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1.
Braz J Med Biol Res ; 52(8): e8341, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31365693

RESUMO

MicroRNAs (miRNAs), as post-transcriptional regulators, have been reported to be involved in the initiation and progression of various types of cancer, including gastric cancer (GC). The present study aimed to investigate the role of miR-383-5p in gastric carcinogenesis. Cell viability was analyzed using CCK-8 kit. Annexin V-fluorescein isothiocyanate/propidium iodide double staining was used to evaluate cell apoptosis. The expression levels of miR-383-5p and histone deacetylase 9 (HDAC9) mRNA in GC tissues and cell lines were analyzed using RT-qPCR. The protein expression of HDAC9 was detected by western blotting. We found that HDAC9 was up-regulated and miR-383-5p was down-regulated in GC tissues and cell lines. High HDAC9 expression or low miR-383-5p expression was closely related to poor prognosis and metastasis in GC patients. HDAC9 knockout or miR-383-5p mimics led to growth inhibition and increased apoptosis in AGS and SGC-7901 cells. More importantly, we validated that miR-383-5p as a post-transcriptional regulator inhibited HDAC9 expression and was inversely correlated with HDAC9 expression in GC tissues. miR-383-5p had the opposite effects to HDAC9 in gastric carcinogenesis. miR-383-5p played an important role in gastric carcinogenesis, and it is one of the important mechanisms to regulate oncogenic HDAC9 in GC, which might be helpful in the development of novel therapeutic strategies for the treatment of GC.


Assuntos
Carcinoma/patologia , Histona Desacetilases/metabolismo , MicroRNAs/metabolismo , Proteínas Repressoras/metabolismo , Neoplasias Gástricas/patologia , Apoptose , Carcinogênese/genética , Carcinoma/genética , Carcinoma/metabolismo , Proliferação de Células/genética , Progressão da Doença , Regulação para Baixo , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , RNA Mensageiro/metabolismo , Neoplasias Gástricas/genética , Neoplasias Gástricas/metabolismo
2.
J Agric Food Chem ; 67(32): 8919-8925, 2019 Aug 14.
Artigo em Inglês | MEDLINE | ID: mdl-31334658

RESUMO

Histone deacetylase (HDAC) performs important functions in plant growth and development, including fruit ripening. As a complex biological process, fruit ripening involves the histone acetylation modification of ripening-associated genes. Histone deacetylase genes (HDACs) have been well studied in Arabidopsis and rice, but the biological functions of HDACs in papaya are poorly understood. In the present work, three CpHDACs, belonging to the RPD3/HDA1 subfamily, were identified from papaya and named as CpHDA1, CpHDA2, and CpHDA3. CpHDA1 and CpHDA2 were induced by propylene, while CpHDA3 was propylene-repressed. Moreover, CpHDA3 protein could physically interact with CpERF9 and enhance the transcriptional repression activities of CpERF9 to downstream genes CpPME1, CpPME2 and CpPG5. Histone acetylation levels of CpPME1 and CpPG5 were increased during fruit ripening. Taken together, these results suggested that CpERF9 recruits CpHDA3 to form a histone deacetylase repressor complex to mediate pectin methylesterase and polygalacturonase genes expression during papaya fruit ripening and softening.


Assuntos
Hidrolases de Éster Carboxílico/genética , Carica/metabolismo , Frutas/crescimento & desenvolvimento , Regulação da Expressão Gênica de Plantas , Histona Desacetilases/metabolismo , Proteínas de Plantas/metabolismo , Poligalacturonase/genética , Fatores de Transcrição/metabolismo , Hidrolases de Éster Carboxílico/metabolismo , Carica/genética , Carica/crescimento & desenvolvimento , Frutas/genética , Frutas/metabolismo , Regulação da Expressão Gênica no Desenvolvimento , Histona Desacetilases/genética , Proteínas de Plantas/genética , Poligalacturonase/metabolismo , Regiões Promotoras Genéticas , Ligação Proteica , Fatores de Transcrição/genética
3.
Toxicol Lett ; 314: 63-74, 2019 Oct 10.
Artigo em Inglês | MEDLINE | ID: mdl-31306741

RESUMO

This study aimed to verify the toxic effects of prenatal caffeine exposure (PCE) on the podocyte development in male offspring, and to explore the underlying intrauterine programming mechanisms. The pregnant rats were administered with caffeine (30 to 120 mg/kg⋅d) during gestational day (GD) 9 to 20. The male fetus on GD20 and the offspring at postnatal week (PW) 6 and PW28 were sacrificed. The results indicated that PCE caused ultrastructural abnormalities on podocyte, and inhibited the expression of podocyte marker genes such as Nephrin, Wilms tumor 1 (WT1), the histone 3 lysine 9 acetylation (H3K9ac) level in the Kruppel-like factor 4 (KLF4) promoter and its expression in the male offspring from GD20 to PW28. Meanwhile, the expression of glucocorticoid receptor (GR) and histone deacetylase 7 (HDAC7) in the fetus were increased by PCE. In vitro, corticosterone increased GR and HDAC7 whereas reduced the H3K9ac level of KLF4 and KLF4/Nephrin expression. KLF4 over-expression reversed the reduction of Nephrin expression, knockdown of HDAC7 and GR antagonist RU486 partially reversed the inhibitory effects of corticosterone on H3K9ac level and KLF4 expression. In conclusion, PCE caused podocyte developmental toxicity in male offspring, which was associated with corticosterone-induced low-functional programming of KLF4 through GR/HDAC7/H3K9ac pathway.


Assuntos
Cafeína/toxicidade , Estimulantes do Sistema Nervoso Central/toxicidade , Histonas/metabolismo , Nefropatias/induzido quimicamente , Fatores de Transcrição Kruppel-Like/metabolismo , Podócitos/efeitos dos fármacos , Efeitos Tardios da Exposição Pré-Natal , Acetilação , Animais , Células Cultivadas , Feminino , Regulação da Expressão Gênica no Desenvolvimento/efeitos dos fármacos , Idade Gestacional , Glucocorticoides/metabolismo , Histona Desacetilases/genética , Histona Desacetilases/metabolismo , Nefropatias/embriologia , Nefropatias/genética , Nefropatias/metabolismo , Fatores de Transcrição Kruppel-Like/genética , Lisina , Masculino , Exposição Materna , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismo , Fenótipo , Podócitos/metabolismo , Podócitos/ultraestrutura , Gravidez , Regiões Promotoras Genéticas , Ratos Wistar , Receptores de Glucocorticoides/genética , Receptores de Glucocorticoides/metabolismo , Transdução de Sinais/efeitos dos fármacos
4.
Life Sci ; 232: 116613, 2019 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-31265853

RESUMO

AIMS: Sepsis is a leading cause of death and disability worldwide. Autophagy may play a protective role in sepsis-induced myocardial dysfunction (SIMD). The present study investigated whether valproic acid (VPA), a class I histone deacetylase (HDAC) inhibitor, can attenuate SIMD by accelerating autophagy. MAIN METHODS: A sepsis model was established via the cecum ligation and puncture of male Sprague-Dawley rats. Cardiac injuries were measured using serum markers, echocardiographic cardiac parameters, and hematoxylin and eosin staining. Cardiac mitochondria injuries were detected with transmission electron microscopy, adenosine triphosphate (ATP) and cardiac mitochondrial DNA (mtDNA) contents. Cardiac oxidative levels were measured using redox markers in the cardiac homogenate. Real-time polymerase chain reaction (RT-PCR) and Western blot were performed to detect the expression levels of relative genes and proteins. HDAC binding to the phosphatase and tensin homolog deleted on chromosome ten (PTEN) promoters and histone acetylation levels of the PTEN promoters were analyzed via chromatin immunoprecipitation and quantitative RT-PCR. KEY FINDINGS: VPA can ameliorate SIMD by enhancing the autophagy level of the myocardium to reduce mitochondrial damage, oxidative stress, and myocardial inflammation in septic rats. Moreover, this study demonstrated that VPA induces autophagy by inhibiting HDAC1- and HDAC3-mediated PTEN expression in the myocardial tissues of septic rats. SIGNIFICANCE: This study found that VPA attenuates SIMD through myocardial autophagy acceleration by increasing PTEN expression and inhibiting the AKT/mTOR pathway. These findings preliminarily suggest that VPA may be a potential approach for the intervention and treatment of SIMD.


Assuntos
PTEN Fosfo-Hidrolase/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Sepse/tratamento farmacológico , Serina-Treonina Quinases TOR/metabolismo , Ácido Valproico/farmacologia , Disfunção Ventricular/tratamento farmacológico , Animais , Autofagia/efeitos dos fármacos , Ceco/metabolismo , Modelos Animais de Doenças , Inibidores de Histona Desacetilases/farmacologia , Histona Desacetilases/metabolismo , Masculino , Miocárdio/metabolismo , Ratos , Ratos Sprague-Dawley , Sepse/fisiopatologia , Transdução de Sinais/efeitos dos fármacos , Disfunção Ventricular/microbiologia , Disfunção Ventricular/patologia
5.
Nat Commun ; 10(1): 3004, 2019 07 08.
Artigo em Inglês | MEDLINE | ID: mdl-31285436

RESUMO

Identity determining transcription factors (TFs), or core regulatory (CR) TFs, are governed by cell-type specific super enhancers (SEs). Drugs to selectively inhibit CR circuitry are of high interest for cancer treatment. In alveolar rhabdomyosarcoma, PAX3-FOXO1 activates SEs to induce the expression of other CR TFs, providing a model system for studying cancer cell addiction to CR transcription. Using chemical genetics, the systematic screening of chemical matter for a biological outcome, here we report on a screen for epigenetic chemical probes able to distinguish between SE-driven transcription and constitutive transcription. We find that chemical probes along the acetylation-axis, and not the methylation-axis, selectively disrupt CR transcription. Additionally, we find that histone deacetylases (HDACs) are essential for CR TF transcription. We further dissect the contribution of HDAC isoforms using selective inhibitors, including the newly developed selective HDAC3 inhibitor LW3. We show HDAC1/2/3 are the co-essential isoforms that when co-inhibited halt CR transcription, making CR TF sites hyper-accessible and disrupting chromatin looping.


Assuntos
Elementos Facilitadores Genéticos/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Inibidores de Histona Desacetilases/farmacologia , Histona Desacetilases/metabolismo , Rabdomiossarcoma/genética , Acetilação/efeitos dos fármacos , Linhagem Celular Tumoral , Cromatina/efeitos dos fármacos , Cromatina/metabolismo , Genômica/métodos , Sequenciamento de Nucleotídeos em Larga Escala , Ensaios de Triagem em Larga Escala , Inibidores de Histona Desacetilases/química , Histona Desacetilases/química , Humanos , Simulação de Dinâmica Molecular , Sondas Moleculares/química , Sondas Moleculares/farmacologia , Proteínas de Fusão Oncogênica/genética , Fatores de Transcrição Box Pareados/genética , Cultura Primária de Células , Isoformas de Proteínas/antagonistas & inibidores , Isoformas de Proteínas/química , Isoformas de Proteínas/metabolismo , Rabdomiossarcoma/patologia , Análise de Sequência de RNA , Transcrição Genética/efeitos dos fármacos
6.
Eur J Med Chem ; 177: 457-466, 2019 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-31181405

RESUMO

Histone deacetylases (HDACs) play an important role in cancer, degenerative diseases and inflammation. The currently applied HDAC inhibitors in the clinic lack selectivity among HDAC isoforms, which limits their application for novel indications such as inflammatory diseases. Recent, literature indicates that HDAC 3 plays an important role among class I HDACs in gene expression in inflammation. In this perspective, the development and understanding of inhibitory selectivity among HDACs 1, 2 and 3 and their respective influence on gene expression need to be characterized to facilitate drug discovery. Towards this aim, we synthesized nine structural analogues of the class I HDAC inhibitor Entinostat and investigated their selectivity profile among HDACs 1, 2 and 3. We found that we can explain the observed structure activity relationships by small structural and conformational differences between HDAC 1 and HDAC 3 in the 'lid' interacting region. Cell-based studies indicated, however, that application of inhibitors with improved HDAC 3 selectivity did not provide an anti-inflammatory response in contrast to expectations from biochemical evidence in literature. Altogether, in this study, we identified structure activity relationships among class I HDACs and we connected isoform selectivity among class I HDACs with pro- and anti-inflammatory gene transcription in macrophages.


Assuntos
Anilidas/farmacologia , Benzamidas/farmacologia , Expressão Gênica/efeitos dos fármacos , Inibidores de Histona Desacetilases/farmacologia , Macrófagos/efeitos dos fármacos , Anilidas/síntese química , Anilidas/química , Anilidas/metabolismo , Animais , Benzamidas/síntese química , Benzamidas/química , Benzamidas/metabolismo , Domínio Catalítico , Histona Desacetilase 1/química , Histona Desacetilase 1/metabolismo , Histona Desacetilase 2/metabolismo , Inibidores de Histona Desacetilases/síntese química , Inibidores de Histona Desacetilases/química , Inibidores de Histona Desacetilases/metabolismo , Histona Desacetilases/química , Histona Desacetilases/metabolismo , Humanos , Inflamação/genética , Interleucina-10/genética , Interleucina-6/genética , Camundongos , Simulação de Acoplamento Molecular , Subunidade p50 de NF-kappa B/metabolismo , Óxido Nítrico Sintase Tipo II/genética , Ligação Proteica , Células RAW 264.7 , Estereoisomerismo , Relação Estrutura-Atividade , Fator de Necrose Tumoral alfa/genética
7.
Chem Biol Interact ; 309: 108701, 2019 Aug 25.
Artigo em Inglês | MEDLINE | ID: mdl-31181187

RESUMO

Pelargonidin, a well-known natural anthocyanidin found in berries strawberries, blueberries, red radishes and other natural foods, has been found to possess health beneficial effects including anti-cancer effect. Herein, we investigated the effect of pelargonidin on cellular transformation in mouse skin epidermal JB6 (JB6 P+) cells induced by tumor promoter 12-O-tetradecanoylphorbol-13-acetate (TPA). Pelargonidin treatment significantly decreased colony formation and suppressed cell viability of JB6 P+ cells. Pelargonidin also induced the anti-oxidant response element (ARE)-luciferase activation in HepG2-C8 cells overexpressing the ARE-luciferase reporter. Knockdown of nuclear factor E2-related factor 2 (Nrf2) in shNrf2 JB6 P+ cells enhanced TPA-induced colony formation and attenuated pelargonidin's blocking effect. Pelargonidin reduced the protein levels of genes encoding methyltransferases (DNMTs) and histone deacetylases (HDACs). Importantly, pelargonidin decreased the DNA methylation in the Nrf2 promoter region of JB6 P+ cells and increased Nrf2 downstream target genes expression, such as NAD(P)H/quinone oxidoreductase 1 (NQO1) and heme oxygenase-1 (HO-1), involved in cellular protection. In summary, our results showed that pelargonidin blocks TPA-induced cell transformation. The possible molecular mechanisms of its potential anti-cancer effects against neoplastic transformation may be attributed to its activation of Nrf2-ARE signaling pathway and its cytoprotective effect.


Assuntos
Antocianinas/farmacologia , Desmetilação do DNA/efeitos dos fármacos , Fator 2 Relacionado a NF-E2/metabolismo , Animais , Antocianinas/química , Elementos de Resposta Antioxidante/genética , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , DNA-Citosina Metilases/metabolismo , Células Epidérmicas/citologia , Células Epidérmicas/efeitos dos fármacos , Células Epidérmicas/metabolismo , Expressão Gênica/efeitos dos fármacos , Células Hep G2 , Histona Desacetilases/metabolismo , Humanos , Camundongos , Fator 2 Relacionado a NF-E2/antagonistas & inibidores , Fator 2 Relacionado a NF-E2/genética , Regiões Promotoras Genéticas , Interferência de RNA , RNA Interferente Pequeno/metabolismo , Acetato de Tetradecanoilforbol/farmacologia
8.
Int J Mol Sci ; 20(9)2019 Apr 30.
Artigo em Inglês | MEDLINE | ID: mdl-31052182

RESUMO

Class I histone deacetylases (HDACs) generally promote cell proliferation and tumorigenesis, whereas class IIA HDACs like HDAC4 and HDAC5 may promote or impede cancer development in a tissue-dependent manner. In urothelial carcinoma (UC), HDAC5 is often downregulated. Accordingly, HDAC5 was weakly expressed in UC cell lines suggesting a possible tumor-suppressive function. We therefore characterized the effects of stable HDAC5 expression in four UC cell lines (RT112, VM-Cub-1, SW1710 and UM-UC-3) with different phenotypes reflecting the heterogeneity of UC, by assessing proliferation, clonogenicity and migration ability. Further, we detailed changes in the proteome and transcriptome by immunoblotting, mass spectrometry and RNA sequencing analysis. We observed that HDAC5 overexpression in general decreased cell proliferation, but in one cell line (VM-Cub-1) induced a dramatic change from an epitheloid to a mesenchymal phenotype, i.e., epithelial-mesenchymal transition (EMT). These phenotypical changes were confirmed by comprehensive proteomics and transcriptomics analyses. In contrast to HDAC5, overexpression of HDAC4 exerted only weak effects on cell proliferation and phenotypes. We conclude that overexpression of HDAC5 may generally decrease proliferation in UC, but, intriguingly, may induce EMT on its own in certain circumstances.


Assuntos
Carcinoma/metabolismo , Proliferação de Células , Transição Epitelial-Mesenquimal , Histona Desacetilases/genética , Neoplasias da Bexiga Urinária/metabolismo , Urotélio/patologia , Carcinoma/genética , Linhagem Celular Tumoral , Células HEK293 , Histona Desacetilases/metabolismo , Humanos , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Neoplasias da Bexiga Urinária/genética , Urotélio/metabolismo
9.
Cell Mol Biol (Noisy-le-grand) ; 65(4): 23-28, 2019 Apr 30.
Artigo em Inglês | MEDLINE | ID: mdl-31078148

RESUMO

In recent years, most related studies have found that chronic hepatitis B virus infection is the main cause of hepatocellular carcinoma (HCC), but the specific pathogenesis is still unclear. To investigate the function of HDAC in hepatocellular carcinoma (HCC), this study used qRT-PCR to determine the expression levels of miR-376a and HDAC9 mNRA in HCC and para-cancerous tissues. The clinical significance of HDAC9 in HCC was assessed in a study cohort containing 37 patients with HCC using immunohistochemistry. The expression level of miR-376a in liver cancer tissues was significantly lower than that in para-cancerous tissues, while the expression level of HDAC9 mRNA in liver cancer tissue was significantly higher than that in para-cancerous tissues. The expression of HDAC9 occurred mainly in the nucleus. There was a significant correlation between tumor differentiation and HDAC9. Survival analysis showed that HCC patients with higher HDAC9 expression had poorer prognosis, and subsequent multivariate analysis showed that HDAC9 expression level was an independent predictor. There was a definite correlation between HDAC9 and the expressions of AFP and Ki67. These results suggest that the expression level of HDAC9 in HCC is abnormally high while the expression level of miR-376a is significantly decreased, indicating that HDAC9 may be a potential prognostic indicator of HCC.


Assuntos
Carcinoma Hepatocelular/enzimologia , Histona Desacetilases/metabolismo , Neoplasias Hepáticas/enzimologia , Proteínas Repressoras/metabolismo , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/patologia , Feminino , Regulação Neoplásica da Expressão Gênica , Histona Desacetilases/genética , Humanos , Antígeno Ki-67/metabolismo , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/patologia , Masculino , MicroRNAs/genética , MicroRNAs/metabolismo , Pessoa de Meia-Idade , Análise Multivariada , Prognóstico , Proteínas Repressoras/genética , Análise de Sobrevida , alfa-Fetoproteínas/metabolismo
10.
J Med Food ; 22(5): 444-450, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-31084542

RESUMO

Studies have identified the potential of chemopreventive effects of sulforaphane (SFN); however, the underlying mechanisms of its effect on breast cancer require further elucidation. This study investigated the anticancer effects of SFN that specifically induces G1/S arrest in breast ductal carcinoma (ZR-75-1) cells. The proliferation of the cancer cells after treatment with SFN was detected by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. DNA content and cell cycle status were analyzed through flow cytometry. Our results demonstrated the inhibition of growth in ZR-75-1 cells upon SFN exposure. In addition, SERTAD1 (SEI-1) caused the accumulation of SFN-treated G1/S-phase cells. The downregulation of SEI-1, cyclin D2, and histone deacetylase 3 suggested that in addition to the identified effects of SFN against breast cancer prevention, it may also exert antitumor activities in established breast cancer cells. In conclusion, SFN can inhibit growth of and induce cell cycle arrest in cancer cells, suggesting its potential role as an anticancer agent.


Assuntos
Antineoplásicos Fitogênicos/farmacologia , Neoplasias da Mama/tratamento farmacológico , Isotiocianatos/farmacologia , Proteínas Nucleares/genética , Transativadores/genética , Neoplasias da Mama/genética , Neoplasias da Mama/metabolismo , Neoplasias da Mama/fisiopatologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Ciclina D2/genética , Ciclina D2/metabolismo , Pontos de Checagem da Fase G1 do Ciclo Celular/efeitos dos fármacos , Histona Desacetilases/genética , Histona Desacetilases/metabolismo , Humanos , Proteínas Nucleares/metabolismo , Extratos Vegetais/farmacologia , Pontos de Checagem da Fase S do Ciclo Celular/efeitos dos fármacos , Transativadores/metabolismo , Verduras/química
11.
Plant Sci ; 283: 355-365, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31128706

RESUMO

Despite recent evidence that HDACs are involved in the environmental stress responses of plants, their roles in the abiotic stress responses of monocot plants remain largely unexplored. We investigated a HDAC gene, Bradi3g08060 (BdHD1), in Brachypodium distachyon. The Brachypodium BdHD1-overexpression plants displayed a hypersensitive phenotype to ABA and exhibited better survival under drought conditions. On the other hand, the RNA-interference plants were insensitive to ABA and showed low survival under drought stress. At the genome-wide level, overexpression of BdHD1 led to lower H3K9 acetylation at the transcriptional start sites of 230 genes than in the wild type plants under the drought treatment. We validated our ChIP-Seq data on 10 selected transcription factor genes from the 230 drought-specific genes. These genes exhibited much lower expression in the BdHD1-overexpression plants compared to the wild type plants under drought stress. We further identified an ABA-inducible transcription factor gene BdWRKY24 that was repressed in BdHD1-OE plants, but highly expressed in RNA-interference plants under drought stress. These results indicate that BdHD1 plays a positive role in ABA sensitivity and drought stress tolerance and they provide a link between the role of BdHD1 and the drought stress response at a genome-wide level in Brachypodium.


Assuntos
Ácido Abscísico/fisiologia , Brachypodium/metabolismo , Histona Desacetilases/fisiologia , Reguladores de Crescimento de Planta/fisiologia , Proteínas de Plantas/fisiologia , Ácido Abscísico/metabolismo , Arabidopsis/enzimologia , Arabidopsis/genética , Brachypodium/enzimologia , Brachypodium/genética , Brachypodium/fisiologia , Desidratação , Regulação da Expressão Gênica de Plantas , Técnicas de Silenciamento de Genes , Histona Desacetilases/metabolismo , Filogenia , Reguladores de Crescimento de Planta/metabolismo , Proteínas de Plantas/metabolismo , Plantas Geneticamente Modificadas , Dedos de Zinco/genética , Dedos de Zinco/fisiologia
12.
Nat Commun ; 10(1): 1566, 2019 04 05.
Artigo em Inglês | MEDLINE | ID: mdl-30952952

RESUMO

The class 3 phosphoinositide 3-kinase (PI3K) is required for lysosomal degradation by autophagy and vesicular trafficking, assuring nutrient availability. Mitochondrial lipid catabolism is another energy source. Autophagy and mitochondrial metabolism are transcriptionally controlled by nutrient sensing nuclear receptors. However, the class 3 PI3K contribution to this regulation is unknown. We show that liver-specific inactivation of Vps15, the essential regulatory subunit of the class 3 PI3K, elicits mitochondrial depletion and failure to oxidize fatty acids. Mechanistically, transcriptional activity of Peroxisome Proliferator Activated Receptor alpha (PPARα), a nuclear receptor orchestrating lipid catabolism, is blunted in Vps15-deficient livers. We find PPARα repressors Histone Deacetylase 3 (Hdac3) and Nuclear receptor co-repressor 1 (NCoR1) accumulated in Vps15-deficient livers due to defective autophagy. Activation of PPARα or inhibition of Hdac3 restored mitochondrial biogenesis and lipid oxidation in Vps15-deficient hepatocytes. These findings reveal roles for the class 3 PI3K and autophagy in transcriptional coordination of mitochondrial metabolism.


Assuntos
Autofagia/fisiologia , Metabolismo dos Lipídeos , Mitocôndrias/metabolismo , PPAR alfa/metabolismo , Fosfatidilinositol 3-Quinases/fisiologia , Animais , Autofagia/efeitos dos fármacos , Autofagia/genética , Fenofibrato/farmacologia , Regulação da Expressão Gênica/efeitos dos fármacos , Células HEK293 , Hepatócitos/citologia , Hepatócitos/efeitos dos fármacos , Hepatócitos/metabolismo , Histona Desacetilases/genética , Histona Desacetilases/metabolismo , Histona Desacetilases/fisiologia , Humanos , Metabolismo dos Lipídeos/efeitos dos fármacos , Masculino , Camundongos , Camundongos Knockout , Correpressor 1 de Receptor Nuclear/genética , Correpressor 1 de Receptor Nuclear/metabolismo , Correpressor 1 de Receptor Nuclear/fisiologia , Fosfatidilinositol 3-Quinases/genética , Fosfatidilinositol 3-Quinases/metabolismo , Transcrição Genética/efeitos dos fármacos , Proteína VPS15 de Distribuição Vacuolar/genética , Proteína VPS15 de Distribuição Vacuolar/metabolismo , Proteína VPS15 de Distribuição Vacuolar/fisiologia
13.
Nat Commun ; 10(1): 1713, 2019 04 12.
Artigo em Inglês | MEDLINE | ID: mdl-30979883

RESUMO

Unlike activation of target genes in response to abscisic acid (ABA), how MYB96 transcription factor represses ABA-repressible genes to further enhance ABA responses remains unknown. Here, we show MYB96 interacts with the histone modifier HDA15 to suppress negative regulators of early ABA signaling. The MYB96-HDA15 complex co-binds to the promoters of a subset of RHO GTPASE OF PLANTS (ROP) genes, ROP6, ROP10, and ROP11, and represses their expression by removing acetyl groups of histone H3 and H4 from the cognate regions, particularly in the presence of ABA. In support, HDA15-deficient mutants display reduced ABA sensitivity and are susceptible to drought stress with derepression of the ROP genes, as observed in the myb96-1 mutant. Biochemical and genetic analyses show that MYB96 and HDA15 are interdependent in the regulation of ROP suppression. Thus, MYB96 confers maximal ABA sensitivity by regulating both positive and negative regulators of ABA signaling through distinctive molecular mechanisms.


Assuntos
Ácido Abscísico/metabolismo , Proteínas de Arabidopsis/metabolismo , Arabidopsis/genética , Regulação da Expressão Gênica de Plantas , Histona Desacetilases/metabolismo , Fatores de Transcrição/metabolismo , Arabidopsis/metabolismo , Proteínas de Arabidopsis/genética , Catálise , Genótipo , Histona Desacetilases/genética , Histonas/metabolismo , Mutação , Plantas Geneticamente Modificadas/metabolismo , Regiões Promotoras Genéticas , Reprodutibilidade dos Testes , Transdução de Sinais , Fatores de Transcrição/genética
14.
Molecules ; 24(7)2019 Apr 06.
Artigo em Inglês | MEDLINE | ID: mdl-30959867

RESUMO

Bone is a dynamic tissue that must respond to developmental, repair, and remodeling cues in a rapid manner with changes in gene expression. Carefully-coordinated cycles of bone resorption and formation are essential for healthy skeletal growth and maintenance. Osteoclasts are large, multinucleated cells that are responsible for breaking down bone by secreting acids to dissolve the bone mineral and proteolytic enzymes that degrade the bone extracellular matrix. Increased osteoclast activity has a severe impact on skeletal health, and therefore, osteoclasts represent an important therapeutic target in skeletal diseases, such as osteoporosis. Progression from multipotent progenitors into specialized, terminally-differentiated cells involves carefully-regulated patterns of gene expression to control lineage specification and emergence of the cellular phenotype. This process requires coordinated action of transcription factors with co-activators and co-repressors to bring about proper activation and inhibition of gene expression. Histone deacetylases (HDACs) are an important group of transcriptional co-repressors best known for reducing gene expression via removal of acetyl modifications from histones at HDAC target genes. This review will cover the progress that has been made recently to understand the role of HDACs and their targets in regulating osteoclast differentiation and activity and, thus, serve as potential therapeutic target.


Assuntos
Osso e Ossos/metabolismo , Diferenciação Celular , Histona Desacetilases/metabolismo , Osteoclastos/citologia , Osteoclastos/metabolismo , Animais , Reabsorção Óssea/genética , Osso e Ossos/efeitos dos fármacos , Diferenciação Celular/efeitos dos fármacos , Diferenciação Celular/genética , Regulação da Expressão Gênica/efeitos dos fármacos , Inibidores de Histona Desacetilases/farmacologia , Humanos , Osteoclastos/efeitos dos fármacos , Transcrição Genética
15.
Gynecol Oncol ; 154(1): 207-217, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-30979588

RESUMO

OBJECTIVE: Though metastasis-associated protein 1 (MTA1) is widely overexpressed in human cancers and is associated with advanced clinicopathological characteristics and survival in related diseases, the association between MTA1 and endometrial cancer (EC) is little known and needs to be studied. METHODS: Western blot and immunohistochemistry were used to analyze protein expression level of cells and tissues, while real-time PCR was used for RNA detection. Bioinformatics tool analysis revealed the relationship between MTA1 and clinicopathological characteristics and survival. CCK-8 assay, colony-formation assay, cell scratch assay, and Transwell assay were performed to determine cell proliferation, migration and invasion abilities, respectively. RESULTS: The expression level of MTA1 was significantly higher in human EC tissues than in normal endometrium. MTA1 expression was correlated positively with lymph nodes metastasis and poor survival rate in EC. Experimentally overexpressed MTA1 could promote cell proliferation, migration and invasion abilities of EC cell lines Ishikawa, HEC-1B, and RL-952, while reduction of MTA1 inhibited these cell biological behaviors. Moreover, MTA1 could also reverse the negative effect of miR-30c, a direct modulator of MTA1, on EC cells. Our research also revealed that overexpression of MTA1 contributed to EC tumor growth, while knockdown of MTA1 resulted in tumor growth inhibition. Additionally, the phosphorylation levels of mTOR (S2448) and 4E-BP1 (T37/46) changed significantly along with AKT (T308) under regulation of MTA1, both in vivo and vitro. CONCLUSION: Our results showed that MTA1, as a downstream target of miR-30c, might promote EC progression via AKT/mTOR/4E-BP1 pathway, which indicated the potential therapy target of MTA1 in EC.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Neoplasias do Endométrio/metabolismo , Histona Desacetilases/metabolismo , MicroRNAs/metabolismo , Fosfoproteínas/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Proteínas Repressoras/metabolismo , Serina-Treonina Quinases TOR/metabolismo , Animais , Movimento Celular , Proliferação de Células , Progressão da Doença , Neoplasias do Endométrio/genética , Neoplasias do Endométrio/patologia , Feminino , Xenoenxertos , Histona Desacetilases/biossíntese , Histona Desacetilases/genética , Humanos , Camundongos , Camundongos Nus , MicroRNAs/genética , Pessoa de Meia-Idade , Invasividade Neoplásica , Fosforilação , Proteínas Repressoras/biossíntese , Proteínas Repressoras/genética , Transdução de Sinais , Células Tumorais Cultivadas
16.
Cell Mol Life Sci ; 76(17): 3263-3282, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-30982077

RESUMO

Dysregulation of the epigenome and constitutional epimutation lead to aberrant expression of the genes, which regulate cancer initiation and progression. Histone deacetylases (HDACs), which are highly conserved in yeast to humans, are known to regulate numerous proteins involved in the transcriptional regulation of chromatin structures, apoptosis, autophagy, and mitophagy. In addition, a non-permissive chromatin conformation is created by HDACs, preventing the transcription of the genes encoding the proteins associated with tumorigenesis. Recently, an expanding perspective has been reported from the clinical trials with HDACis (HDAC inhibitors), which has emerged as a determining target for the study of the detailed mechanisms underlying cancer progression. Therefore, the present review focuses on the comprehensive lucubration of post-translational modifications and the molecular mechanisms through which HDACs alter the ambiguities associated with epigenome, with particular insights into the initiation, progression, and regulation of cancer.


Assuntos
Apoptose , Autofagia , Histona Desacetilases/metabolismo , Apoptose/efeitos dos fármacos , Autofagia/efeitos dos fármacos , Epigenômica , Inibidores de Histona Desacetilases/farmacologia , Inibidores de Histona Desacetilases/uso terapêutico , Histona Desacetilases/química , Humanos , Invasividade Neoplásica , Metástase Neoplásica , Neoplasias/tratamento farmacológico , Neoplasias/patologia , Processamento de Proteína Pós-Traducional
17.
Curr Med Sci ; 39(2): 228-236, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-31016515

RESUMO

Histone deacetylases (HDACs) inhibitors are novel in cancer therapy nowadays. HDAC6-selective inhibitors exert advantageous effects due to higher selectivity and less toxicity. We explored the anti-tumor effect and the molecular mechanism of cay10603, a potent HDAC6 inhibitor in Burkitt's lymphoma cells. Our study revealed cay10603 inhibited the proliferation of Burkitt's lymphoma cell lines, and induced caspase-dependent apoptosis. Cay10603 inhibited the expression of CDKs and cyclins to impede cell cycle progression in both Burkitt's lymphoma cell lines. Cay10603 also showed the additive effect with vp16 notably. Our data presented the promising anti-tumor effect of cay10603 in the Burkitt's lymphoma therapy.


Assuntos
Antineoplásicos/farmacologia , Linfoma de Burkitt/tratamento farmacológico , Ciclo Celular/efeitos dos fármacos , Inibidores de Histona Desacetilases/farmacologia , Histona Desacetilases/metabolismo , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Humanos
18.
Ann Clin Lab Sci ; 49(2): 189-192, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31028063

RESUMO

OBJECTIVES: Histone deacetylase 4 (HDAC4) is involved in the development of multiple types of cancers. In this study, we aimed to investigate the expression and clinical significance of HDAC4 in hepatocellular carcinoma (HCC). METHODS: 49 patients with stage B HCC who underwent surgical resection were enrolled in this study. All patients were followed up with an observation time of 4.8 to 7 years. Immunohistochemistry was applied to investigate the expression level of HDAC4. RESULTS: HDAC4 protein is over-expressed in HCC tissues compared with matched adjacent non-cancer tissues. Kaplan-Meier analysis shows that the positive expression of HDAC4 is associated with poor survival in these patients. CONCLUSIONS: Our study shows that HDAC4 over-expression is important for the development of advanced HCC, which may serve as a useful prognostic biomarker and therapeutic target for this malignancy.


Assuntos
Carcinoma Hepatocelular/enzimologia , Carcinoma Hepatocelular/patologia , Histona Desacetilases/metabolismo , Neoplasias Hepáticas/enzimologia , Neoplasias Hepáticas/patologia , Proteínas Repressoras/metabolismo , Linhagem Celular Tumoral , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Análise de Sobrevida
19.
J Immunol Res ; 2019: 9678098, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31001564

RESUMO

Valproic acid (VPA) is widely recognized for its use in the control of epilepsy and other neurological disorders in the past 50 years. Recent evidence has shown the potential of VPA in the control of certain cancers, owed in part to its role in modulating epigenetic changes through the inhibition of histone deacetylases, affecting the expression of genes involved in the cell cycle, differentiation, and apoptosis. The direct impact of VPA in cells of the immune system has only been explored recently. In this review, we discuss the effects of VPA in the suppression of some activation mechanisms in several immune cells that lead to an anti-inflammatory response. As expected, immune cells are not exempt from the effect of VPA, as it also affects the expression of genes of the cell cycle and apoptosis through epigenetic modifications. In addition to inhibiting histone deacetylases, VPA promotes RNA interference, activates histone methyltransferases, or represses the activation of transcription factors. However, during the infectious process, the effectiveness of VPA is subject to the biological nature of the pathogen and the associated immune response; this is because VPA can promote the control or the progression of the infection. Due to its various effects, VPA is a promising alternative for the control of autoimmune diseases and hypersensitivity and needs to be further explored.


Assuntos
Imunidade Adaptativa , Reposicionamento de Medicamentos , Imunidade Inata , Neoplasias/tratamento farmacológico , Ácido Valproico/uso terapêutico , Animais , Apoptose/efeitos dos fármacos , Ciclo Celular/efeitos dos fármacos , Diferenciação Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Epigênese Genética , Inibidores de Histona Desacetilases/administração & dosagem , Histona Desacetilases/metabolismo , Humanos , Camundongos , Interferência de RNA
20.
Int J Mol Sci ; 20(8)2019 Apr 16.
Artigo em Inglês | MEDLINE | ID: mdl-31014028

RESUMO

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.


Assuntos
Inibidores de Histona Desacetilases/farmacologia , Miócitos Cardíacos/efeitos dos fármacos , Vorinostat/farmacologia , Trifosfato de Adenosina/metabolismo , Animais , Cálcio/metabolismo , Células Cultivadas , Diabetes Mellitus Experimental/patologia , Histona Desacetilases/química , Histona Desacetilases/metabolismo , Masculino , Miócitos Cardíacos/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Ratos , Ratos Wistar , Espécies Reativas de Oxigênio/metabolismo
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