands of potential substrates, acetylated protein sequences, have been identified in mammalian cells. Properly regulated acetylation and deacetylation have been linked to many biological processes, while aberrant KDAC activity has also been linked to numerous diseases. Commercially available peptide substrates that are conjugated to fluorescent dye molecules, such as 7-amino-4-methylcoumarin (AMC), are commonly used to monitor deacetylation in studies addressing both substrate specificity and small molecule modulators of activity. Here, we have compared the activity of several KDACs, representing all major classes of KDACs, with substrates in the presence and absence of AMC as well as peptides for which tryptophan has been substituted for AMC. Our results unequivocally demonstrate that AMC has a significant effect on activity for all KDACs tested. Furthermore, in neither the nature of the effect nor the magnitude is consistent across KDACs, making it impossible to predict the effect of AMC on a particular enzyme-substrate pair. AMC did not affect acetyllysine preference in a multiply acetylated substrate. In contrast, AMC significantly enhanced KDAC6 substrate affinity, greatly reduced Sirt1 activity, eliminated the substrate sequence specificity of KDAC4, and had no consistent effect with KDAC8 substrates. These results indicate that profiling of KDAC activity with labeled peptides is unlikely to produce biologically relevant data.
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Affiliation(s)
- Tasha B. Toro
- Department of Chemistry, Xavier University of Louisiana, New Orleans, Louisiana 70125-1098, United States
| | - Jenae R. Bryant
- Department of Chemistry, Xavier University of Louisiana, New Orleans, Louisiana 70125-1098, United States
| | - Terry J. Watt
- Department of Chemistry, Xavier University of Louisiana, New Orleans, Louisiana 70125-1098, United States
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Laguesse S, Close P, Van Hees L, Chariot A, Malgrange B, Nguyen L. Loss of Elp3 Impairs the Acetylation and Distribution of Connexin-43 in the Developing Cerebral Cortex. Front Cell Neurosci 2017; 11:122. [PMID: 28507509 PMCID: PMC5410572 DOI: 10.3389/fncel.2017.00122] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2017] [Accepted: 04/12/2017] [Indexed: 12/19/2022] Open
Abstract
The Elongator complex is required for proper development of the cerebral cortex. Interfering with its activity in vivo delays the migration of postmitotic projection neurons, at least through a defective α-tubulin acetylation. However, this complex is already expressed by cortical progenitors where it may regulate the early steps of migration by targeting additional proteins. Here we report that connexin-43 (Cx43), which is strongly expressed by cortical progenitors and whose depletion impairs projection neuron migration, requires Elongator expression for its proper acetylation. Indeed, we show that Cx43 acetylation is reduced in the cortex of Elp3cKO embryos, as well as in a neuroblastoma cell line depleted of Elp1 expression, suggesting that Cx43 acetylation requires Elongator in different cellular contexts. Moreover, we show that histones deacetylase 6 (HDAC6) is a deacetylase of Cx43. Finally, we report that acetylation of Cx43 regulates its membrane distribution in apical progenitors of the cerebral cortex.
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Affiliation(s)
- Sophie Laguesse
- GIGA-Neurosciences, University of LiègeLiège, Belgium.,Interdisciplinary Cluster for Applied Genoproteomics (GIGA-R), University of LiègeLiège, Belgium
| | - Pierre Close
- Interdisciplinary Cluster for Applied Genoproteomics (GIGA-R), University of LiègeLiège, Belgium.,GIGA-Molecular Biology of Diseases, University of LiègeLiège, Belgium
| | - Laura Van Hees
- GIGA-Neurosciences, University of LiègeLiège, Belgium.,Interdisciplinary Cluster for Applied Genoproteomics (GIGA-R), University of LiègeLiège, Belgium
| | - Alain Chariot
- Interdisciplinary Cluster for Applied Genoproteomics (GIGA-R), University of LiègeLiège, Belgium.,GIGA-Molecular Biology of Diseases, University of LiègeLiège, Belgium.,Walloon Excellence in Lifesciences and Biotechnology (WELBIO)Wallonia, Belgium
| | - Brigitte Malgrange
- GIGA-Neurosciences, University of LiègeLiège, Belgium.,Interdisciplinary Cluster for Applied Genoproteomics (GIGA-R), University of LiègeLiège, Belgium
| | - Laurent Nguyen
- GIGA-Neurosciences, University of LiègeLiège, Belgium.,Interdisciplinary Cluster for Applied Genoproteomics (GIGA-R), University of LiègeLiège, Belgium
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40
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Angiolilli C, Kabala PA, Grabiec AM, Van Baarsen IM, Ferguson BS, García S, Malvar Fernandez B, McKinsey TA, Tak PP, Fossati G, Mascagni P, Baeten DL, Reedquist KA. Histone deacetylase 3 regulates the inflammatory gene expression programme of rheumatoid arthritis fibroblast-like synoviocytes. Ann Rheum Dis 2017; 76:277-285. [PMID: 27457515 PMCID: PMC5264225 DOI: 10.1136/annrheumdis-2015-209064] [Citation(s) in RCA: 105] [Impact Index Per Article: 13.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2015] [Revised: 03/29/2016] [Accepted: 04/24/2016] [Indexed: 12/12/2022]
Abstract
OBJECTIVES Non-selective histone deacetylase (HDAC) inhibitors (HDACi) have demonstrated anti-inflammatory properties in both in vitro and in vivo models of rheumatoid arthritis (RA). Here, we investigated the potential contribution of specific class I and class IIb HDACs to inflammatory gene expression in RA fibroblast-like synoviocytes (FLS). METHODS RA FLS were incubated with pan-HDACi (ITF2357, givinostat) or selective HDAC1/2i, HDAC3/6i, HDAC6i and HDAC8i. Alternatively, FLS were transfected with HDAC3, HDAC6 or interferon (IFN)-α/β receptor alpha chain (IFNAR1) siRNA. mRNA expression of interleukin (IL)-1β-inducible genes was measured by quantitative PCR (qPCR) array and signalling pathway activation by immunoblotting and DNA-binding assays. RESULTS HDAC3/6i, but not HDAC1/2i and HDAC8i, significantly suppressed the majority of IL-1β-inducible genes targeted by pan-HDACi in RA FLS. Silencing of HDAC3 expression reproduced the effects of HDAC3/6i on gene regulation, contrary to HDAC6-specific inhibition and HDAC6 silencing. Screening of the candidate signal transducers and activators of transcription (STAT)1 transcription factor revealed that HDAC3/6i abrogated STAT1 Tyr701 phosphorylation and DNA binding, but did not affect STAT1 acetylation. HDAC3 activity was required for type I IFN production and subsequent STAT1 activation in FLS. Suppression of type I IFN release by HDAC3/6i resulted in reduced expression of a subset of IFN-dependent genes, including the chemokines CXCL9 and CXCL11. CONCLUSIONS Inhibition of HDAC3 in RA FLS largely recapitulates the effects of pan-HDACi in suppressing inflammatory gene expression, including type I IFN production in RA FLS. Our results identify HDAC3 as a potential therapeutic target in the treatment of RA and type I IFN-driven autoimmune diseases.
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Affiliation(s)
- Chiara Angiolilli
- Department of Experimental Immunology and Department of Clinical Immunology and Rheumatology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands
- Laboratory of Translational Immunology and Department of Rheumatology and Clinical Immunology, University Medical Center Utrecht, Utrecht, The Netherlands
| | - Pawel A Kabala
- Department of Experimental Immunology and Department of Clinical Immunology and Rheumatology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands
- Laboratory of Translational Immunology and Department of Rheumatology and Clinical Immunology, University Medical Center Utrecht, Utrecht, The Netherlands
| | - Aleksander M Grabiec
- Department of Experimental Immunology and Department of Clinical Immunology and Rheumatology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands
- Manchester Collaborative Centre for Inflammation Research, The University of Manchester, Manchester, UK
| | - Iris M Van Baarsen
- Department of Experimental Immunology and Department of Clinical Immunology and Rheumatology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands
| | - Bradley S Ferguson
- Division of Cardiology, Department of Medicine, University of Colorado Denver, Aurora, Colorado, USA
| | - Samuel García
- Department of Experimental Immunology and Department of Clinical Immunology and Rheumatology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands
- Laboratory of Translational Immunology and Department of Rheumatology and Clinical Immunology, University Medical Center Utrecht, Utrecht, The Netherlands
| | - Beatriz Malvar Fernandez
- Department of Experimental Immunology and Department of Clinical Immunology and Rheumatology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands
- Laboratory of Translational Immunology and Department of Rheumatology and Clinical Immunology, University Medical Center Utrecht, Utrecht, The Netherlands
| | - Timothy A McKinsey
- Division of Cardiology, Department of Medicine, University of Colorado Denver, Aurora, Colorado, USA
| | - Paul P Tak
- Department of Experimental Immunology and Department of Clinical Immunology and Rheumatology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands
- GlaxoSmithKline, Stevenage, UK
- Cambridge University, Cambridge, UK
| | | | | | - Dominique L Baeten
- Department of Experimental Immunology and Department of Clinical Immunology and Rheumatology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands
| | - Kris A Reedquist
- Department of Experimental Immunology and Department of Clinical Immunology and Rheumatology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands
- Laboratory of Translational Immunology and Department of Rheumatology and Clinical Immunology, University Medical Center Utrecht, Utrecht, The Netherlands
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41
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Trazzi S, Fuchs C, Viggiano R, De Franceschi M, Valli E, Jedynak P, Hansen FK, Perini G, Rimondini R, Kurz T, Bartesaghi R, Ciani E. HDAC4: a key factor underlying brain developmental alterations in CDKL5 disorder. Hum Mol Genet 2016; 25:3887-3907. [PMID: 27466189 DOI: 10.1093/hmg/ddw231] [Citation(s) in RCA: 65] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2016] [Revised: 07/07/2016] [Accepted: 07/08/2016] [Indexed: 12/12/2022] Open
Abstract
Cyclin-dependent kinase-like 5 (CDKL5) is a Ser/Thr protein kinase predominantly expressed in the brain. Mutations of the CDKL5 gene lead to CDKL5 disorder, a neurodevelopmental pathology that shares several features with Rett Syndrome and is characterized by severe intellectual disability. The phosphorylation targets of CDKL5 are largely unknown, which hampers the discovery of therapeutic strategies for improving the neurological phenotype due to CDKL5 mutations. Here, we show that the histone deacetylase 4 (HDAC4) is a direct phosphorylation target of CDKL5 and that CDKL5-dependent phosphorylation promotes HDAC4 cytoplasmic retention. Nuclear HDAC4 binds to chromatin as well as to MEF2A transcription factor, leading to histone deacetylation and altered neuronal gene expression. By using a Cdkl5 knockout (Cdkl5 -/Y) mouse model, we found that hypophosphorylated HDAC4 translocates to the nucleus of neural precursor cells, thereby reducing histone 3 acetylation. This effect was reverted by re-expression of CDKL5 or by inhibition of HDAC4 activity through the HDAC4 inhibitor LMK235. In Cdkl5 -/Y mice treated with LMK235, defective survival and maturation of neuronal precursor cells and hippocampus-dependent memory were fully normalized. These results demonstrate a critical role of HDAC4 in the neurodevelopmental alterations due to CDKL5 mutations and suggest the possibility of HDAC4-targeted pharmacological interventions.
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Affiliation(s)
- Stefania Trazzi
- Department of Biomedical and Neuromotor Sciences, University of Bologna, Italy
| | - Claudia Fuchs
- Department of Biomedical and Neuromotor Sciences, University of Bologna, Italy
| | - Rocchina Viggiano
- Department of Biomedical and Neuromotor Sciences, University of Bologna, Italy
| | | | - Emanuele Valli
- Department of Pharmacy and Biotechnology, and CIRI Health Sciences and Technologies
| | - Paulina Jedynak
- Department of Biomedical and Neuromotor Sciences, University of Bologna, Italy
| | - Finn K Hansen
- Institut für Pharmazeutische und Medizinische Chemie, Heinrich Heine Universität, Düsseldorf, Germany
| | - Giovanni Perini
- Department of Pharmacy and Biotechnology, and CIRI Health Sciences and Technologies
| | - Roberto Rimondini
- Department of Medical and Clinical Sciences, University of Bologna, Italy
| | - Thomas Kurz
- Institut für Pharmazeutische und Medizinische Chemie, Heinrich Heine Universität, Düsseldorf, Germany
| | - Renata Bartesaghi
- Department of Biomedical and Neuromotor Sciences, University of Bologna, Italy
| | - Elisabetta Ciani
- Department of Biomedical and Neuromotor Sciences, University of Bologna, Italy
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42
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Chang I, Wang CY. Inhibition of HDAC6 Protein Enhances Bortezomib-induced Apoptosis in Head and Neck Squamous Cell Carcinoma (HNSCC) by Reducing Autophagy. J Biol Chem 2016; 291:18199-209. [PMID: 27369083 DOI: 10.1074/jbc.m116.717793] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2016] [Indexed: 12/20/2022] Open
Abstract
Chemoresistance is a major barrier to effective chemotherapy of solid tumors, including head and neck squamous cell carcinoma (HNSCC). Recently, autophagy, a highly conservative intracellular recycling system, has shown to be associated with chemoresistance in cancer cells. However, little is known about how autophagy plays a role in the development of chemoresistance in HNSCC and how autophagy is initiated when HNSCC cells undergo cytotoxic stress. Here, we report that autophagy was activated when HNSCC cells are treated with the proteasome inhibitor bortezomib, proposed as an alternative chemotherapeutic agent for both primary and cisplatin-resistant HNSCC cells. Ablation of histone deacetylase 6 (HDAC6) expression and its activity in HNSCC cells significantly inhibited autophagy induction by altering the phosphorylation status of mammalian target of rapamycin and enhanced the bortezomib cytotoxicity. Similarly, a combination regimen of bortezomib and the histone deacetylase inhibitor trichostatin A abolished HDAC6 activity and decreased autophagy induction while significantly enhancing bortezomib-induced apoptosis in HNSCC cells. These data uncover a novel molecular mechanism indicating that HDAC6 may serve as a critical causal link between autophagy, apoptosis, and the cell survival response in HNSCC. A combination regimen resulting in regression of autophagy improves chemotherapeutic efficacy, thereby providing a new strategy to overcome chemoresistance and to improve the treatment and survival of HNSCC patients.
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Affiliation(s)
- Insoon Chang
- From the Division of Oral Biology and Medicine, UCLA School of Dentistry, Los Angeles, California 90095
| | - Cun-Yu Wang
- From the Division of Oral Biology and Medicine, UCLA School of Dentistry, Los Angeles, California 90095
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43
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Drazic A, Myklebust LM, Ree R, Arnesen T. The world of protein acetylation. BIOCHIMICA ET BIOPHYSICA ACTA-PROTEINS AND PROTEOMICS 2016; 1864:1372-401. [PMID: 27296530 DOI: 10.1016/j.bbapap.2016.06.007] [Citation(s) in RCA: 563] [Impact Index Per Article: 62.6] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Received: 03/01/2016] [Revised: 06/04/2016] [Accepted: 06/08/2016] [Indexed: 12/30/2022]
Abstract
Acetylation is one of the major post-translational protein modifications in the cell, with manifold effects on the protein level as well as on the metabolome level. The acetyl group, donated by the metabolite acetyl-coenzyme A, can be co- or post-translationally attached to either the α-amino group of the N-terminus of proteins or to the ε-amino group of lysine residues. These reactions are catalyzed by various N-terminal and lysine acetyltransferases. In case of lysine acetylation, the reaction is enzymatically reversible via tightly regulated and metabolism-dependent mechanisms. The interplay between acetylation and deacetylation is crucial for many important cellular processes. In recent years, our understanding of protein acetylation has increased significantly by global proteomics analyses and in depth functional studies. This review gives a general overview of protein acetylation and the respective acetyltransferases, and focuses on the regulation of metabolic processes and physiological consequences that come along with protein acetylation.
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Affiliation(s)
- Adrian Drazic
- Department of Molecular Biology, University of Bergen, N-5020 Bergen, Norway
| | - Line M Myklebust
- Department of Molecular Biology, University of Bergen, N-5020 Bergen, Norway
| | - Rasmus Ree
- Department of Molecular Biology, University of Bergen, N-5020 Bergen, Norway; Department of Surgery, Haukeland University Hospital, N-5021 Bergen, Norway
| | - Thomas Arnesen
- Department of Molecular Biology, University of Bergen, N-5020 Bergen, Norway; Department of Surgery, Haukeland University Hospital, N-5021 Bergen, Norway.
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44
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Ozcan L, Ghorpade DS, Zheng Z, de Souza JC, Chen K, Bessler M, Bagloo M, Schrope B, Pestell R, Tabas I. Hepatocyte DACH1 Is Increased in Obesity via Nuclear Exclusion of HDAC4 and Promotes Hepatic Insulin Resistance. Cell Rep 2016; 15:2214-2225. [PMID: 27239042 PMCID: PMC5068925 DOI: 10.1016/j.celrep.2016.05.006] [Citation(s) in RCA: 37] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2015] [Revised: 03/19/2016] [Accepted: 04/24/2016] [Indexed: 01/29/2023] Open
Abstract
Defective insulin signaling in hepatocytes is a key factor in type 2 diabetes. In obesity, activation of calcium/calmodulin-dependent protein kinase II (CaMKII) in hepatocytes suppresses ATF6, which triggers a PERK-ATF4-TRB3 pathway that disrupts insulin signaling. Elucidating how CaMKII suppresses ATF6 is therefore essential to understanding this insulin resistance pathway. We show that CaMKII phosphorylates and blocks nuclear translocation of histone deacetylase 4 (HDAC4). As a result, HDAC4-mediated SUMOylation of the corepressor DACH1 is decreased, which protects DACH1 from proteasomal degradation. DACH1, together with nuclear receptor corepressor (NCOR), represses Atf6 transcription, leading to activation of the PERK-TRB3 pathway and defective insulin signaling. DACH1 is increased in the livers of obese mice and humans, and treatment of obese mice with liver-targeted constitutively nuclear HDAC4 or DACH1 small hairpin RNA (shRNA) increases ATF6, improves hepatocyte insulin signaling, and protects against hyperglycemia and hyperinsulinemia. Thus, DACH1-mediated corepression in hepatocytes emerges as an important link between obesity and insulin resistance.
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Affiliation(s)
- Lale Ozcan
- Department of Medicine, Columbia University, New York, NY 10032, USA.
| | - Devram S Ghorpade
- Department of Medicine, Columbia University, New York, NY 10032, USA
| | - Ze Zheng
- Department of Medicine, Columbia University, New York, NY 10032, USA
| | | | - Ke Chen
- Department of Cancer Biology, Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA 19107, USA
| | - Marc Bessler
- Department of Surgery, Columbia University, New York, NY 10032, USA
| | - Melissa Bagloo
- Department of Surgery, Columbia University, New York, NY 10032, USA
| | - Beth Schrope
- Department of Surgery, Columbia University, New York, NY 10032, USA
| | - Richard Pestell
- Department of Cancer Biology, Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA 19107, USA
| | - Ira Tabas
- Department of Medicine, Columbia University, New York, NY 10032, USA; Department of Physiology and Cellular Biophysics, Columbia University, New York, NY 10032, USA; Department of Pathology and Cell Biology, Columbia University, New York, NY 10032, USA.
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Toro TB, Pingali S, Nguyen TP, Garrett DS, Dodson KA, Nichols KA, Haynes RA, Payton-Stewart F, Watt TJ. KDAC8 with High Basal Velocity Is Not Activated by N-Acetylthioureas. PLoS One 2016; 11:e0146900. [PMID: 26745872 PMCID: PMC4706426 DOI: 10.1371/journal.pone.0146900] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2015] [Accepted: 12/24/2015] [Indexed: 12/04/2022] Open
Abstract
Lysine deacetylases (KDACs) are enzymes that reverse the post-translational modification of lysine acetylation. Recently, a series of N-acetylthioureas were synthesized and reported to enhance the activity of KDAC8 with a fluorogenic substrate. To determine if the activation was general, we synthesized three of the most potent N-acetylthioureas and measured their effect with peptide substrates and the fluorogenic substrate under multiple reaction conditions and utilizing two enzyme purification approaches. No activation was observed for any of the three N-acetylthioureas under any assayed conditions. Further characterization of KDAC8 kinetics with the fluorogenic substrate yielded a kcat/KM of 164 ± 17 in the absence of any N-acetylthioureas. This catalytic efficiency is comparable to or higher than that previously reported when KDAC8 was activated by the N-acetylthioureas, suggesting that the previously reported activation effect may be due to use of an enzyme preparation that contains a large fraction of inactive enzyme. Further characterization with a less active preparation and additional substrates leads us to conclude that N-acetylthioureas are not true activators of KDAC8 and only increase activity if the enzyme preparation is below the maximal basal activity.
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Affiliation(s)
- Tasha B. Toro
- Department of Chemistry, Xavier University of Louisiana, 1 Drexel Dr., New Orleans, Louisiana, United States of America
| | - Subramanya Pingali
- Department of Chemistry, Xavier University of Louisiana, 1 Drexel Dr., New Orleans, Louisiana, United States of America
| | - Thao P. Nguyen
- Department of Chemistry, Xavier University of Louisiana, 1 Drexel Dr., New Orleans, Louisiana, United States of America
| | - Destane S. Garrett
- Department of Chemistry, Xavier University of Louisiana, 1 Drexel Dr., New Orleans, Louisiana, United States of America
| | - Kyra A. Dodson
- Department of Chemistry, Xavier University of Louisiana, 1 Drexel Dr., New Orleans, Louisiana, United States of America
| | - Kyara A. Nichols
- Department of Chemistry, Xavier University of Louisiana, 1 Drexel Dr., New Orleans, Louisiana, United States of America
| | - Rashad A. Haynes
- Department of Chemistry, Xavier University of Louisiana, 1 Drexel Dr., New Orleans, Louisiana, United States of America
| | - Florastina Payton-Stewart
- Department of Chemistry, Xavier University of Louisiana, 1 Drexel Dr., New Orleans, Louisiana, United States of America
| | - Terry J. Watt
- Department of Chemistry, Xavier University of Louisiana, 1 Drexel Dr., New Orleans, Louisiana, United States of America
- * E-mail:
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Target engagement and drug residence time can be observed in living cells with BRET. Nat Commun 2015; 6:10091. [PMID: 26631872 PMCID: PMC4686764 DOI: 10.1038/ncomms10091] [Citation(s) in RCA: 204] [Impact Index Per Article: 20.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2015] [Accepted: 10/30/2015] [Indexed: 12/18/2022] Open
Abstract
The therapeutic action of drugs is predicated on their physical engagement with cellular targets. Here we describe a broadly applicable method using bioluminescence resonance energy transfer (BRET) to reveal the binding characteristics of a drug with selected targets within intact cells. Cell-permeable fluorescent tracers are used in a competitive binding format to quantify drug engagement with the target proteins fused to Nanoluc luciferase. The approach enabled us to profile isozyme-specific engagement and binding kinetics for a panel of histone deacetylase (HDAC) inhibitors. Our analysis was directed particularly to the clinically approved prodrug FK228 (Istodax/Romidepsin) because of its unique and largely unexplained mechanism of sustained intracellular action. Analysis of the binding kinetics by BRET revealed remarkably long intracellular residence times for FK228 at HDAC1, explaining the protracted intracellular behaviour of this prodrug. Our results demonstrate a novel application of BRET for assessing target engagement within the complex milieu of the intracellular environment.
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Toro TB, Watt TJ. KDAC8 substrate specificity quantified by a biologically relevant, label-free deacetylation assay. Protein Sci 2015; 24:2020-32. [PMID: 26402585 DOI: 10.1002/pro.2813] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2015] [Revised: 08/21/2015] [Accepted: 09/20/2015] [Indexed: 01/25/2023]
Abstract
Analysis of the human proteome has identified thousands of unique protein sequences that contain acetylated lysine residues in vivo. These modifications regulate a variety of biological processes and are reversed by the lysine deacetylase (KDAC) family of enzymes. Despite the known prevalence and importance of acetylation, the details of KDAC substrate recognition are not well understood. While several methods have been developed to monitor protein deacetylation, none are particularly suited for identifying enzyme-substrate pairs of label-free substrates across the entire family of lysine deacetylases. Here, we present a fluorescamine-based assay which is more biologically relevant than existing methods and amenable to probing substrate specificity. Using this assay, we evaluated the activity of KDAC8 and other lysine deacetylases, including a sirtuin, for several peptides derived from known acetylated proteins. KDAC8 showed clear preferences for some peptides over others, indicating that the residues immediately surrounding the acetylated lysine play an important role in substrate specificity. Steady-state kinetics suggest that the sequence surrounding the acetylated lysine affects binding affinity and catalytic rate independently. Our results provide direct evidence that potential KDAC8 substrates previously identified through cell based experiments can be directly deacetylated by KDAC8. Conversely, the data from this assay did not correlate well with predictions from previous screens for KDAC8 substrates using less biologically relevant substrates and assay conditions. Combining results from our assay with mass spectrometry-based experiments and cell-based experiments will allow the identification of specific KDAC-substrate pairs and lead to a better understanding of the biological consequences of these interactions.
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Affiliation(s)
- Tasha B Toro
- Department of Chemistry, Xavier University of Louisiana, New Orleans, Louisiana, 70125
| | - Terry J Watt
- Department of Chemistry, Xavier University of Louisiana, New Orleans, Louisiana, 70125
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HDAC1/2-Dependent P0 Expression Maintains Paranodal and Nodal Integrity Independently of Myelin Stability through Interactions with Neurofascins. PLoS Biol 2015; 13:e1002258. [PMID: 26406915 PMCID: PMC4583457 DOI: 10.1371/journal.pbio.1002258] [Citation(s) in RCA: 33] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2015] [Accepted: 08/19/2015] [Indexed: 12/16/2022] Open
Abstract
The pathogenesis of peripheral neuropathies in adults is linked to maintenance mechanisms that are not well understood. Here, we elucidate a novel critical maintenance mechanism for Schwann cell (SC)–axon interaction. Using mouse genetics, ablation of the transcriptional regulators histone deacetylases 1 and 2 (HDAC1/2) in adult SCs severely affected paranodal and nodal integrity and led to demyelination/remyelination. Expression levels of the HDAC1/2 target gene myelin protein zero (P0) were reduced by half, accompanied by altered localization and stability of neurofascin (NFasc)155, NFasc186, and loss of Caspr and septate-like junctions. We identify P0 as a novel binding partner of NFasc155 and NFasc186, both in vivo and by in vitro adhesion assay. Furthermore, we demonstrate that HDAC1/2-dependent P0 expression is crucial for the maintenance of paranodal/nodal integrity and axonal function through interaction of P0 with neurofascins. In addition, we show that the latter mechanism is impaired by some P0 mutations that lead to late onset Charcot-Marie-Tooth disease. The well-studied Schwann cell protein P0 is revealed to have an unsuspected function critical for the stability of paranodes and nodes in adult nerves. This function is specifically impaired by P0 mutations that lead to late-onset forms of Charcot-Marie-Tooth disease. Peripheral nerves consist mainly of axons and Schwann cells, which form myelin sheaths around axons. Peripheral neuropathies primarily affect axons, their myelin, or both. Etiologies are multiple: they can be inherited, autoimmune, infectious, metabolic (e.g., diabetes), or be due to tumors or toxic agents. However, the pathogenesis mechanisms of these disorders are not well understood. Here, we elucidate a novel critical mechanism in peripheral nerves for the stability of two adjacent structures of major importance for axonal function, the paranodes and nodes of Ranvier. We find that disruption of these structures causes a form of peripheral neuropathy. Ablation of the transcriptional regulators histone deacetylases (HDAC)1 and 2 in adult Schwann cells results in motor and sensory dysfunction, disruption of paranodal/nodal integrity, and loss of myelin. Expression of the HDAC1/2 target gene myelin protein zero (P0) was reduced by half, leading to altered localization of paranodal and nodal neurofascins, loss of paranodal Caspr, and impairment of axon–Schwann cell interaction in paranodal/nodal regions. We demonstrate that P0, the most abundant protein of peripheral compact myelin, extends to paranodes/nodes to maintain their stability by binding neurofascins. P0–neurofascins binding is affected by P0 mutations responsible for late onset forms of the inherited peripheral neuropathy Charcot-Marie-Tooth disease, identifying a pathogenesis mechanism of these disorders.
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McConnell MJ, Durand L, Langley E, Coste-Sarguet L, Zelent A, Chomienne C, Kouzarides T, Licht JD, Guidez F. Post transcriptional control of the epigenetic stem cell regulator PLZF by sirtuin and HDAC deacetylases. Epigenetics Chromatin 2015; 8:38. [PMID: 26405459 PMCID: PMC4581162 DOI: 10.1186/s13072-015-0030-8] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2015] [Accepted: 09/14/2015] [Indexed: 01/09/2023] Open
Abstract
BACKGROUND The transcriptional repressor promyelocytic leukemia zinc finger protein (PLZF) is critical for the regulation of normal stem cells maintenance by establishing specific epigenetic landscape. We have previously shown that CBP/p300 acetyltransferase induces PLZF acetylation in order to increase its deoxynucleotidic acid (DNA) binding activity and to enhance its epigenetic function (repression of PLZF target genes). However, how PLZF is inactivated is not yet understood. RESULTS In this study, we demonstrate that PLZF is deacetylated by both histone deacetylase 3 and the NAD+ dependent deacetylase silent mating type information regulation 2 homolog 1 (SIRT1). Unlike other PLZF-interacting deacetylases, these two proteins interact with the zinc finger domain of PLZF, where the activating CBP/p300 acetylation site was previously described, inducing deacetylation of lysines 647/650/653. Overexpression of histone deacetylase 3 (HDAC3) and SIRT1 is associated with loss of PLZF DNA binding activity and decreases PLZF transcriptional repression. As a result, the chromatin status of the promoters of PLZF target genes, involved in oncogenesis, shift from a heterochromatin to an open euchromatin environment leading to gene expression even in the presence of PLZF. CONCLUSIONS Consequently, SIRT1 and HDAC3 mediated-PLZF deacetylation provides for rapid control and fine-tuning of PLZF activity through post-transcriptional modification to regulate gene expression and cellular homeostasis.
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Affiliation(s)
- Melanie J. McConnell
- />Malaghan Institute for Medical Research, P.O. Box 7060, Wellington, New Zealand
- />Division of Hematology/Oncology, Mount Sinai School of Medicine, New York, NY 10029 USA
| | - Laetitia Durand
- />INSERM UMRS-1131, Institut universitaire d’Hématologie, Université Paris Diderot, 1 avenue Claude Vellefaux, hôpital Saint-Louis, 75010 Paris, France
| | - Emma Langley
- />Wellcome Institute/Cancer Research UK, Department of Pathology, University of Cambridge, Tennis Court Road, Cambridge, CB2 1QR UK
- />Biogen Idec, San Diego, CA 92122 USA
| | - Lise Coste-Sarguet
- />INSERM UMRS-1131, Institut universitaire d’Hématologie, Université Paris Diderot, 1 avenue Claude Vellefaux, hôpital Saint-Louis, 75010 Paris, France
| | - Arthur Zelent
- />Division of Hemato-oncology, Miller School of Medicine, Miami, FL 33136 USA
| | - Christine Chomienne
- />INSERM UMRS-1131, Institut universitaire d’Hématologie, Université Paris Diderot, 1 avenue Claude Vellefaux, hôpital Saint-Louis, 75010 Paris, France
| | - Tony Kouzarides
- />Wellcome Institute/Cancer Research UK, Department of Pathology, University of Cambridge, Tennis Court Road, Cambridge, CB2 1QR UK
| | - Jonathan D. Licht
- />Division of Hematology/Oncology, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611 USA
- />Division of Hematology/Oncology, Mount Sinai School of Medicine, New York, NY 10029 USA
| | - Fabien Guidez
- />INSERM UMRS-1131, Institut universitaire d’Hématologie, Université Paris Diderot, 1 avenue Claude Vellefaux, hôpital Saint-Louis, 75010 Paris, France
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Pinto G, Shtaif B, Phillip M, Gat-Yablonski G. Growth attenuation is associated with histone deacetylase 10-induced autophagy in the liver. J Nutr Biochem 2015; 27:171-80. [PMID: 26462881 DOI: 10.1016/j.jnutbio.2015.08.031] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2015] [Revised: 08/26/2015] [Accepted: 08/26/2015] [Indexed: 11/26/2022]
Abstract
Our previous data suggested that the histone deacetylase (HDAC) SIRT1 is involved in mediating the effect of nutrition on growth. The aim of the present research was to study the mechanism by which additional HDACs may be involved in nutrition-induced linear growth. The in vivo studies were performed in young male Sprague-Dawley rats that were either fed ad libitum (AL) or subjected to 10days of 40% food restriction (RES) and then refed (CU). For in vitro studies, Huh7 hepatoma cells were used. Food restriction led to significant reduction in liver weight, concomitant with increased autophagy (i.e., a decrease in the level of P62 and an increase in the expression level of Ambra1 and Atg16L2 genes in the RES group). At the same time, we found that the level of HDAC10 was significantly increased. Overexpression of HDAC10 in Huh7 hepatoma cells led to reduced cell viability and increased autophagy as shown by increased conversion of LC3-I to LC3-II. An increase in the level of HDAC10 was also obtained when mTOR was inhibited by Rapamycin. siRNA directed against HDAC10 abolished the effect of Rapamycin on cell viability and Ambra1 and Atg16L2 increased expression. These results suggest that increased levels of HDAC10 may mediate the effect of malnutrition on growth attenuation and autophagy. Deciphering the role of epigenetic regulation in the nutrition-growth connection may pave the way for the development of new forms of treatment for children with growth disorders.
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Affiliation(s)
- Galit Pinto
- Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel; Felsenstein Medical Research Center, Petach Tikva, Israel.
| | - Biana Shtaif
- Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel; Felsenstein Medical Research Center, Petach Tikva, Israel.
| | - Moshe Phillip
- Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel; Felsenstein Medical Research Center, Petach Tikva, Israel; The Jesse Z and Sara Lea Shafer Institute for Endocrinology and Diabetes, National Center for Childhood Diabetes, Schneider Children's Medical Center of Israel, Petach Tikva, Israel.
| | - Galia Gat-Yablonski
- Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel; Felsenstein Medical Research Center, Petach Tikva, Israel; The Jesse Z and Sara Lea Shafer Institute for Endocrinology and Diabetes, National Center for Childhood Diabetes, Schneider Children's Medical Center of Israel, Petach Tikva, Israel.
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