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Histone Deacetylase Inhibitors in Health and Disease

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Biochemistry".

Deadline for manuscript submissions: closed (31 January 2019) | Viewed by 135268

Special Issue Editors

Department of Biochemistry, Faculty of Science, Charles University, Albertov 2030, CZ-12843 Prague 2, Czech Republic
Interests: biochemistry of carcinogenesis; xenobiochemistry; anticancer drugs; DNA-damaging drugs; epigenetic regulation; drug metabolism; drug targeting
Department of Pharmacology and Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, Taipei 110, Taiwan
Interests: neuroinflammation; retinopathies; epigenetic regulations; microglia; inflammatory mediators; cell signaling; pharmacology
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Alteration of the histone proteins associated with DNA is a crucial process in the epigenetic regulation of DNA structure and function. Such epigenetic modifications, which play a fundamental role in human development, are also relevant for the initiation and progression of complex degenerative diseases and cancer. Histone deacetylases (HDACs) catalyze deacetylation of lysine residues leading to changes in expression of genes encoded by DNA linked to the histone molecule. HDAC inhibitors (HDACi) that consecutively regulate the activity of HDACs, have been extensively researched as therapeutics in psychiatry and neurology, in which a number of adverse outcomes are associated with aberrant HDAC function. Furthermore, HDACi have shown potential for the treatment of cardiac, neurodegenerative and inflammatory lung diseases. On the other hand, increased HDAC activity and expression was found in the development of different cancers, HDACi have also been shown to serve in, and have been approved for, potential cancer treatments, either on their own or in combination with other therapies, such as chemotherapy drugs. The mechanisms of action of HDAC inhibitors are based on changed gene expression and on alterations of histone or non-histone protein molecules through modulation of epigenetic and post-translational modifications, respectively. The shift to an enhanced acetylation/deacetylation status in a variety of tumors due to HDAC inhibition can result in modified gene expression, alteration of cell signaling processes, and can influence the proteasome system, activities of some protein kinases, as well as DNA demethylation. As a result, several biological processes, such as cell cycle arrest or apoptosis, are modified. In addition, HDAC inhibitors have antiangiogenic effects or can influence some cell signaling pathways, having a wide spectrum of effects. These findings indicate that HDACi play a crucial role, both in physiological development and the progression of many human diseases.

In this context, we would like to invite review and original articles that focus on understanding HDACi function in health and disease, especially in human cancer. In addition, articles associated with model disease systems, drug resistance, and therapy are requested for this Special Issue.

Prof. Dr. Marie Stiborova
Prof. Dr. George Hsiao
Guest Editors

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Keywords

  • Epigenetic regulations
  • Histone modifications
  • Deacetylases of histone lysines
  • Histone deacetylases as chromatin modifying enzymes
  • Histone deacetylase inhibitors
  • Role of histone deacetylase inhibitors in cancer, neurological diseases and immune disorders
  • Histone deacetylase inhibitors in human therapy

Published Papers (26 papers)

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Research

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7 pages, 881 KiB  
Communication
A Tiny Change Makes a Big Difference in the Anti-Parasitic Activities of an HDAC Inhibitor
by Corinne Loeuillet, Bastien Touquet, Jean François Guichou, Gilles Labesse and Denis Sereno
Int. J. Mol. Sci. 2019, 20(12), 2973; https://doi.org/10.3390/ijms20122973 - 18 Jun 2019
Cited by 9 | Viewed by 2871
Abstract
We previously synthesized an hydroxamate derivative (N-hydroxy-4-[2-(3- methoxyphenyl)acetamido]benzamide) named 363 with potent anti-Toxoplasma gondii activity and histone deacetylase inhibitor (HDACi) effects. Here we show that 1-N-hydroxy-4-N- [(2-methoxyphenyl)methyl]benzene-1,4-dicarboxamide, a 363 isomer, does not have antiparasitic potency and has a 13-fold decrease in HDACi [...] Read more.
We previously synthesized an hydroxamate derivative (N-hydroxy-4-[2-(3- methoxyphenyl)acetamido]benzamide) named 363 with potent anti-Toxoplasma gondii activity and histone deacetylase inhibitor (HDACi) effects. Here we show that 1-N-hydroxy-4-N- [(2-methoxyphenyl)methyl]benzene-1,4-dicarboxamide, a 363 isomer, does not have antiparasitic potency and has a 13-fold decrease in HDACi activity. The in silico modeling of T. gondii HDACs of the type II strain discloses identity varying from 25% to 62% on more than 250 residues for S8EP32_TOXG and A0A125YPH4_TOXGM. We observed a high conservation degree with the human HDAC2 (53% and 64% identity, respectively) and a moderate one with the human HDAC8 (30–40%). Two other TgHDACs, S8F6L4_TOXGM and S8GEI3_TOXGM, were identified as displaying a higher similarity with some bacterial orthologs (~35%) than with the human enzymes (~25%). The docking in parallel of the two compounds on the models generated allowed us to gain insights on the docking of these hydroxamate derivatives that guide their specificity and potency against T. gondii histone deacetylase. This information would constitute the rationale from which more specific derivatives can be synthetized. Full article
(This article belongs to the Special Issue Histone Deacetylase Inhibitors in Health and Disease)
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21 pages, 3528 KiB  
Article
Cellular Effects of Butyrate on Vascular Smooth Muscle Cells are Mediated through Disparate Actions on Dual Targets, Histone Deacetylase (HDAC) Activity and PI3K/Akt Signaling Network
by Omana P. Mathew, Kasturi Ranganna, Joseph Mathew, Meiling Zhu, Zivar Yousefipour, Chelliah Selvam and Shirlette G. Milton
Int. J. Mol. Sci. 2019, 20(12), 2902; https://doi.org/10.3390/ijms20122902 - 14 Jun 2019
Cited by 31 | Viewed by 4051
Abstract
Vascular remodeling is a characteristic feature of cardiovascular diseases. Altered cellular processes of vascular smooth muscle cells (VSMCs) is a crucial component in vascular remodeling. Histone deacetylase inhibitor (HDACI), butyrate, arrests VSMC proliferation and promotes cell growth. The objective of the study is [...] Read more.
Vascular remodeling is a characteristic feature of cardiovascular diseases. Altered cellular processes of vascular smooth muscle cells (VSMCs) is a crucial component in vascular remodeling. Histone deacetylase inhibitor (HDACI), butyrate, arrests VSMC proliferation and promotes cell growth. The objective of the study is to determine the mechanism of butyrate-induced VSMC growth. Using proliferating VSMCs exposed to 5 mM butyrate, immunoblotting studies are performed to determine whether PI3K/Akt pathway that regulates different cellular effects is a target of butyrate-induced VSMC growth. Butyrate inhibits phosphorylation-dependent activation of PI3K, PDK1, and Akt, eliciting differential effects on downstream targets of Akt. Along with previously reported Ser9 phosphorylation-mediated GSK3 inactivation leading to stability, increased expression and accumulation of cyclin D1, and epigenetic histone modifications, inactivation of Akt by butyrate results in: transcriptional activation of FOXO1 and FOXO3 promoting G1 arrest through p21Cip1/Waf1 and p15INK4B upregulation; inactivation of mTOR inhibiting activation of its targets p70S6K and 4E-BP1 impeding protein synthesis; inhibition of caspase 3 cleavage and downregulation of PARP preventing apoptosis. Our findings imply butyrate abrogates Akt activation, causing differential effects on Akt targets promoting convergence of cross-talk between their complimentary actions leading to VSMC growth by arresting proliferation and inhibiting apoptosis through its effect on dual targets, HDAC activity and PI3K/Akt pathway network. Full article
(This article belongs to the Special Issue Histone Deacetylase Inhibitors in Health and Disease)
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12 pages, 1315 KiB  
Article
The Histone Deacetylase Inhibitor Suberoylanilide Hydroxamic Acid (SAHA) Restores Cardiomyocyte Contractility in a Rat Model of Early Diabetes
by Leonardo Bocchi, Benedetta M. Motta, Monia Savi, Rocchina Vilella, Viviana Meraviglia, Federica Rizzi, Serena Galati, Annamaria Buschini, Mirca Lazzaretti, Peter P. Pramstaller, Alessandra Rossini and Donatella Stilli
Int. J. Mol. Sci. 2019, 20(8), 1873; https://doi.org/10.3390/ijms20081873 - 16 Apr 2019
Cited by 14 | Viewed by 3844
Abstract
In early diabetes, hyperglycemia and the associated metabolic dysregulation promote early changes in the functional properties of cardiomyocytes, progressively leading to the appearance of the diabetic cardiomyopathy phenotype. Recently, the interplay between histone acetyltransferases (HAT) and histone deacetylases (HDAC) has emerged as a [...] Read more.
In early diabetes, hyperglycemia and the associated metabolic dysregulation promote early changes in the functional properties of cardiomyocytes, progressively leading to the appearance of the diabetic cardiomyopathy phenotype. Recently, the interplay between histone acetyltransferases (HAT) and histone deacetylases (HDAC) has emerged as a crucial factor in the development of cardiac disorders. The present study evaluates whether HDAC inhibition can prevent the development of cardiomyocyte contractile dysfunction induced by a short period of hyperglycemia, with focus on the potential underlying mechanisms. Cell contractility and calcium dynamics were measured in unloaded ventricular myocytes isolated from the heart of control and diabetic rats. Cardiomyocytes were either untreated or exposed to the pan-HDAC inhibitor suberoylanilide hydroxamic acid (SAHA) for 90 min. Then, a fraction of each group of cells was used to evaluate the expression levels of proteins involved in the excitation–contraction coupling, and the cardiomyocyte metabolic activity, ATP content, and reactive oxygen species levels. SAHA treatment was able to counteract the initial functional derangement in cardiomyocytes by reducing cell oxidative damage. These findings suggest that early HDAC inhibition could be a promising adjuvant approach for preventing diabetes-induced cardiomyocyte oxidative damage, which triggers the pro-inflammatory signal cascade, mitochondrial damage, and ventricular dysfunction. Full article
(This article belongs to the Special Issue Histone Deacetylase Inhibitors in Health and Disease)
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15 pages, 2265 KiB  
Article
Hydroxamic Acid-Based Histone Deacetylase (HDAC) Inhibitors Bearing a Pyrazole Scaffold and a Cinnamoyl Linker
by Chiara Zagni, Andrea Citarella, Mahjoub Oussama, Antonio Rescifina, Alessandro Maugeri, Michele Navarra, Angela Scala, Anna Piperno and Nicola Micale
Int. J. Mol. Sci. 2019, 20(4), 945; https://doi.org/10.3390/ijms20040945 - 21 Feb 2019
Cited by 23 | Viewed by 5357
Abstract
Genetic abnormalities have been conventionally considered as hallmarks of cancer. However, recent studies have demonstrated that epigenetic mechanisms are also implicated in the insurgence and development of cancer. Patterns of the epigenetic component include DNA methylation and histone modifications. Acetylation of histones is [...] Read more.
Genetic abnormalities have been conventionally considered as hallmarks of cancer. However, recent studies have demonstrated that epigenetic mechanisms are also implicated in the insurgence and development of cancer. Patterns of the epigenetic component include DNA methylation and histone modifications. Acetylation of histones is controlled by histone acetyltransferases (HATs) and histone deacetylases (HDACs). Imbalance of these two enzymatic systems is known to be a key factor in tumor progression. Because HDACs have been found to function incorrectly in cancer, various HDAC inhibitors (HDACIs) are being investigated to act as cancer chemotherapeutics. Herein, we report the synthesis, docking studies and biological activity of a series of hydroxamic acid-based HDACIs bearing an N1-aryl or N1-H pyrazole nucleus as surface recognition motif and a cinnamoyl group as a linker to the hydroxamic acid zinc-binding group (ZBG). Some of the tested compounds exhibited inhibitory properties towards HDACs and antiproliferative activity against neuroblastoma SH-SY5Y tumor cell line both at micromolar concentrations. Full article
(This article belongs to the Special Issue Histone Deacetylase Inhibitors in Health and Disease)
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14 pages, 5499 KiB  
Article
Cytotoxic Activity of the Histone Deacetylase 3-Selective Inhibitor Pojamide on MDA-MB-231 Triple-Negative Breast Cancer Cells
by Claudio Luparello, Dalia Maria Lucia Asaro, Ilenia Cruciata, Storm Hassell-Hart, Supojjanee Sansook, John Spencer and Fabio Caradonna
Int. J. Mol. Sci. 2019, 20(4), 804; https://doi.org/10.3390/ijms20040804 - 13 Feb 2019
Cited by 15 | Viewed by 3398
Abstract
We examined the effects of the ferrocene-based histone deacetylase-3 inhibitor Pojamide (N1-(2-aminophenyl)-N8-ferrocenyloctanediamide) and its two derivatives N1-(2-aminophenyl)-N6-ferrocenyladipamide and N1-(2-aminophenyl)-N8-ferroceniumoctanediamide tetrafluoroborate on triple-negative MDA-MB-231 breast cancer cells. Viability/growth [...] Read more.
We examined the effects of the ferrocene-based histone deacetylase-3 inhibitor Pojamide (N1-(2-aminophenyl)-N8-ferrocenyloctanediamide) and its two derivatives N1-(2-aminophenyl)-N6-ferrocenyladipamide and N1-(2-aminophenyl)-N8-ferroceniumoctanediamide tetrafluoroborate on triple-negative MDA-MB-231 breast cancer cells. Viability/growth assays indicated that only the first two compounds at 70 μM concentration caused an approximate halving of cell number after 24 h of exposure, whereas the tetrafluoroborate derivative exerted no effect on cell survival nor proliferation. Flow cytometric and protein blot analyses were performed on cells exposed to both Pojamide and the ferrocenyladipamide derivative to evaluate cell cycle distribution, apoptosis/autophagy modulation, and mitochondrial metabolic state in order to assess the cellular basis of the cytotoxic effect. The data obtained show that the cytotoxic effect of the two deacetylase inhibitors may be ascribed to the onset of non-apoptotic cell death conceivably linked to a down-regulation of autophagic processes and an impairment of mitochondrial function with an increase in intracellular reactive oxygen species. Our work expands the list of autophagy-regulating drugs and also provides a further example of the role played by the inhibition of autophagy in breast cancer cell death. Moreover, the compounds studied may represent attractive and promising targets for subsequent molecular modeling for anti-neoplastic agents in malignant breast cancer. Full article
(This article belongs to the Special Issue Histone Deacetylase Inhibitors in Health and Disease)
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15 pages, 2572 KiB  
Article
The Histone Deacetylase Inhibitor AN7, Attenuates Choroidal Neovascularization in a Mouse Model
by Mor Dahbash, Ruti Sella, Elinor Megiddo-Barnir, Yael Nisgav, Nataly Tarasenko, Dov Weinberger, Ada Rephaeli and Tami Livnat
Int. J. Mol. Sci. 2019, 20(3), 714; https://doi.org/10.3390/ijms20030714 - 07 Feb 2019
Cited by 8 | Viewed by 3355
Abstract
Choroidal neovascularization (CNV) is a complication of age-related macular degeneration and a major contributing factor to vision loss. In this paper, we show that in a mouse model of laser-induced CNV, systemic administration of Butyroyloxymethyl-diethyl phosphate (AN7), a histone deacetylase inhibitor (HDACi), significantly [...] Read more.
Choroidal neovascularization (CNV) is a complication of age-related macular degeneration and a major contributing factor to vision loss. In this paper, we show that in a mouse model of laser-induced CNV, systemic administration of Butyroyloxymethyl-diethyl phosphate (AN7), a histone deacetylase inhibitor (HDACi), significantly reduced CNV area and vascular leakage, as measured by choroidal flatmounts and fluorescein angiography. CNV area reduction by systemic AN7 treatment was similar to that achieved by intravitreal bevacizumab treatment. The expression of vascular endothelial growth factor (VEGF), fibroblast growth factor (FGF-2), and the endothelial cells marker CD31, was lower in the AN7 treated group in comparison to the control group at the laser lesion site. In vitro, AN7 facilitated retinal pigmented epithelium (RPE) cells tight junctions’ integrity during hypoxia, by protecting the hexagonal pattern of ZO-1 protein in the cell borders, hence reducing RPE permeability. In conclusion, systemic AN7 should be further investigated as a possible effective treatment for CNV. Full article
(This article belongs to the Special Issue Histone Deacetylase Inhibitors in Health and Disease)
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20 pages, 3015 KiB  
Article
HDAC8 Inhibitor WK2-16 Therapeutically Targets Lipopolysaccharide-Induced Mouse Model of Neuroinflammation and Microglial Activation
by Fan-Li Lin, Jing-Lun Yen, Yu-Cheng Kuo, Jaw-Jou Kang, Yu-Wen Cheng, Wei-Jan Huang and George Hsiao
Int. J. Mol. Sci. 2019, 20(2), 410; https://doi.org/10.3390/ijms20020410 - 18 Jan 2019
Cited by 19 | Viewed by 5103
Abstract
Glial activation and neuroinflammatory processes play important roles in the pathogenesis of brain abscess and neurodegenerative diseases. Activated glial cells can secrete various proinflammatory cytokines and neurotoxic mediators, which contribute to the exacerbation of neuronal cell death. The inhibition of glial activation has [...] Read more.
Glial activation and neuroinflammatory processes play important roles in the pathogenesis of brain abscess and neurodegenerative diseases. Activated glial cells can secrete various proinflammatory cytokines and neurotoxic mediators, which contribute to the exacerbation of neuronal cell death. The inhibition of glial activation has been shown to alleviate neurodegenerative conditions. The present study was to investigate the specific HDAC8 inhibitor WK2-16, especially its effects on the neuroinflammatory responses through glial inactivation. WK2-16 significantly reduced the gelatinolytic activity of MMP-9, and expression of COX-2/iNOS proteins in striatal lipopolysaccharide (LPS)-induced neuroinflammation in C57BL/6 mice. The treatment of WK2-16 markedly improved neurobehavioral deficits. Immunofluorescent staining revealed that WK2-16 reduced LPS-stimulated astrogliosis and microglial activation in situ. Consistently, cellular studies revealed that WK2-16 significantly suppressed LPS-induced mouse microglia BV-2 cell proliferation. WK2-16 was proven to concentration-dependently induce the levels of acetylated SMC3 in microglial BV-2 cells. It also reduced the expression of COX-2/iNOS proteins and TNF-α production in LPS-activated microglial BV-2 cells. The signaling studies demonstrated that WK2-16 markedly inhibited LPS-activated STAT-1/-3 and Akt activation, but not NF-κB or MAPK signaling. In summary, the HDAC8 inhibitor WK2-16 exhibited neuroprotective effects through its anti-neuroinflammation and glial inactivation properties, especially in microglia in vitro and in vivo. Full article
(This article belongs to the Special Issue Histone Deacetylase Inhibitors in Health and Disease)
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17 pages, 5766 KiB  
Article
Butyrate Stimulates Histone H3 Acetylation, 8-Isoprostane Production, RANKL Expression, and Regulated Osteoprotegerin Expression/Secretion in MG-63 Osteoblastic Cells
by Mei-Chi Chang, Yunn-Jy Chen, Yun-Chia Lian, Bei-En Chang, Chih-Chia Huang, Wei-Ling Huang, Yu-Hwa Pan and Jiiang-Huei Jeng
Int. J. Mol. Sci. 2018, 19(12), 4071; https://doi.org/10.3390/ijms19124071 - 17 Dec 2018
Cited by 33 | Viewed by 4496
Abstract
Butyric acid as a histone deacetylase (HDAC) inhibitor is produced by a number of periodontal and root canal microorganisms (such as Porphyromonas, Fusobacterium, etc.). Butyric acid may affect the biological activities of periodontal/periapical cells such as osteoblasts, periodontal ligament cells, etc., [...] Read more.
Butyric acid as a histone deacetylase (HDAC) inhibitor is produced by a number of periodontal and root canal microorganisms (such as Porphyromonas, Fusobacterium, etc.). Butyric acid may affect the biological activities of periodontal/periapical cells such as osteoblasts, periodontal ligament cells, etc., and thus affect periodontal/periapical tissue destruction and healing. The purposes of this study were to study the toxic effects of butyrate on the matrix and mineralization marker expression in MG-63 osteoblasts. Cell viability was determined by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) assay. Cellular apoptosis and necrosis were analyzed by propidium iodide/annexin V flow cytometry. The protein and mRNA expression of osteoprotegerin (OPG) and receptor activator of nuclear factor kappa-B ligand (RANKL) were analyzed by Western blotting and reverse transcriptase-polymerase chain reaction (RT-PCR). OPG, soluble RANKL (sRANKL), 8-isoprostane, pro-collagen I, matrix metalloproteinase-2 (MMP-2), osteonectin (SPARC), osteocalcin and osteopontin (OPN) secretion into culture medium were measured by enzyme-linked immunosorbant assay. Alkaline phosphatase (ALP) activity was checked by ALP staining. Histone H3 acetylation levels were evaluated by immunofluorescent staining (IF) and Western blot. We found that butyrate activated the histone H3 acetylation of MG-63 cells. Exposure of MG-63 cells to butyrate partly decreased cell viability with no marked increase in apoptosis and necrosis. Twenty-four hours of exposure to butyrate stimulated RANKL protein expression, whereas it inhibited OPG protein expression. Butyrate also inhibited the secretion of OPG in MG-63 cells, whereas the sRANKL level was below the detection limit. However, 3 days of exposure to butyrate (1 to 8 mM) or other HDAC inhibitors such as phenylbutyrate, valproic acid and trichostatin stimulated OPG secretion. Butyrate stimulated 8-isoprostane, MMP-2 and OPN secretion, but not procollagen I, or osteocalcin in MG-63 cells. Exposure to butyrate (2–4 mM) for 3 days markedly stimulated osteonectin secretion and ALP activity. In conclusion, higher concentrations of butyric acid generated by periodontal and root canal microorganisms may potentially induce bone destruction and impair bone repair by the alteration of OPG/RANKL expression/secretion, 8-isoprostane, MMP-2 and OPN secretion, and affect cell viability. However, lower concentrations of butyrate (1–4 mM) may stimulate ALP, osteonectin and OPG. These effects are possibly related to increased histone acetylation. These events are important in the pathogenesis and repair of periodontal and periapical destruction. Full article
(This article belongs to the Special Issue Histone Deacetylase Inhibitors in Health and Disease)
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17 pages, 4805 KiB  
Article
Repression of Transcriptional Activity of Forkhead Box O1 by Histone Deacetylase Inhibitors Ameliorates Hyperglycemia in Type 2 Diabetic Rats
by Hyun Min Cho, Young Mi Seok, Hae Ahm Lee, Minji Song and InKyeom Kim
Int. J. Mol. Sci. 2018, 19(11), 3539; https://doi.org/10.3390/ijms19113539 - 09 Nov 2018
Cited by 13 | Viewed by 3836
Abstract
Type 2 diabetes mellitus (T2DM) is a chronic disease manifested by hyperglycemia. It is essential to effectively control hyperglycemia to prevent complications of T2DM. Here, we hypothesize that repression of transcriptional activity of forkhead box O1 (FoxO1) via histone deacetylase inhibitors (HDACi) ameliorates [...] Read more.
Type 2 diabetes mellitus (T2DM) is a chronic disease manifested by hyperglycemia. It is essential to effectively control hyperglycemia to prevent complications of T2DM. Here, we hypothesize that repression of transcriptional activity of forkhead box O1 (FoxO1) via histone deacetylase inhibitors (HDACi) ameliorates hyperglycemia in T2DM rats. Methods: Male Long-Evans Tokushima Otsuka (LETO) and Otsuka Long-Evans Tokushima Fatty (OLETF) rats aged 14 weeks were administered sodium valproate (VPA, 0.71% w/v) dissolved in water for 20 weeks. Electrophoretic mobility shift assay (EMSA) and luciferase assay were performed for elucidation of transcriptional regulation through acetylation of FoxO1 by HDACi. Results: VPA attenuated blood glucose levels in accordance with a decrease in the expression of gluconeogenic genes in hyperglycemic OLETF rats. It has been shown that HDAC class I-specific and HDAC class IIa-specific inhibitors, as well as pan-HDAC inhibitors decrease FoxO1 enrichment at the cis-element of target gene promoters. Mutations in FoxO1 prevent its acetylation, thereby increasing its transcriptional activity. HDAC3 and HDAC4 interact with FoxO1, and knockdown of HDAC3, HDAC4, or their combination increases FoxO1 acetylation, thereby decreasing the expression of gluconeogenic genes. Conclusions: These results indicate that HDACi attenuates the transcriptional activity of FoxO1 by impeding deacetylation, thereby ameliorating hyperglycemia in T2DM rats. Full article
(This article belongs to the Special Issue Histone Deacetylase Inhibitors in Health and Disease)
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12 pages, 2437 KiB  
Article
A New Synthetic Histone Deacetylase Inhibitor, MHY2256, Induces Apoptosis and Autophagy Cell Death in Endometrial Cancer Cells via p53 Acetylation
by Umasankar De, Ji Yeon Son, Richa Sachan, Yu Jin Park, Dongwan Kang, Kyungsil Yoon, Byung Mu Lee, In Su Kim, Hyung Ryong Moon and Hyung Sik Kim
Int. J. Mol. Sci. 2018, 19(9), 2743; https://doi.org/10.3390/ijms19092743 - 13 Sep 2018
Cited by 48 | Viewed by 5060
Abstract
We previously discovered a novel sirtuin (SIRT) inhibitor, MHY2256, that exerts anticancer activity through p53 acetylation in MCF-7 human breast cancer cells. We investigated the anticancer activity of MHY2256 against hormone-related cancer, an endometrial cancer with a poor prognosis. The IC50 values [...] Read more.
We previously discovered a novel sirtuin (SIRT) inhibitor, MHY2256, that exerts anticancer activity through p53 acetylation in MCF-7 human breast cancer cells. We investigated the anticancer activity of MHY2256 against hormone-related cancer, an endometrial cancer with a poor prognosis. The IC50 values of MHY2256 were shown to be much lower than those of salermide, a well-known SIRT inhibitor. Furthermore, MHY2256 significantly reduced the protein expression and activities of SIRT1, 2, and 3, with similar effects to salermide. Particularly, MHY2256 markedly inhibited tumor growth in a tumor xenograft mouse model of Ishikawa cancer cells. During the experimental period, there was no significant change in the body weight of mice treated with MHY2256. A detailed analysis of the sensitization mechanisms of Ishikawa cells revealed that late apoptosis was largely increased by MHY2256. Additionally, MHY2256 increased G1 arrest and reduced the number of cell cyclic-related proteins, suggesting that apoptosis by MHY2256 was achieved by cellular arrest. Particularly, p21 was greatly increased by MHY225656, suggesting that cell cycle arrest by p21 is a major factor in MHY2256 sensitization in Ishikawa cells. We also detected a significant increase in acetylated p53, a target protein of SIRT1, in Ishikawa cells after MHY2256 treatment. In a mouse xenograft model, MHY2256 significantly reduced tumor growth and weight without apparent side effects. These results suggest that MHY2256 exerts its anticancer activity through p53 acetylation in endometrial cancer and can be used for targeting hormone-related cancers. Full article
(This article belongs to the Special Issue Histone Deacetylase Inhibitors in Health and Disease)
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15 pages, 2766 KiB  
Article
Deacetylation of Histone H4 Accompanying Cardiomyogenesis is Weakened in HDAC1-Depleted ES Cells
by Orazio Angelo Arcidiacono, Jana Krejčí, Jana Suchánková and Eva Bártová
Int. J. Mol. Sci. 2018, 19(8), 2425; https://doi.org/10.3390/ijms19082425 - 16 Aug 2018
Cited by 9 | Viewed by 4040
Abstract
Cell differentiation into cardiomyocytes requires activation of differentiation-specific genes and epigenetic factors that contribute to these physiological processes. This study is focused on the in vitro differentiation of mouse embryonic stem cells (mESCs) induced into cardiomyocytes. The effects of clinically promising inhibitors of [...] Read more.
Cell differentiation into cardiomyocytes requires activation of differentiation-specific genes and epigenetic factors that contribute to these physiological processes. This study is focused on the in vitro differentiation of mouse embryonic stem cells (mESCs) induced into cardiomyocytes. The effects of clinically promising inhibitors of histone deacetylases (HDACi) on mESC cardiomyogenesis and on explanted embryonic hearts were also analyzed. HDAC1 depletion caused early beating of cardiomyocytes compared with those of the wild-type (wt) counterpart. Moreover, the adherence of embryonic bodies (EBs) was reduced in HDAC1 double knockout (dn) mESCs. The most important finding was differentiation-specific H4 deacetylation observed during cardiomyocyte differentiation of wt mESCs, while H4 deacetylation was weakened in HDAC1-depleted cells induced to the cardiac pathway. Analysis of the effect of HDACi showed that Trichostatin A (TSA) is a strong hyperacetylating agent, especially in wt mESCs, but only SAHA reduced the size of the beating areas in EBs that originated from HDAC1 dn mESCs. Additionally, explanted embryonic hearts (e15) responded to treatment with HDACi: all of the tested HDACi (TSA, SAHA, VPA) increased the levels of H3K9ac, H4ac, H4K20ac, and pan-acetylated lysines in embryonic hearts. This observation shows that explanted tissue can be maintained in a hyperacetylation state several hours after excision, which appears to be useful information from the view of transplantation strategy and the maintenance of gene upregulation via acetylation in tissue intended for transplantation. Full article
(This article belongs to the Special Issue Histone Deacetylase Inhibitors in Health and Disease)
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16 pages, 3285 KiB  
Article
Differences in Functional Expression of Connexin43 and NaV1.5 by Pan- and Class-Selective Histone Deacetylase Inhibition in Heart
by Xian Zhang, Dakshesh Patel, Qin Xu and Richard Veenstra
Int. J. Mol. Sci. 2018, 19(8), 2288; https://doi.org/10.3390/ijms19082288 - 04 Aug 2018
Cited by 3 | Viewed by 3620
Abstract
Class-selective histone deacetylase (HDAC) inhibitors were designed to improve safety profiles and therapeutic effectiveness in the treatment of multiple cancers relative to pan-HDAC inhibitors. However, the underlying mechanisms for their therapeutic and cardiotoxic potentials remain poorly understood. Cardiac sodium currents (INa) [...] Read more.
Class-selective histone deacetylase (HDAC) inhibitors were designed to improve safety profiles and therapeutic effectiveness in the treatment of multiple cancers relative to pan-HDAC inhibitors. However, the underlying mechanisms for their therapeutic and cardiotoxic potentials remain poorly understood. Cardiac sodium currents (INa) and gap junction conductance (gj) were measured by whole cell patch clamp techniques on primary cultures of neonatal cardiomyocytes. Cardiac NaV1.5 sodium channel and connexin43 (Cx43) gap junction protein levels were assessed by Western blot analyses. Panobinostat produced concentration-dependent reductions in ventricular gj, peak INa density, and NaV1.5 protein expression levels. Membrane voltage (Vm)-dependent activation of INa was shifted by +3 to 6 mV with no effect on inactivation. Entinostat (1 μM) did not affect ventricular gj, peak INa density, or INa activation. However, the INa half-inactivation voltage (V½) was shifted by −3.5 mV. Ricolinostat had only minor effects on ventricular gj and INa properties, though INa activation was shifted by −4 mV. Cx43 and NaV1.5 protein expression levels were not altered by class-selective HDAC inhibitors. The lack of effects of class-selective HDAC inhibitors on ventricular gj and INa may help explain the improved cardiac safety profile of entinostat and ricolinostat. Full article
(This article belongs to the Special Issue Histone Deacetylase Inhibitors in Health and Disease)
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Review

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29 pages, 325 KiB  
Review
Immunoepigenetics Combination Therapies: An Overview of the Role of HDACs in Cancer Immunotherapy
by Debarati Banik, Sara Moufarrij and Alejandro Villagra
Int. J. Mol. Sci. 2019, 20(9), 2241; https://doi.org/10.3390/ijms20092241 - 07 May 2019
Cited by 80 | Viewed by 4654
Abstract
Long-standing efforts to identify the multifaceted roles of histone deacetylase inhibitors (HDACis) have positioned these agents as promising drug candidates in combatting cancer, autoimmune, neurodegenerative, and infectious diseases. The same has also encouraged the evaluation of multiple HDACi candidates in preclinical studies in [...] Read more.
Long-standing efforts to identify the multifaceted roles of histone deacetylase inhibitors (HDACis) have positioned these agents as promising drug candidates in combatting cancer, autoimmune, neurodegenerative, and infectious diseases. The same has also encouraged the evaluation of multiple HDACi candidates in preclinical studies in cancer and other diseases as well as the FDA-approval towards clinical use for specific agents. In this review, we have discussed how the efficacy of immunotherapy can be leveraged by combining it with HDACis. We have also included a brief overview of the classification of HDACis as well as their various roles in physiological and pathophysiological scenarios to target key cellular processes promoting the initiation, establishment, and progression of cancer. Given the critical role of the tumor microenvironment (TME) towards the outcome of anticancer therapies, we have also discussed the effect of HDACis on different components of the TME. We then have gradually progressed into examples of specific pan-HDACis, class I HDACi, and selective HDACis that either have been incorporated into clinical trials or show promising preclinical effects for future consideration. Finally, we have included examples of ongoing trials for each of the above categories of HDACis as standalone agents or in combination with immunotherapeutic approaches. Full article
(This article belongs to the Special Issue Histone Deacetylase Inhibitors in Health and Disease)
21 pages, 438 KiB  
Review
Mechanism of Action for HDAC Inhibitors—Insights from Omics Approaches
by Wenbo Li and Zheng Sun
Int. J. Mol. Sci. 2019, 20(7), 1616; https://doi.org/10.3390/ijms20071616 - 01 Apr 2019
Cited by 46 | Viewed by 6876
Abstract
Histone deacetylase inhibitors (HDIs) are a class of prominent epigenetic drugs that are currently being tested in hundreds of clinical trials against a variety of diseases. A few compounds have already been approved for treating lymphoma or myeloma. HDIs bind to the zinc-containing [...] Read more.
Histone deacetylase inhibitors (HDIs) are a class of prominent epigenetic drugs that are currently being tested in hundreds of clinical trials against a variety of diseases. A few compounds have already been approved for treating lymphoma or myeloma. HDIs bind to the zinc-containing catalytic domain of the histone deacetylase (HDACs) and they repress the deacetylase enzymatic activity. The broad therapeutic effect of HDIs with seemingly low toxicity is somewhat puzzling when considering that most HDIs lack strict specificity toward any individual HDAC and, even if they do, each individual HDAC has diverse functions under different physiology scenarios. Here, we review recent mechanistic studies using omics approaches, including epigenomics, transcriptomics, proteomics, metabolomics, and chemoproteomics, methods. These omics studies provide non-biased insights into the mechanism of action for HDIs. Full article
(This article belongs to the Special Issue Histone Deacetylase Inhibitors in Health and Disease)
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18 pages, 1156 KiB  
Review
HDAC6 Modulates Signaling Pathways Relevant to Synaptic Biology and Neuronal Differentiation in Human Stem Cell-Derived Neurons
by Jonathan Iaconelli, Lucius Xuan and Rakesh Karmacharya
Int. J. Mol. Sci. 2019, 20(7), 1605; https://doi.org/10.3390/ijms20071605 - 31 Mar 2019
Cited by 22 | Viewed by 5719
Abstract
Recent studies show that histone deacetylase 6 (HDAC6) has important roles in the human brain, especially in the context of a number of nervous system disorders. Animal models of neurodevelopmental, neurodegenerative, and neuropsychiatric disorders show that HDAC6 modulates important biological processes relevant to [...] Read more.
Recent studies show that histone deacetylase 6 (HDAC6) has important roles in the human brain, especially in the context of a number of nervous system disorders. Animal models of neurodevelopmental, neurodegenerative, and neuropsychiatric disorders show that HDAC6 modulates important biological processes relevant to disease biology. Pan-selective histone deacetylase (HDAC) inhibitors had been studied in animal behavioral assays and shown to induce synaptogenesis in rodent neuronal cultures. While most studies of HDACs in the nervous system have focused on class I HDACs located in the nucleus (e.g., HDACs 1,2,3), recent findings in rodent models suggest that the cytoplasmic class IIb HDAC, HDAC6, plays an important role in regulating mood-related behaviors. Human studies suggest a significant role for synaptic dysfunction in the prefrontal cortex (PFC) and hippocampus in depression. Studies of HDAC inhibitors (HDACi) in human neuronal cells show that HDAC6 inhibitors (HDAC6i) increase the acetylation of specific lysine residues in proteins involved in synaptogenesis. This has led to the hypothesis that HDAC6i may modulate synaptic biology not through effects on the acetylation of histones, but by regulating acetylation of non-histone proteins. Full article
(This article belongs to the Special Issue Histone Deacetylase Inhibitors in Health and Disease)
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15 pages, 2502 KiB  
Review
Apoptosis Induction byHistone Deacetylase Inhibitors in Cancer Cells: Role of Ku70
by Ping Gong, Yuetong Wang and Yongkui Jing
Int. J. Mol. Sci. 2019, 20(7), 1601; https://doi.org/10.3390/ijms20071601 - 30 Mar 2019
Cited by 41 | Viewed by 5588
Abstract
Histone deacetylases (HDACs) are a group of enzymes that regulate gene transcription by controlling deacetylation of histones and non-histone proteins. Overexpression of HDACs is found in some types of tumors and predicts poor prognosis. Five HDAC inhibitors are approved for the treatment of [...] Read more.
Histone deacetylases (HDACs) are a group of enzymes that regulate gene transcription by controlling deacetylation of histones and non-histone proteins. Overexpression of HDACs is found in some types of tumors and predicts poor prognosis. Five HDAC inhibitors are approved for the treatment of cutaneous T-cell lymphoma, peripheral T-cell lymphoma, and multiple myeloma. Treatment with HDAC inhibitors regulates gene expression with increased acetylated histones with unconfirmed connection with therapy. Apoptosis is a key mechanism by which HDAC inhibitors selectively kill cancer cells, probably due to acetylation of non-histone proteins. Ku70 is a protein that repairs DNA breaks and stabilizes anti-apoptotic protein c-FLIP and proapoptotic protein Bax, which is regulated by acetylation. HDAC inhibitors induce Ku70 acetylation with repressed c-FLIP and activated Bax in cancer cells. Current studies indicate that Ku70 is a potential target of HDAC inhibitors and plays an important role during the induction of apoptosis. Full article
(This article belongs to the Special Issue Histone Deacetylase Inhibitors in Health and Disease)
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15 pages, 547 KiB  
Review
HDAC Inhibitors: Therapeutic Potential in Fibrosis-Associated Human Diseases
by Somy Yoon, Gaeun Kang and Gwang Hyeon Eom
Int. J. Mol. Sci. 2019, 20(6), 1329; https://doi.org/10.3390/ijms20061329 - 16 Mar 2019
Cited by 68 | Viewed by 8304
Abstract
Fibrosis is characterized by excessive deposition of the extracellular matrix and develops because of fibroblast differentiation during the process of inflammation. Various cytokines stimulate resident fibroblasts, which differentiate into myofibroblasts. Myofibroblasts actively synthesize an excessive amount of extracellular matrix, which indicates pathologic fibrosis. [...] Read more.
Fibrosis is characterized by excessive deposition of the extracellular matrix and develops because of fibroblast differentiation during the process of inflammation. Various cytokines stimulate resident fibroblasts, which differentiate into myofibroblasts. Myofibroblasts actively synthesize an excessive amount of extracellular matrix, which indicates pathologic fibrosis. Although initial fibrosis is a physiologic response, the accumulated fibrous material causes failure of normal organ function. Cardiac fibrosis interferes with proper diastole, whereas pulmonary fibrosis results in chronic hypoxia; liver cirrhosis induces portal hypertension, and overgrowth of fibroblasts in the conjunctiva is a major cause of glaucoma surgical failure. Recently, several reports have clearly demonstrated the functional relevance of certain types of histone deacetylases (HDACs) in various kinds of fibrosis and the successful alleviation of the condition in animal models using HDAC inhibitors. In this review, we discuss the therapeutic potential of HDAC inhibitors in fibrosis-associated human diseases using results obtained from animal models. Full article
(This article belongs to the Special Issue Histone Deacetylase Inhibitors in Health and Disease)
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27 pages, 684 KiB  
Review
Regulation of Chemokines and Cytokines by Histone Deacetylases and an Update on Histone Decetylase Inhibitors in Human Diseases
by Himavanth Reddy Gatla, Nethaji Muniraj, Prashanth Thevkar, Siddhartha Yavvari, Sahithi Sukhavasi and Monish Ram Makena
Int. J. Mol. Sci. 2019, 20(5), 1110; https://doi.org/10.3390/ijms20051110 - 05 Mar 2019
Cited by 57 | Viewed by 9915
Abstract
Histone acetyltransferases (HATs) and histone deacetylases (HDACs) counteract with each other to regulate gene expression by altering chromatin structure. Aberrant HDAC activity was reported in many human diseases including wide range of cancers, viral infections, cardiovascular complications, auto-immune diseases and kidney diseases. HDAC [...] Read more.
Histone acetyltransferases (HATs) and histone deacetylases (HDACs) counteract with each other to regulate gene expression by altering chromatin structure. Aberrant HDAC activity was reported in many human diseases including wide range of cancers, viral infections, cardiovascular complications, auto-immune diseases and kidney diseases. HDAC inhibitors are small molecules designed to block the malignant activity of HDACs. Chemokines and cytokines control inflammation, immunological and other key biological processes and are shown to be involved in various malignancies. Various HDACs and HDAC inhibitors were reported to regulate chemokines and cytokines. Even though HDAC inhibitors have remarkable anti-tumor activity in hematological cancers, they are not effective in treating many diseases and many patients relapse after treatment. However, the role of HDACs and cytokines in regulating these diseases still remain unclear. Therefore, understanding exact mechanisms and effector functions of HDACs are urgently needed to selectively inhibit them and to establish better a platform to combat various malignancies. In this review, we address regulation of chemokines and cytokines by HDACs and HDAC inhibitors and update on HDAC inhibitors in human diseases. Full article
(This article belongs to the Special Issue Histone Deacetylase Inhibitors in Health and Disease)
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13 pages, 1004 KiB  
Review
Histone Deacetylation Inhibitors as Therapy Concept in Sepsis
by Andreas von Knethen and Bernhard Brüne
Int. J. Mol. Sci. 2019, 20(2), 346; https://doi.org/10.3390/ijms20020346 - 16 Jan 2019
Cited by 36 | Viewed by 4536
Abstract
Sepsis is characterized by dysregulated gene expression, provoking a hyper-inflammatory response occurring in parallel to a hypo-inflammatory reaction. This is often associated with multi-organ failure, leading to the patient’s death. Therefore, reprogramming of these pro- and anti-inflammatory, as well as immune-response genes which [...] Read more.
Sepsis is characterized by dysregulated gene expression, provoking a hyper-inflammatory response occurring in parallel to a hypo-inflammatory reaction. This is often associated with multi-organ failure, leading to the patient’s death. Therefore, reprogramming of these pro- and anti-inflammatory, as well as immune-response genes which are involved in acute systemic inflammation, is a therapy approach to prevent organ failure and to improve sepsis outcomes. Considering epigenetic, i.e., reversible, modifications of chromatin, not altering the DNA sequence as one tool to adapt the expression profile, inhibition of factors mediating these changes is important. Acetylation of histones by histone acetyltransferases (HATs) and initiating an open-chromatin structure leading to its active transcription is counteracted by histone deacetylases (HDACs). Histone deacetylation triggers a compact nucleosome structure preventing active transcription. Hence, inhibiting the activity of HDACs by specific inhibitors can be used to restore the expression profile of the cells. It can be assumed that HDAC inhibitors will reduce the expression of pro-, as well as anti-inflammatory mediators, which blocks sepsis progression. However, decreased cytokine expression might also be unfavorable, because it can be associated with decreased bacterial clearance. Full article
(This article belongs to the Special Issue Histone Deacetylase Inhibitors in Health and Disease)
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15 pages, 404 KiB  
Review
The Crosstalk between Acetylation and Phosphorylation: Emerging New Roles for HDAC Inhibitors in the Heart
by Justine Habibian and Bradley S. Ferguson
Int. J. Mol. Sci. 2019, 20(1), 102; https://doi.org/10.3390/ijms20010102 - 28 Dec 2018
Cited by 30 | Viewed by 6651
Abstract
Approximately five million United States (U.S.) adults are diagnosed with heart failure (HF), with eight million U.S. adults projected to suffer from HF by 2030. With five-year mortality rates following HF diagnosis approximating 50%, novel therapeutic treatments are needed for HF patients. Pre-clinical [...] Read more.
Approximately five million United States (U.S.) adults are diagnosed with heart failure (HF), with eight million U.S. adults projected to suffer from HF by 2030. With five-year mortality rates following HF diagnosis approximating 50%, novel therapeutic treatments are needed for HF patients. Pre-clinical animal models of HF have highlighted histone deacetylase (HDAC) inhibitors as efficacious therapeutics that can stop and potentially reverse cardiac remodeling and dysfunction linked with HF development. HDACs remove acetyl groups from nucleosomal histones, altering DNA-histone protein electrostatic interactions in the regulation of gene expression. However, HDACs also remove acetyl groups from non-histone proteins in various tissues. Changes in histone and non-histone protein acetylation plays a key role in protein structure and function that can alter other post translational modifications (PTMs), including protein phosphorylation. Protein phosphorylation is a well described PTM that is important for cardiac signal transduction, protein activity and gene expression, yet the functional role for acetylation-phosphorylation cross-talk in the myocardium remains less clear. This review will focus on the regulation and function for acetylation-phosphorylation cross-talk in the heart, with a focus on the role for HDACs and HDAC inhibitors as regulators of acetyl-phosphorylation cross-talk in the control of cardiac function. Full article
(This article belongs to the Special Issue Histone Deacetylase Inhibitors in Health and Disease)
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14 pages, 3672 KiB  
Review
Role of HDAC3-miRNA-CAGE Network in Anti-Cancer Drug-Resistance
by Yoojung Kwon, Youngmi Kim, Hyun Suk Jung and Dooil Jeoung
Int. J. Mol. Sci. 2019, 20(1), 51; https://doi.org/10.3390/ijms20010051 - 23 Dec 2018
Cited by 20 | Viewed by 5294
Abstract
Histone modification is associated with resistance to anti-cancer drugs. Epigenetic modifications of histones can regulate resistance to anti-cancer drugs. It has been reported that histone deacetylase 3 (HDAC3) regulates responses to anti-cancer drugs, angiogenic potential, and tumorigenic potential of cancer cells in association [...] Read more.
Histone modification is associated with resistance to anti-cancer drugs. Epigenetic modifications of histones can regulate resistance to anti-cancer drugs. It has been reported that histone deacetylase 3 (HDAC3) regulates responses to anti-cancer drugs, angiogenic potential, and tumorigenic potential of cancer cells in association with cancer-associated genes (CAGE), and in particular, a cancer/testis antigen gene. In this paper, we report the roles of microRNAs that regulate the expression of HDAC3 and CAGE involved in resistance to anti-cancer drugs and associated mechanisms. In this review, roles of HDAC3-miRNAs-CAGE molecular networks in resistance to anti-cancer drugs, and the relevance of HDAC3 as a target for developing anti-cancer drugs are discussed. Full article
(This article belongs to the Special Issue Histone Deacetylase Inhibitors in Health and Disease)
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18 pages, 1073 KiB  
Review
The Impact of Protein Acetylation/Deacetylation on Systemic Lupus Erythematosus
by Jingjing Ren, Eric Panther, Xiaofeng Liao, Amrie C. Grammer, Peter E. Lipsky and Chris M. Reilly
Int. J. Mol. Sci. 2018, 19(12), 4007; https://doi.org/10.3390/ijms19124007 - 12 Dec 2018
Cited by 14 | Viewed by 4471
Abstract
Systemic lupus erythematosus (SLE) is a chronic inflammatory autoimmune disease in which the body’s immune system mistakenly attacks healthy cells. Although the exact cause of SLE has not been identified, it is clear that both genetics and environmental factors trigger the disease. Identical [...] Read more.
Systemic lupus erythematosus (SLE) is a chronic inflammatory autoimmune disease in which the body’s immune system mistakenly attacks healthy cells. Although the exact cause of SLE has not been identified, it is clear that both genetics and environmental factors trigger the disease. Identical twins have a 24% chance of getting lupus disease if the other one is affected. Internal factors such as female gender and sex hormones, the major histocompatibility complex (MHC) locus and other genetic polymorphisms have been shown to affect SLE, as well as external, environmental influences such as sunlight exposure, smoking, vitamin D deficiency, and certain infections. Several studies have reported and proposed multiple associations between the alteration of the epigenome and the pathogenesis of autoimmune disease. Epigenetic factors contributing to SLE include microRNAs, DNA methylation status, and the acetylation/deacetylation of histone proteins. Additionally, the acetylation of non-histone proteins can also influence cellular function. A better understanding of non-genomic factors that regulate SLE will provide insight into the mechanisms that initiate and facilitate disease and also contribute to the development of novel therapeutics that can specifically target pathogenic molecular pathways. Full article
(This article belongs to the Special Issue Histone Deacetylase Inhibitors in Health and Disease)
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18 pages, 1535 KiB  
Review
Epigenetic Modifiers in Myeloid Malignancies: The Role of Histone Deacetylase Inhibitors
by Johanna S. Ungerstedt
Int. J. Mol. Sci. 2018, 19(10), 3091; https://doi.org/10.3390/ijms19103091 - 09 Oct 2018
Cited by 23 | Viewed by 5630
Abstract
Myeloid hematological malignancies are clonal bone marrow neoplasms, comprising of acute myeloid leukemia (AML), the myelodysplastic syndromes (MDS), chronic myelomonocytic leukemia (CMML), the myeloproliferative neoplasms (MPN) and systemic mastocytosis (SM). The field of epigenetic regulation of normal and malignant hematopoiesis is rapidly growing. [...] Read more.
Myeloid hematological malignancies are clonal bone marrow neoplasms, comprising of acute myeloid leukemia (AML), the myelodysplastic syndromes (MDS), chronic myelomonocytic leukemia (CMML), the myeloproliferative neoplasms (MPN) and systemic mastocytosis (SM). The field of epigenetic regulation of normal and malignant hematopoiesis is rapidly growing. In recent years, heterozygous somatic mutations in genes encoding epigenetic regulators have been found in all subtypes of myeloid malignancies, supporting the rationale for treatment with epigenetic modifiers. Histone deacetylase inhibitors (HDACi) are epigenetic modifiers that, in vitro, have been shown to induce growth arrest, apoptotic or autophagic cell death, and terminal differentiation of myeloid tumor cells. These effects were observed both at the bulk tumor level and in the most immature CD34+38 cell compartments containing the leukemic stem cells. Thus, there is a strong rationale supporting HDACi therapy in myeloid malignancies. However, despite initial promising results in phase I trials, HDACi in monotherapy as well as in combination with other drugs, have failed to improve responses or survival. This review provides an overview of the rationale for HDACi in myeloid malignancies, clinical results and speculations on why clinical trials have thus far not met the expectations, and how this may be improved in the future. Full article
(This article belongs to the Special Issue Histone Deacetylase Inhibitors in Health and Disease)
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20 pages, 827 KiB  
Review
Histone Deacetylase Inhibitors and Diabetic Kidney Disease
by Mitchell J. Hadden and Andrew Advani
Int. J. Mol. Sci. 2018, 19(9), 2630; https://doi.org/10.3390/ijms19092630 - 05 Sep 2018
Cited by 61 | Viewed by 7330
Abstract
Despite recent clinical trial advances and improvements in clinical care, kidney disease due to diabetes remains the most common cause of chronic kidney failure worldwide. In the search for new treatments, recent attentions have turned to drug repurposing opportunities, including study of the [...] Read more.
Despite recent clinical trial advances and improvements in clinical care, kidney disease due to diabetes remains the most common cause of chronic kidney failure worldwide. In the search for new treatments, recent attentions have turned to drug repurposing opportunities, including study of the histone deacetylase (HDAC) inhibitor class of agents. HDACs are a group of enzymes that remove functional acetyl groups from histone and non-histone proteins and they can affect cellular function through both epigenetic and non-epigenetic means. Over the past decade, several HDAC inhibitors have been adopted into clinical practice, primarily for the treatment of hematological malignancy, whereas other existing therapies (for instance valproate) have been found to have HDAC inhibitory effects. Here we review the current HDAC inhibitors in the clinic and under development; the literature evidence supporting the renoprotective effects of HDAC inhibitors in experimental diabetic kidney disease; and the adverse effect profiles that may prevent existing therapies from entering the clinic for this indication. Whereas recent research efforts have shed light on the fundamental actions of HDACs in the diabetic kidney, whether these efforts will translate into novel therapies for patients will require more specific and better-tolerated therapies. Full article
(This article belongs to the Special Issue Histone Deacetylase Inhibitors in Health and Disease)
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26 pages, 1174 KiB  
Review
The Therapeutic Strategy of HDAC6 Inhibitors in Lymphoproliferative Disease
by Maria Cosenza and Samantha Pozzi
Int. J. Mol. Sci. 2018, 19(8), 2337; https://doi.org/10.3390/ijms19082337 - 09 Aug 2018
Cited by 59 | Viewed by 6004
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 [...] Read more.
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. Full article
(This article belongs to the Special Issue Histone Deacetylase Inhibitors in Health and Disease)
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11 pages, 672 KiB  
Review
Therapeutic Opportunities of Targeting Histone Deacetylase Isoforms to Eradicate Cancer Stem Cells
by Peng-Chan Lin, Hao-Yu Hsieh, Po-Chen Chu and Ching S. Chen
Int. J. Mol. Sci. 2018, 19(7), 1939; https://doi.org/10.3390/ijms19071939 - 02 Jul 2018
Cited by 22 | Viewed by 4133
Abstract
Cancer stem cells (CSCs), or tumor-initiating cells, are a small subset of cancer cells with the capacity for self-renewal and differentiation, which have been shown to drive tumor initiation, progression, and metastasis in many types of cancer. Moreover, therapeutic regimens, such as cisplatin [...] Read more.
Cancer stem cells (CSCs), or tumor-initiating cells, are a small subset of cancer cells with the capacity for self-renewal and differentiation, which have been shown to drive tumor initiation, progression, and metastasis in many types of cancer. Moreover, therapeutic regimens, such as cisplatin and radiation were reported to induce the enrichment of CSCs, thereby conferring chemoresistance on cancer cells. Therefore, therapeutic targeting of CSCs represents a clinical challenge that needs to be addressed to improve patient outcome. In this context, the effectiveness of pan or class-I histone deacetylase (HDAC) inhibitors in suppressing the CSC population is especially noteworthy in light of the new paradigm of combination therapy. Evidence suggests that this anti-CSC activity is associated with the ability of HDAC inhibitors to target multiple signaling pathways at different molecular levels. Beyond chromatin remodeling via histone acetylation, HDAC inhibitors can also block key signaling pathways pertinent to CSC maintenance. Especially noteworthy is the ability of different HDAC isoforms to regulate the protein stability and/or activity of a series of epithelial-mesenchymal transition (EMT)-inducing transcription factors, including HIF-1α, Stat3, Notch1, β-catenin, NF-κB, and c-Jun, each of which plays a critical role in regulating CSCs. From the translational perspective, these mechanistic links constitute a rationale to develop isoform-selective HDAC inhibitors as anti-CSC agents. Thus, this review aims to provide an overview on the roles of HDAC isoforms in maintaining CSC homeostasis via distinct signaling pathways independent of histone acetylation. Full article
(This article belongs to the Special Issue Histone Deacetylase Inhibitors in Health and Disease)
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