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      Targeted inhibition of histone deacetylase 6 in inflammatory diseases

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          Abstract

          Targeting epigenetic modification of gene expression represents a promising new approach under investigation for the treatment of inflammatory diseases. Accumulating evidence suggests that epigenetic mechanisms, such as histone modification, play a crucial role in a number of inflammatory diseases, including rheumatoid arthritis, asthma, and contact hypersensitivity. Consistent with this role, histone deacetylase (HDAC) inhibitors have shown efficacy in the treatment of inflammatory diseases. In particular, selective inhibitors of HDAC6, a cytoplasmic member of the HDAC family that contains two deacetylase domains, are under investigation as a potential treatment strategy for inflammatory diseases due to their ability to regulate inflammatory cells and cytokines. Here, we review recent findings highlighting the critical roles of HDAC6 in a variety of inflammatory diseases, and discuss the therapeutic potential of HDAC6 inhibitors in these settings.

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          Most cited references65

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          Origin and physiological roles of inflammation.

          Inflammation underlies a wide variety of physiological and pathological processes. Although the pathological aspects of many types of inflammation are well appreciated, their physiological functions are mostly unknown. The classic instigators of inflammation - infection and tissue injury - are at one end of a large range of adverse conditions that induce inflammation, and they trigger the recruitment of leukocytes and plasma proteins to the affected tissue site. Tissue stress or malfunction similarly induces an adaptive response, which is referred to here as para-inflammation. This response relies mainly on tissue-resident macrophages and is intermediate between the basal homeostatic state and a classic inflammatory response. Para-inflammation is probably responsible for the chronic inflammatory conditions that are associated with modern human diseases.
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            HDAC6 modulates cell motility by altering the acetylation level of cortactin.

            Histone deacetylase 6 (HDAC6) is a tubulin-specific deacetylase that regulates microtubule-dependent cell movement. In this study, we identify the F-actin-binding protein cortactin as a HDAC6 substrate. We demonstrate that HDAC6 binds cortactin and that overexpression of HDAC6 leads to hypoacetylation of cortactin, whereas inhibition of HDAC6 activity leads to cortactin hyperacetylation. HDAC6 alters the ability of cortactin to bind F-actin by modulating a "charge patch" in its repeat region. Introduction of charge-preserving or charge-neutralizing mutations in this cortactin repeat region correlates with the gain or loss of F-actin binding ability, respectively. Cells expressing a charge-neutralizing cortactin mutant were less motile than control cells or cells expressing a charge-preserving mutant. These findings suggest that, in addition to its role in microtubule-dependent cell motility, HDAC6 influences actin-dependent cell motility by altering the acetylation status of cortactin, which, in turn, changes the F-actin binding activity of cortactin.
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              HDAC6, at the crossroads between cytoskeleton and cell signaling by acetylation and ubiquitination.

              Histone deacetylase 6 (HDAC6) is a unique enzyme with specific structural and functional features. It is actively or stably maintained in the cytoplasm and is the only member, within the histone deacetylase family, that harbors a full duplication of its deacetylase homology region followed by a specific ubiquitin-binding domain at the C-terminus end. Accordingly, this deacetylase functions at the heart of a cellular regulatory mechanism capable of coordinating various cellular functions largely relying on the microtubule network. Moreover, HDAC6 action as a regulator of the HSP90 chaperone activity adds to the multifunctionality of the protein, and allows us to propose a critical role for HDAC6 in mediating and coordinating various cellular events in response to different stressful stimuli.
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                Author and article information

                Contributors
                jran@sdnu.edu.cn
                Journal
                Thorac Cancer
                Thorac Cancer
                10.1111/(ISSN)1759-7714
                TCA
                Thoracic Cancer
                John Wiley & Sons Australia, Ltd (Melbourne )
                1759-7706
                1759-7714
                21 January 2019
                March 2019
                : 10
                : 3 ( doiID: 10.1111/tca.2019.10.issue-3 )
                : 405-412
                Affiliations
                [ 1 ] Shandong Provincial Key Laboratory of Animal Resistance Biology Institute of Biomedical Sciences, College of Life Sciences, Shandong Normal University Jinan China
                Author notes
                [*] [* ] Correspondence

                Jie Ran, College of Life Sciences, Shandong Normal University, Jinan 250014, China.

                Tel: +86 531 8618 2516

                Fax: +86 531 8618 2518

                Email: jran@ 123456sdnu.edu.cn

                Author information
                https://orcid.org/0000-0002-0744-7126
                Article
                TCA12974
                10.1111/1759-7714.12974
                6397899
                30666796
                6c472e57-00ed-4531-b543-efca1d07dee5
                © 2019 The Authors. Thoracic Cancer published by China Lung Oncology Group and John Wiley & Sons Australia, Ltd

                This is an open access article under the terms of the http://creativecommons.org/licenses/by-nc/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.

                History
                : 03 December 2018
                : 22 December 2018
                : 22 December 2018
                Page count
                Figures: 2, Tables: 1, Pages: 8, Words: 5780
                Funding
                Funded by: National Natural Science Foundation of China
                Award ID: 31701169
                Funded by: China Postdoctoral Science Foundation
                Award ID: 2016M600552
                Categories
                Mini Review
                Mini Reviews
                Custom metadata
                2.0
                tca12974
                March 2019
                Converter:WILEY_ML3GV2_TO_NLMPMC version:5.6.1 mode:remove_FC converted:04.03.2019

                cytokine,histone deacetylase,histone deacetylase inhibitor,inflammatory cell,inflammatory disease

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