Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 7.620
Filtrar
1.
Nat Commun ; 11(1): 4639, 2020 09 15.
Artigo em Inglês | MEDLINE | ID: mdl-32934238

RESUMO

The ability to detect, respond and adapt to mitochondrial stress ensures the development and survival of organisms. Caenorhabditis elegans responds to mitochondrial stress by activating the mitochondrial unfolded protein response (UPRmt) to buffer the mitochondrial folding environment, rewire the metabolic state, and promote innate immunity and lifespan extension. Here we show that HDA-1, the C. elegans ortholog of mammalian histone deacetylase (HDAC) is required for mitochondrial stress-mediated activation of UPRmt. HDA-1 interacts and coordinates with the genome organizer DVE-1 to induce the transcription of a broad spectrum of UPRmt, innate immune response and metabolic reprogramming genes. In rhesus monkey and human tissues, HDAC1/2 transcript levels correlate with the expression of UPRmt genes. Knocking down or pharmacological inhibition of HDAC1/2 disrupts the activation of the UPRmt and the mitochondrial network in mammalian cells. Our results underscore an evolutionarily conserved mechanism of HDAC1/2 in modulating mitochondrial homeostasis and regulating longevity.


Assuntos
Proteínas de Caenorhabditis elegans/metabolismo , Caenorhabditis elegans/enzimologia , Histona Desacetilase 1/metabolismo , Histona Desacetilase 2/metabolismo , Histona Desacetilases/metabolismo , Longevidade , Mitocôndrias/enzimologia , Animais , Caenorhabditis elegans/genética , Caenorhabditis elegans/crescimento & desenvolvimento , Proteínas de Caenorhabditis elegans/genética , Histona Desacetilase 1/genética , Histona Desacetilase 2/genética , Histona Desacetilases/genética , Macaca mulatta , Estresse Fisiológico , Resposta a Proteínas não Dobradas
2.
Mol Cell ; 80(1): 43-58.e7, 2020 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-32937100

RESUMO

Immune cell function depends on specific metabolic programs dictated by mitochondria, including nutrient oxidation, macromolecule synthesis, and post-translational modifications. Mitochondrial adaptations have been linked to acute and chronic inflammation, but the metabolic cues and precise mechanisms remain unclear. Here we reveal that histone deacetylase 3 (HDAC3) is essential for shaping mitochondrial adaptations for IL-1ß production in macrophages through non-histone deacetylation. In vivo, HDAC3 promoted lipopolysaccharide-induced acute inflammation and high-fat diet-induced chronic inflammation by enhancing NLRP3-dependent caspase-1 activation. HDAC3 configured the lipid profile in stimulated macrophages and restricted fatty acid oxidation (FAO) supported by exogenous fatty acids for mitochondria to acquire their adaptations and depolarization. Rather than affecting nuclear gene expression, HDAC3 translocated to mitochondria to deacetylate and inactivate an FAO enzyme, mitochondrial trifunctional enzyme subunit α. HDAC3 may serve as a controlling node that balances between acquiring mitochondrial adaptations and sustaining their fitness for IL-1ß-dependent inflammation.


Assuntos
Ácidos Graxos/metabolismo , Histona Desacetilases/metabolismo , Inflamação/metabolismo , Interleucina-1beta/metabolismo , Mitocôndrias/metabolismo , Adulto , Animais , Caspase 1/metabolismo , Feminino , Humanos , Inflamação/patologia , Metabolismo dos Lipídeos , Masculino , Camundongos Endogâmicos C57BL , Camundongos Knockout , Pessoa de Meia-Idade , Mitocôndrias/ultraestrutura , Subunidade alfa da Proteína Mitocondrial Trifuncional/metabolismo , Células Mieloides/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Oxirredução , Fosforilação Oxidativa , Adulto Jovem
3.
Nature ; 584(7820): 286-290, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32760002

RESUMO

The histone deacetylases (HDACs) are a superfamily of chromatin-modifying enzymes that silence transcription through the modification of histones. Among them, HDAC3 is unique in that interaction with nuclear receptor corepressors 1 and 2 (NCoR1/2) is required to engage its catalytic activity1-3. However, global loss of HDAC3 also results in the repression of transcription, the mechanism of which is currently unclear4-8. Here we report that, during the activation of macrophages by lipopolysaccharides, HDAC3 is recruited to activating transcription factor 2 (ATF2)-bound sites without NCoR1/2 and activates the expression of inflammatory genes through a non-canonical mechanism. By contrast, the deacetylase activity of HDAC3 is selectively engaged at ATF3-bound sites that suppress Toll-like receptor signalling. Loss of HDAC3 in macrophages safeguards mice from lethal exposure to lipopolysaccharides, but this protection is not conferred upon genetic or pharmacological abolition of the catalytic activity of HDAC3. Our findings show that HDAC3 is a dichotomous transcriptional activator and repressor, with a non-canonical deacetylase-independent function that is vital for the innate immune system.


Assuntos
Histona Desacetilases/metabolismo , Inflamação/genética , Inflamação/metabolismo , Fator 2 Ativador da Transcrição/metabolismo , Fator 3 Ativador da Transcrição/metabolismo , Animais , Biocatálise , Regulação da Expressão Gênica/efeitos dos fármacos , Imunidade Inata/efeitos dos fármacos , Imunidade Inata/genética , Lipopolissacarídeos/imunologia , Lipopolissacarídeos/farmacologia , Macrófagos/imunologia , Masculino , Camundongos , Correpressor 1 de Receptor Nuclear , Correpressor 2 de Receptor Nuclear , Proteínas Repressoras/metabolismo , Transcrição Genética/efeitos dos fármacos
4.
Nat Commun ; 11(1): 4154, 2020 08 19.
Artigo em Inglês | MEDLINE | ID: mdl-32814778

RESUMO

The DNA damage response (DDR) coordinates DNA metabolism with nuclear and non-nuclear processes. The DDR kinase Rad53CHK1/CHK2 controls histone degradation to assist DNA repair. However, Rad53 deficiency causes histone-dependent growth defects in the absence of DNA damage, pointing out unknown physiological functions of the Rad53-histone axis. Here we show that histone dosage control by Rad53 ensures metabolic homeostasis. Under physiological conditions, Rad53 regulates histone levels through inhibitory phosphorylation of the transcription factor Spt21NPAT on Ser276. Rad53-Spt21 mutants display severe glucose dependence, caused by excess histones through two separable mechanisms: dampening of acetyl-coenzyme A-dependent carbon metabolism through histone hyper-acetylation, and Sirtuin-mediated silencing of starvation-induced subtelomeric domains. We further demonstrate that repression of subtelomere silencing by physiological Tel1ATM and Rpd3HDAC activities coveys tolerance to glucose restriction. Our findings identify DDR mutations, histone imbalances and aberrant subtelomeric chromatin as interconnected causes of glucose dependence, implying that DDR kinases coordinate metabolism and epigenetic changes.


Assuntos
Proteínas de Ciclo Celular/metabolismo , Quinase do Ponto de Checagem 2/metabolismo , Glucose/metabolismo , Histonas/metabolismo , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Proteínas Serina-Treonina Quinases/metabolismo , Proteínas de Saccharomyces cerevisiae/metabolismo , Saccharomyces cerevisiae/metabolismo , Fatores de Transcrição/metabolismo , Acetilação , Proteínas Mutadas de Ataxia Telangiectasia/genética , Proteínas Mutadas de Ataxia Telangiectasia/metabolismo , Proteínas de Ciclo Celular/genética , Quinase do Ponto de Checagem 2/genética , Dano ao DNA , Reparo do DNA , Inativação Gênica , Histona Desacetilases/genética , Histona Desacetilases/metabolismo , Peptídeos e Proteínas de Sinalização Intracelular/genética , Mutação , Fosforilação , Proteínas Serina-Treonina Quinases/genética , Saccharomyces cerevisiae/genética , Proteínas de Saccharomyces cerevisiae/genética , Serina/genética , Serina/metabolismo , Telômero/genética , Fatores de Transcrição/genética
5.
PLoS Pathog ; 16(8): e1008802, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32822428

RESUMO

Hepatitis B virus (HBV) is a worldwide health problem without curative treatments. Investigation of the regulation of HBV biosynthesis by class I and II histone deacetylases (HDACs) demonstrated that catalytically active HDAC5 upregulates HBV biosynthesis. HDAC5 expression increased both the stability and splicing of the HBV 3.5 kb RNA without altering the translational efficiency of the viral pregenomic or spliced 2.2 kb RNAs. Together, these observations point to a broader role of HDAC5 in regulating RNA splicing and transcript stability while specifically identifying a potentially novel approach toward antiviral HBV therapeutic development.


Assuntos
Genoma Viral , Vírus da Hepatite B/metabolismo , Hepatite B/virologia , Histona Desacetilases/metabolismo , Estabilidade de RNA , RNA Viral/biossíntese , RNA Viral/química , Regulação Viral da Expressão Gênica , Células Hep G2 , Vírus da Hepatite B/genética , Histona Desacetilases/genética , Humanos , Transcrição Genética , Replicação Viral
6.
Nat Commun ; 11(1): 3822, 2020 07 30.
Artigo em Inglês | MEDLINE | ID: mdl-32732898

RESUMO

Alveolar macrophages (AMs) derived from embryonic precursors seed the lung before birth and self-maintain locally throughout adulthood, but are regenerated by bone marrow (BM) under stress conditions. However, the regulation of AM development and maintenance remains poorly understood. Here, we show that histone deacetylase 3 (HDAC3) is a key epigenetic factor required for AM embryonic development, postnatal homeostasis, maturation, and regeneration from BM. Loss of HDAC3 in early embryonic development affects AM development starting at E14.5, while loss of HDAC3 after birth affects AM homeostasis and maturation. Single-cell RNA sequencing analyses reveal four distinct AM sub-clusters and a dysregulated cluster-specific pathway in the HDAC3-deficient AMs. Moreover, HDAC3-deficient AMs exhibit severe mitochondrial oxidative dysfunction and deteriorative cell death. Mechanistically, HDAC3 directly binds to Pparg enhancers, and HDAC3 deficiency impairs Pparg expression and its signaling pathway. Our findings identify HDAC3 as a key epigenetic regulator of lung AM development and homeostasis.


Assuntos
Histona Desacetilases/genética , Homeostase/genética , Pulmão/metabolismo , Macrófagos Alveolares/metabolismo , Animais , Apoptose/genética , Diferenciação Celular/genética , Linhagem Celular , Células Cultivadas , Feminino , Perfilação da Expressão Gênica/métodos , Regulação da Expressão Gênica no Desenvolvimento , Ontologia Genética , Histona Desacetilases/deficiência , Histona Desacetilases/metabolismo , Pulmão/embriologia , Pulmão/crescimento & desenvolvimento , Macrófagos Alveolares/citologia , Masculino , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Transgênicos
7.
Nat Commun ; 11(1): 3841, 2020 07 31.
Artigo em Inglês | MEDLINE | ID: mdl-32737323

RESUMO

Histone deacetylases (HDACs) are key enzymes in epigenetics and important drug targets in cancer biology. Whilst it has been established that HDACs regulate many cellular processes, far less is known about the regulation of these enzymes themselves. Here, we show that HDAC8 is allosterically regulated by shifts in populations between exchanging states. An inactive state is identified, which is stabilised by a range of mutations and resembles a sparsely-populated state in equilibrium with active HDAC8. Computational models show that the inactive and active states differ by small changes in a regulatory region that extends up to 28 Å from the active site. The regulatory allosteric region identified here in HDAC8 corresponds to regions in other class I HDACs known to bind regulators, thus suggesting a general mechanism. The presented results pave the way for the development of allosteric HDAC inhibitors and regulators to improve the therapy for several disease states.


Assuntos
Inibidores de Histona Desacetilases/química , Histona Desacetilases/química , Ácidos Hidroxâmicos/química , Indóis/química , Proteínas Repressoras/química , Vorinostat/química , Regulação Alostérica , Sítio Alostérico , Domínio Catalítico , Clonagem Molecular , Cristalografia por Raios X , Ativação Enzimática , Escherichia coli/genética , Escherichia coli/metabolismo , Expressão Gênica , Vetores Genéticos/química , Vetores Genéticos/metabolismo , Inibidores de Histona Desacetilases/metabolismo , Histona Desacetilases/genética , Histona Desacetilases/metabolismo , Humanos , Ácidos Hidroxâmicos/metabolismo , Indóis/metabolismo , Simulação de Dinâmica Molecular , Mutação , Ligação Proteica , Conformação Proteica em alfa-Hélice , Conformação Proteica em Folha beta , Domínios e Motivos de Interação entre Proteínas , Proteínas Recombinantes/química , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismo , Proteínas Repressoras/antagonistas & inibidores , Proteínas Repressoras/genética , Proteínas Repressoras/metabolismo , Especificidade por Substrato , Termodinâmica , Vorinostat/metabolismo
8.
Nat Commun ; 11(1): 3282, 2020 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-32612176

RESUMO

Osteocytes, cells ensconced within mineralized bone matrix, are the primary skeletal mechanosensors. Osteocytes sense mechanical cues by changes in fluid flow shear stress (FFSS) across their dendritic projections. Loading-induced reductions of osteocytic Sclerostin (encoded by Sost) expression stimulates new bone formation. However, the molecular steps linking mechanotransduction and Sost suppression remain unknown. Here, we report that class IIa histone deacetylases (HDAC4 and HDAC5) are required for loading-induced Sost suppression and bone formation. FFSS signaling drives class IIa HDAC nuclear translocation through a signaling pathway involving direct HDAC5 tyrosine 642 phosphorylation by focal adhesion kinase (FAK), a HDAC5 post-translational modification that controls its subcellular localization. Osteocyte cell adhesion supports FAK tyrosine phosphorylation, and FFSS triggers FAK dephosphorylation. Pharmacologic FAK catalytic inhibition reduces Sost mRNA expression in vitro and in vivo. These studies demonstrate a role for HDAC5 as a transducer of matrix-derived cues to regulate cell type-specific gene expression.


Assuntos
Proteína-Tirosina Quinases de Adesão Focal/genética , Histona Desacetilases/genética , Mecanotransdução Celular/genética , Osteócitos/metabolismo , Transdução de Sinais/genética , Animais , Linhagem Celular , Linhagem Celular Tumoral , Proteína-Tirosina Quinases de Adesão Focal/metabolismo , Perfilação da Expressão Gênica/métodos , Histona Desacetilases/metabolismo , Humanos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Osteogênese/genética , Fosforilação
9.
Plant Mol Biol ; 104(1-2): 67-79, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32621165

RESUMO

Acetylation and deacetylation of histones are important for regulating a series of biological processes in plants. Histone deacetylases (HDACs) control the histone deacetylation that plays an important role in plant response to abiotic stress. In our study, we show the evidence that GhHDT4D (a member of the HD2 subfamily of HDACs) is involved in cotton (Gossypium hirsutum) response to drought stress. Overexpression of GhHDT4D in Arabidopsis increased plant tolerance to drought, whereas silencing GhHDT4D in cotton resulted in plant sensitivity to drought. Simultaneously, the H3K9 acetylation level was altered in the GhHDT4D silenced cotton, compared with the controls. Further study revealed that GhHDT4D suppressed the transcription of GhWRKY33, which plays a negative role in cotton defense to drought, by reducing its H3K9 acetylation level. The expressions of the stress-related genes, such as GhDREB2A, GhDREB2C, GhSOS2, GhRD20-1, GhRD20-2 and GhRD29A, were significantly decreased in the GhHDT4D silenced cotton, but increased in the GhWRKY33 silenced cotton. Given these data together, our findings suggested that GhHDT4D may enhance drought tolerance by suppressing the expression of GhWRKY33, thereby activating the downstream drought response genes in cotton.


Assuntos
Secas , Gossypium/metabolismo , Histona Desacetilases/metabolismo , Estresse Fisiológico/fisiologia , Acetilação , Arabidopsis/genética , Arabidopsis/metabolismo , Proteínas de Arabidopsis/genética , Proteínas de Arabidopsis/metabolismo , Regulação da Expressão Gênica de Plantas , Inativação Gênica , Gossypium/genética , Histona Desacetilases/genética , Histonas/genética , Histonas/metabolismo , Filogenia , Plantas Geneticamente Modificadas , Regiões Promotoras Genéticas , Estresse Fisiológico/genética , Transcriptoma
10.
Nat Rev Endocrinol ; 16(9): 495-505, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32632275

RESUMO

Exercise is fundamental for good health, whereas physical inactivity underpins many chronic diseases of modern society. It is well appreciated that regular exercise improves metabolism and the metabolic phenotype in a number of tissues. The phenotypic alterations observed in skeletal muscle are partly mediated by transcriptional responses that occur following each individual bout of exercise. This adaptive response increases oxidative capacity and influences the function of myokines and extracellular vesicles that signal to other tissues. Our understanding of the epigenetic and transcriptional mechanisms that mediate the skeletal muscle gene expression response to exercise as well as of their upstream signalling pathways has advanced substantially in the past 10 years. With this knowledge also comes the opportunity to design new therapeutic strategies based on the biology of exercise for a variety of chronic conditions where regular exercise might be a challenge. This Review provides an overview of the beneficial adaptive responses to exercise and details the molecular mechanisms involved. The possibility of designing therapeutic interventions based on these molecular mechanisms is addressed, using relevant examples that have exploited this approach.


Assuntos
Doença Crônica/prevenção & controle , Exercício Físico/fisiologia , Promoção da Saúde , Proteínas Quinases Ativadas por AMP/metabolismo , Adaptação Fisiológica , Animais , Glândulas Endócrinas/fisiologia , Epigênese Genética , Expressão Gênica , Histona Desacetilases/metabolismo , Humanos , Músculo Esquelético/fisiologia , Condicionamento Físico Animal/fisiologia , Transdução de Sinais/fisiologia , Transcrição Genética/fisiologia
11.
Nat Commun ; 11(1): 3252, 2020 06 26.
Artigo em Inglês | MEDLINE | ID: mdl-32591534

RESUMO

MiDAC is one of seven distinct, large multi-protein complexes that recruit class I histone deacetylases to the genome to regulate gene expression. Despite implications of involvement in cell cycle regulation and in several cancers, surprisingly little is known about the function or structure of MiDAC. Here we show that MiDAC is important for chromosome alignment during mitosis in cancer cell lines. Mice lacking the MiDAC proteins, DNTTIP1 or MIDEAS, die with identical phenotypes during late embryogenesis due to perturbations in gene expression that result in heart malformation and haematopoietic failure. This suggests that MiDAC has an essential and unique function that cannot be compensated by other HDAC complexes. Consistent with this, the cryoEM structure of MiDAC reveals a unique and distinctive mode of assembly. Four copies of HDAC1 are positioned at the periphery with outward-facing active sites suggesting that the complex may target multiple nucleosomes implying a processive deacetylase function.


Assuntos
Desenvolvimento Embrionário , Histona Desacetilases/metabolismo , Complexos Multiproteicos/metabolismo , Sequência de Aminoácidos , Animais , Linhagem Celular , Cromatina/metabolismo , Cromossomos de Mamíferos/metabolismo , Embrião de Mamíferos/citologia , Fibroblastos/metabolismo , Redes Reguladoras de Genes , Heterozigoto , Homozigoto , Humanos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Mitose , Modelos Moleculares , Complexos Multiproteicos/química , Complexos Multiproteicos/ultraestrutura , Proteínas Nucleares/metabolismo , Domínios Proteicos , Multimerização Proteica
12.
Life Sci ; 256: 117912, 2020 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-32504755

RESUMO

Histone deacetylase enzymes were prominent chromatin remodeling drug that targets in the pathophysiology of Alzheimer's disease associated with transcriptional dysregulation. In vitro and in vivo models of AD have demonstrated overexpression of HDAC activity. Non-specificity and non-selectivity of HDAC are the major problems of existing HDAC inhibitors. Hence, we aim to set up a methodology describing the rational development of isoform-selective HDAC inhibitor targeting class, I and class IIb. A convenient multistage virtual screening followed by machine learning and IC50 screenings were used to classify the 5064 compounds into inhibitors and non-inhibitors classes retrieved from the ChEMBL database. ADMET analysis identified the pharmacokinetics and pharmacodynamics properties of selected compounds. Molecular docking, along with mutational analysis of eleven compounds, characterized the inhibiting potency. Herein, for the first time, we reported ChEMBL1834473 (2-[[5-(4-chlorophenyl)-1,3,4-thiadiazol-2-yl]amino]-N-hydroxypyrimidine-5-carboxamide) as the isoform-selective HDAC inhibitor, which interact central Zn2+ atom. The negative energy and interacting residue of the ChEMBL1834473 with six HDAC isoform has also been tabulated and mapped. Moreover, our findings concluded histidine, glycine, phenylalanine, and aspartic acid as key residues in protein-ligand interaction and classify 2347 compounds as HDAC inhibitors. Later, a protein-protein interaction network of six HDAC with the key proteins involved in the progression of an AD and signaling pathway, which describes the relationship between ChEMBL1834473 and AD, has been demonstrated using PPI network where the chosen inhibitor will work. Altogether, we conclude that the compound ChEMBL1834473 may be capable of inhibiting all isoforms of class I and class IIb HDAC based on computational analysis for AD therapeutics.


Assuntos
Doença de Alzheimer/tratamento farmacológico , Inibidores de Histona Desacetilases/química , Inibidores de Histona Desacetilases/uso terapêutico , Pirimidinas/química , Pirimidinas/uso terapêutico , Ácido Aspártico/metabolismo , Bases de Dados de Compostos Químicos , Avaliação Pré-Clínica de Medicamentos , Glicina/metabolismo , Histona Desacetilases/metabolismo , Humanos , Aprendizado de Máquina , Simulação de Acoplamento Molecular , Estrutura Molecular , Terapia de Alvo Molecular , Fenilalanina/metabolismo , Isoformas de Proteínas/química , Termodinâmica , Zinco/metabolismo
13.
Rev Fac Cien Med Univ Nac Cordoba ; 77(2): 117-125, 2020 06 16.
Artigo em Espanhol | MEDLINE | ID: mdl-32558516

RESUMO

Introduction: The NAD+dependent proteins deacetylases are called Sirtuins (SIRT). Objectives: Objectives: this review is to study the sirtuins involved in cancer, as well as SIRT1 inhibition studies in patients with coronavirus disease COVID-19. Data source and selection: For this, a search was made in Medline, Scopus and WOS, where descriptive studies of each of the functions of sirtuins were included, adjusted to recent scientific research. SIRT1 inhibition reduces CD8 T cell cytotoxicity in patients with systemic erythematosus lupus, being susceptible to SARS Cov-2 infections. SIRT2 is regulated by the secretion of IL-4 by eosinophils and the increase in SIRT2 increases hyperplasia, in contrast, SIRT3 promotes angiogenesis, inducing cardiac remodeling. SIRT4 is a tumor suppressor, in contrastto SIRT5 that promotes cell proliferation causing colorectal cancer; SIRT6 attenuates herpes virus associated with Kaposi's Sarcoma (KSHV) in immune compromised patients. Suppression of SIRT7 inhibits the growth of endometrial cancer cells. Conclusions: It is concluded that SIRT1, SIRT2 and SIRT4 are involved in the development of cancer, the suppression of SIRT5 and SIRT7 promotes the apoptosis of cancer cells and SIRT6 attenuates the replication of KSHV, in addition to the molecular pathology pathway of COVID-19 is associated with the inhibition of SIRT1 activity that may be related to inflammatory processes.


Assuntos
Betacoronavirus , Infecções por Coronavirus/metabolismo , Neoplasias/metabolismo , Pneumonia Viral/metabolismo , Sirtuína 1/antagonistas & inibidores , Biomarcadores Tumorais/metabolismo , Histona Desacetilases/metabolismo , Humanos , Imuno-Histoquímica , Pandemias
14.
Cancer Immunol Immunother ; 69(9): 1929-1936, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32435850

RESUMO

Myeloid-derived suppressor cells (MDSCs) are widely implicated in negative regulation of immune responses in cancer. Inhibition of class I histone deacetylases (HDAC) with entinostat has anti-MDSC activity. However, as single agent, it did not delay tumor growth in EL4 and LLC tumor models. Here, we found that entinostat reduced immune suppressive activity of only one type of MDSC-polymorphonuclear, PMN-MDSC, whereas it had no effect on monocytic M-MDSC or macrophages. M-MDSC had high amount of class II HDAC-HDAC6, which was further increased after the treatment of mice with entinostat. Inhibition of HDAC6 with ricolinostat reduced suppressive activity of M-MDSC, but did not affect PMN-MDSC or delayed tumor growth. However, combination of entinostat and ricolinostat abrogated suppressive activity of both populations of MDSC and substantially delayed tumor progression. Thus, inactivation of MDSC required targeting of both major subsets of these cells via inhibitors of class I and class II HDAC.


Assuntos
Inibidores de Histona Desacetilases/farmacologia , Histona Desacetilases/metabolismo , Células Mieloides/efeitos dos fármacos , Células Supressoras Mieloides/efeitos dos fármacos , Animais , Benzamidas/farmacologia , Linhagem Celular Tumoral , Feminino , Humanos , Ácidos Hidroxâmicos/farmacologia , Camundongos , Camundongos Endogâmicos C57BL , Monócitos/efeitos dos fármacos , Neoplasias/tratamento farmacológico , Piridinas/farmacologia , Pirimidinas/farmacologia
15.
PLoS Genet ; 16(5): e1008770, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32453730

RESUMO

Hormone-dependent activation of enhancers includes histone hyperacetylation and mediator recruitment. Histone hyperacetylation is mostly explained by a bimodal switch model, where histone deacetylases (HDACs) disassociate from chromatin, and histone acetyl transferases (HATs) are recruited. This model builds on decades of research on steroid receptor regulation of transcription. Yet, the general concept of the bimodal switch model has not been rigorously tested genome wide. We have used a genomics approach to study enhancer hyperacetylation by the thyroid hormone receptor (TR), described to operate as a bimodal switch. H3 acetylation, HAT and HDAC ChIP-seq analyses of livers from hypo- and hyperthyroid wildtype, TR deficient and NCOR1 disrupted mice reveal three types of thyroid hormone (T3)-regulated enhancers. One subset of enhancers is bound by HDAC3-NCOR1 in the absence of hormone and constitutively occupy TR and HATs irrespective of T3 levels, suggesting a poised enhancer state in absence of hormone. In presence of T3, HDAC3-NCOR1 dissociates from these enhancers leading to histone hyperacetylation, suggesting a histone acetylation rheostat function of HDACs at poised enhancers. Another subset of enhancers, not occupied by HDACs, is hyperacetylated in a T3-dependent manner, where TR is recruited to chromatin together with HATs. Lastly, a subset of enhancers, is not occupied directly by TR yet requires TR for histone hyperacetylation. This indirect enhancer activation involves co-association with TR bound enhancers within super-enhancers or topological associated domains. Collectively, this demonstrates various mechanisms controlling hormone-dependent transcription and adds significant details to the otherwise simple bimodal switch model.


Assuntos
Elementos Facilitadores Genéticos/efeitos dos fármacos , Histona Acetiltransferases/metabolismo , Histonas/metabolismo , Receptores dos Hormônios Tireóideos/genética , Hormônios Tireóideos/farmacologia , Acetilação , Animais , Regulação da Expressão Gênica/efeitos dos fármacos , Histona Desacetilases/metabolismo , Fígado/química , Masculino , Camundongos , Correpressor 1 de Receptor Nuclear/genética , Correpressor 1 de Receptor Nuclear/metabolismo
16.
Mol Carcinog ; 59(8): 955-966, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32391971

RESUMO

Maspin repression is frequently observed in prostate cancer; however, the molecular mechanism(s) causing the loss is not completely understood. Here, we demonstrate that inhibition of class I histone deacetylases (HDACs) mediates re-expression of maspin which plays an essential role in suppressing proliferation and migration capability in prostate cancer cells. Human prostate cancer LNCaP and DU145 cells treated with HDAC inhibitors, sodium butyrate, and trichostatin A, resulted in maspin re-expression. Interestingly, an exploration into the molecular mechanisms demonstrates that maspin repression in prostate tumor and human prostate cancer cell lines occurs via epigenetic silencing through an increase in HDAC activity/expression, independent of promoter DNA hypermethylation. Furthermore, transcriptional activation of maspin was accompanied with the suppression of HDAC1 and HDAC8 with significant p53 enrichment at the maspin promoter associated with an increase in histone H3/H4 acetylation. Our results provide evidence of maspin induction as a critical epigenetic event altered by class I HDACs in the restoration of balance to delay proliferation and migration ability of prostate cancer cells.


Assuntos
Biomarcadores Tumorais/metabolismo , Metilação de DNA , Regulação Neoplásica da Expressão Gênica , Histona Desacetilases/metabolismo , Neoplasias da Próstata/patologia , Serpinas/genética , Apoptose , Biomarcadores Tumorais/genética , Proliferação de Células , Epigênese Genética , Inibidores de Histona Desacetilases/farmacologia , Histona Desacetilases/química , Histona Desacetilases/genética , Histonas , Humanos , Ácidos Hidroxâmicos/farmacologia , Masculino , Prognóstico , Regiões Promotoras Genéticas , Neoplasias da Próstata/tratamento farmacológico , Neoplasias da Próstata/genética , Neoplasias da Próstata/metabolismo , Serpinas/metabolismo , Células Tumorais Cultivadas
17.
Food Chem ; 324: 126887, 2020 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-32339788

RESUMO

Epigenetic regulation and salt ions play essential roles in senescence control, but the underlying regulatory mechanism of senescence has not been thoroughly revealed in broccoli postharvest buds. Here, we found 200 mmol·L-1 NaCl, 400 mmol·L-1 KCl, 40 mmol·L-1 CaCl2 and 0.5 µmol·L-1 Trichostatin-A (TSA, a histone deacetylase inhibitor) delayed the bud senescence. They resulted in significantly inhibiting the malondialdehyde (MDA) content, and dramatically promoting the contents of superoxide dismutase (SOD), peroxidase (POD) and Chlorophyll. Furthermore, the expression of PHEOPHYTINASE (PPH) and NONYELLOWING (NYE1), but not SUPPRESSOR OF OVEREXPRESSION OF CONSTANS 1 (SOC1), were remarkably repressed by salt ions and TSA. Interestingly, HISTONE DEACETYLASE 9 (HDA9) and CATION/Ca2+ EXCHANGER 1 (CCX1) were down-regulated by NaCl, CaCl2 and TSA. Further assays demonstrated that HDA9 could not interact with CCX1 promoter. It suggested that CCX1 along with HDA9 were involved in inhibiting the senescence of broccoli buds, and regulated aging by indirect interaction.


Assuntos
Antioxidantes/metabolismo , Brassica/metabolismo , Regulação para Baixo/efeitos dos fármacos , Histona Desacetilases/metabolismo , Proteínas de Plantas/metabolismo , Sais/farmacologia , Sequência de Aminoácidos , Antiporters/química , Antiporters/genética , Antiporters/metabolismo , Brassica/química , Brassica/classificação , Cloreto de Cálcio/química , Cloreto de Cálcio/farmacologia , Clorofila/metabolismo , Flores/química , Flores/metabolismo , Ácidos Hidroxâmicos/química , Ácidos Hidroxâmicos/farmacologia , Íons/química , Filogenia , Sais/química , Alinhamento de Sequência
18.
PLoS Biol ; 18(4): e3000220, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32315298

RESUMO

Many lines of evidence point to links between sleep regulation and energy homeostasis, but mechanisms underlying these connections are unknown. During Caenorhabditis elegans sleep, energetic stores are allocated to nonneural tasks with a resultant drop in the overall fat stores and energy charge. Mutants lacking KIN-29, the C. elegans homolog of a mammalian Salt-Inducible Kinase (SIK) that signals sleep pressure, have low ATP levels despite high-fat stores, indicating a defective response to cellular energy deficits. Liberating energy stores corrects adiposity and sleep defects of kin-29 mutants. kin-29 sleep and energy homeostasis roles map to a set of sensory neurons that act upstream of fat regulation as well as of central sleep-controlling neurons, suggesting hierarchical somatic/neural interactions regulating sleep and energy homeostasis. Genetic interaction between kin-29 and the histone deacetylase hda-4 coupled with subcellular localization studies indicate that KIN-29 acts in the nucleus to regulate sleep. We propose that KIN-29/SIK acts in nuclei of sensory neuroendocrine cells to transduce low cellular energy charge into the mobilization of energy stores, which in turn promotes sleep.


Assuntos
Proteínas de Caenorhabditis elegans/metabolismo , Caenorhabditis elegans/fisiologia , Proteínas Serina-Treonina Quinases/metabolismo , Sono/fisiologia , Trifosfato de Adenosina/metabolismo , Animais , Animais Geneticamente Modificados , Caenorhabditis elegans/metabolismo , Proteínas de Caenorhabditis elegans/genética , Núcleo Celular/metabolismo , Metabolismo Energético/genética , Histona Desacetilases/genética , Histona Desacetilases/metabolismo , Mutação , Células Neuroendócrinas/metabolismo , Proteínas Serina-Treonina Quinases/genética , Células Receptoras Sensoriais/metabolismo
19.
Zhongguo Zhen Jiu ; 40(4): 405-10, 2020 Apr 12.
Artigo em Chinês | MEDLINE | ID: mdl-32275370

RESUMO

OBJECTIVE: To observe the effect of early intervention of bone-nearby acupuncture (BNA) combined with electroacupuncture (EA) on the expression of histone deacetylase1(HDAC1), histone deacetylase 2 (HDAC2) andµ-opioid recepter (MOR) in dorsal root ganglia (DRG) of bone cancer pain-morphine tolerance (BCP-MT) rats, and to explore its possible mechanism. METHODS: A total of 35 SD rats were randomized into a sham BCP group (n=6), a BCP group (n=7), a MT group (n=7), a BNA+EA group (n=8) and a shame BNA group (n=7). Except of the sham BCP group, cancer cell inoculation operation at left tibia was given in the other 4 groups to establish the bone cancer pain model. In the MT group, the BNA+EA group and the shame BNA group, intraperitoneal injection of morphine hydrochloride was given to establish the morphine tolerance model. After the operation, bone-nearby acupuncture combined with electroacupuncture was applied at "Zusanli" (ST 36) and "Kunlun" (BL 60) in the BNA+EA group, with dilatational wave, 2 Hz/100 Hz in frequency, 0.5 to 1.5 mA in intensity. Intervention in the shame BNA group was applied at the same time and acupoints as those in the BNA+EA group, the needles were pierced the skin without any electrical stimulation. The needles were retained for 30 min, once a day for continuous 7 days in both BNA+EA and shame BNA groups. Before and 10, 11, 15, 22 days after the operation, the left paw withdrawal threshold (PWT) was measured in the 5 groups. The levels of HDAC1, HDAC2 and MOR in DRG were detected by Western blot. RESULTS: Ten days after the cancer cell inoculation operation, the PWT of the BCP, MT, BNA+EA and sham BNA groups was decreased compared with the sham BCP group (P<0.01). Eleven days after the operation, the PWT of the MT, BNA+EA and sham BNA groups was increased compared with the BCP group (P<0.01). Twenty-two days after the operation, the difference was no significant between the BCP group and MT group (P>0.05); the PWT of the BNA+EA group was increased compared with the MT and sham BNA group (P<0.01). In the BCP group, the DRG levels of HDAC1 and HDCA2 were increased, while the level of MOR was decreased compared with the sham BCP group (P<0.05, P<0.01). In the MT group, the DRG level of HDAC1 was increased compared with the BCP group (P<0.05). In the BNA+EA group, the DRG level of HDAC1 was decreased compared with the MT group and the sham BNA group (P<0.01, P<0.05), while the level of MOR was increased (P<0.01). CONCLUSION: Early intervention of bone-nearby acupuncture combined with electroacupuncture can relieve the morphine tolerance in bone cancer pain rats, it may relate to down-regulating the expression of HDAC1 and up-regulating the expression of MOR in the dorsal root ganglia.


Assuntos
Neoplasias Ósseas/complicações , Dor do Câncer/terapia , Eletroacupuntura , Gânglios Espinais/metabolismo , Histona Desacetilases/metabolismo , Receptores Opioides mu/metabolismo , Pontos de Acupuntura , Animais , Tolerância a Medicamentos , Morfina , Distribuição Aleatória , Ratos , Ratos Sprague-Dawley
20.
Proc Natl Acad Sci U S A ; 117(12): 6509-6520, 2020 03 24.
Artigo em Inglês | MEDLINE | ID: mdl-32152128

RESUMO

Among all of the Super Elongation Complex (SEC) components, ELL1 (also known as ELL) is the only bona fide elongation factor that directly stimulates transcription elongation by RNA polymerase II. However, the mechanism(s) of functional regulation of ELL1 (referred to as ELL hereafter), through its stabilization, is completely unknown. Here, we report a function of human DBC1 in regulating ELL stability involving HDAC3, p300, and Siah1. Mechanistically, we show that p300-mediated site-specific acetylation increases, whereas HDAC3-mediated deacetylation decreases, ELL stability through polyubiquitylation by the E3 ubiquitin ligase Siah1. DBC1 competes with HDAC3 for the same binding sites on ELL and thus increases its acetylation and stability. Knockdown of DBC1 reduces ELL levels and expression of a significant number of genes, including those involved in glucose metabolism. Consistently, Type 2 diabetes patient-derived peripheral blood mononuclear cells show reduced expression of DBC1 and ELL and associated key target genes required for glucose homeostasis. Thus, we describe a pathway of regulating stability and functions of key elongation factor ELL for expression of diverse sets of genes, including ones that are linked to Type 2 diabetes pathogenesis.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Proteína p300 Associada a E1A/metabolismo , Regulação da Expressão Gênica , Histona Desacetilases/metabolismo , Proteínas Nucleares/metabolismo , Fatores de Elongação da Transcrição/metabolismo , Ubiquitina-Proteína Ligases/metabolismo , Acetilação , Proteínas Adaptadoras de Transdução de Sinal/genética , Animais , Sítios de Ligação , Linhagem Celular , Diabetes Mellitus Tipo 2/patologia , Proteína p300 Associada a E1A/genética , Técnicas de Silenciamento de Genes , Glucose/metabolismo , Histona Desacetilases/genética , Humanos , Leucócitos Mononucleares/metabolismo , Mutação , Ligação Proteica , Estabilidade Proteica , Transcrição Genética , Fatores de Elongação da Transcrição/química , Fatores de Elongação da Transcrição/genética , Ubiquitinação
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA