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1.
Sheng Wu Gong Cheng Xue Bao ; 37(8): 2645-2657, 2021 Aug 25.
Artigo em Chinês | MEDLINE | ID: mdl-34472285

RESUMO

Lysine acetylation is one of the major post-translational modifications and plays critical roles in regulating gene expression and protein function. Histone deacetylases (HDACs) are responsible for the removal of acetyl groups from the lysines of both histone and non-histone proteins. The RPD3 family is the most widely studied HDACs. This article summarizes the regulatory mechanisms of Arabidopsis RPD3 family in several growth and development processes, which provide a reference for studying the mechanisms of RPD3 family members in regulating plant development. Moreover, this review may provide ideas and clues for exploring the functions of other members of HDACs family.


Assuntos
Arabidopsis , Desenvolvimento Vegetal , Arabidopsis/genética , Arabidopsis/metabolismo , Histona Desacetilases/genética , Histona Desacetilases/metabolismo , Histonas , Desenvolvimento Vegetal/genética
2.
Nat Commun ; 12(1): 5548, 2021 09 20.
Artigo em Inglês | MEDLINE | ID: mdl-34545082

RESUMO

Isoniazid (INH) is a first-line anti-tuberculosis drug used for nearly 70 years. However, the mechanism underlying the side effects of INH has remained elusive. Here, we report that INH and its metabolites induce a post-translational modification (PTM) of histones, lysine isonicotinylation (Kinic), also called 4-picolinylation, in cells and mice. INH promotes the biosynthesis of isonicotinyl-CoA (Inic-CoA), a co-factor of intracellular isonicotinylation. Mass spectrometry reveals 26 Kinic sites in histones in HepG2 cells. Acetyltransferases CREB-binding protein (CBP) and P300 catalyse histone Kinic, while histone deacetylase HDAC3 functions as a deisonicotinylase. Notably, MNase sensitivity assay and RNA-seq analysis show that histone Kinic relaxes chromatin structure and promotes gene transcription. INH-mediated histone Kinic upregulates PIK3R1 gene expression and activates the PI3K/Akt/mTOR signalling pathway in liver cancer cells, linking INH to tumourigenicity in the liver. We demonstrate that Kinic is a histone acylation mark with a pyridine ring, which may have broad biological effects. Therefore, INH-induced isonicotinylation potentially accounts for the side effects in patients taking INH long-term for anti-tuberculosis therapy, and this modification may increase the risk of cancer in humans.


Assuntos
Antituberculosos/farmacologia , Código das Histonas , Isoniazida/farmacologia , Ácidos Isonicotínicos/metabolismo , Acetilação , Sequência de Aminoácidos , Animais , Cromatina/metabolismo , Coenzima A/metabolismo , Células HeLa , Células Hep G2 , Histona Desacetilases/metabolismo , Histonas/química , Histonas/metabolismo , Humanos , Ácidos Isonicotínicos/química , Lisina/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Neoplasias/metabolismo , Transdução de Sinais/efeitos dos fármacos , Transcrição Genética , Regulação para Cima/efeitos dos fármacos , Fatores de Transcrição de p300-CBP/metabolismo
3.
Molecules ; 26(17)2021 Aug 25.
Artigo em Inglês | MEDLINE | ID: mdl-34500583

RESUMO

Histone deacetylases (HDACs) remove acetyl groups from acetylated lysine residues and have a large variety of substrates and interaction partners. Therefore, it is not surprising that HDACs are involved in many diseases. Most inhibitors of zinc-dependent HDACs (HDACis) including approved drugs contain a hydroxamate as a zinc-binding group (ZBG), which is by far the biggest contributor to affinity, while chemical variation of the residual molecule is exploited to create more or less selectivity against HDAC isozymes or other metalloproteins. Hydroxamates have a propensity for nonspecificity and have recently come under considerable suspicion because of potential mutagenicity. Therefore, there are significant concerns when applying hydroxamate-containing compounds as therapeutics in chronic diseases beyond oncology due to unwanted toxic side effects. In the last years, several alternative ZBGs have been developed, which can replace the critical hydroxamate group in HDACis, while preserving high potency. Moreover, these compounds can be developed into highly selective inhibitors. This review aims at providing an overview of the progress in the field of non-hydroxamic HDACis in the time period from 2015 to present. Formally, ZBGs are clustered according to their binding mode and structural similarity to provide qualitative assessments and predictions based on available structural information.


Assuntos
Proteínas de Transporte/metabolismo , Histona Desacetilases/metabolismo , Ácidos Hidroxâmicos/metabolismo , Zinco/metabolismo , Animais , Inibidores de Histona Desacetilases/farmacologia , Humanos , Hidroxilamina/metabolismo , Relação Estrutura-Atividade
4.
Int J Mol Sci ; 22(17)2021 Aug 25.
Artigo em Inglês | MEDLINE | ID: mdl-34502112

RESUMO

Silver nanoparticles (AgNPs) are frequently detected in many convenience goods, such as cosmetics, that are applied directly to the skin. AgNPs accumulated in cells can modulate a wide range of molecular pathways, causing direct changes in cells. The aim of this study is to assess the capability of AgNPs to modulate the metastasis of breast cancer cells through the induction of epithelial-to-mesenchymal transition (EMT). The effect of the AgNPs on MCF-7 cells was investigated via the sulforhodamine B method, the wound healing test, generation of reactive oxygen species (ROS), the standard cytofluorimetric method of measuring the cell cycle, and the expression of EMT marker proteins and the MTA3 protein via Western blot. To fulfill the results, calcium flux and HDAC activity were measured. Additionally, mitochondrial membrane potential was measured to assess the direct impact of AgNPs on mitochondria. The results indicated that the MCF-7 cells are resistant to the cytotoxic effect of AgNPs and have higher mobility than the control cells. Treatment with AgNPs induced a generation of ROS; however, it did not affect the cell cycle but modulated the expression of EMT marker proteins and the MTA3 protein. Mitochondrial membrane potential and calcium flux were not altered; however, the AgNPs did modulate the total HDAC activity. The presented data support our hypothesis that AgNPs modulate the metastasis of MCF-7 cells through the EMT pathway. These results suggest that AgNPs, by inducing reactive oxygen species generation, alter the metabolism of breast cancer cells and trigger several pathways related to metastasis.


Assuntos
Neoplasias da Mama/metabolismo , Transição Epitelial-Mesenquimal , Nanopartículas Metálicas/toxicidade , Sinalização do Cálcio , Ciclo Celular , Movimento Celular , Estrogênios/metabolismo , Feminino , Histona Desacetilases/genética , Histona Desacetilases/metabolismo , Humanos , Células MCF-7 , Potencial da Membrana Mitocondrial , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/metabolismo , Espécies Reativas de Oxigênio , Prata/química
5.
Int J Mol Sci ; 22(17)2021 Aug 24.
Artigo em Inglês | MEDLINE | ID: mdl-34502048

RESUMO

Nuclear hormone receptors (NRs) regulate transcription of the target genes in a ligand-dependent manner in either a positive or negative direction, depending on the case. Deacetylation of histone tails is associated with transcriptional repression. A nuclear receptor corepressor (N-CoR) and a silencing mediator for retinoid and thyroid hormone receptors (SMRT) are the main corepressors responsible for gene suppression mediated by NRs. Among numerous histone deacetylases (HDACs), HDAC3 is the core component of the N-CoR/SMRT complex, and plays a central role in NR-dependent repression. Here, the roles of HDAC3 in ligand-independent repression, gene repression by orphan NRs, NRs antagonist action, ligand-induced repression, and the activation of a transcriptional coactivator are reviewed. In addition, some perspectives regarding the non-canonical mechanisms of HDAC3 action are discussed.


Assuntos
Histona Desacetilases/metabolismo , Receptores Citoplasmáticos e Nucleares/metabolismo , Animais , Proteínas Correpressoras/metabolismo , Humanos
6.
Molecules ; 26(16)2021 Aug 19.
Artigo em Inglês | MEDLINE | ID: mdl-34443600

RESUMO

Organotin(IV) compounds are a class of non-platinum metallo-conjugates exhibiting antitumor activity. The effects of different organotin types has been related to several mechanisms, including their ability to modify acetylation protein status and to promote apoptosis. Here, we focus on triorganotin(IV) complexes of butyric acid, a well-known HDAC inhibitor with antitumor properties. The conjugated compounds were synthesized and characterised by FTIR spectroscopy, multi-nuclear (1H, 13C and 119Sn) NMR, and mass spectrometry (ESI-MS). In the triorganotin(IV) complexes, an anionic monodentate butyrate ligand was observed, which coordinated the tin atom on a tetra-coordinated, monomeric environment similar to ester. FTIR and NMR findings confirm this structure both in solid state and solution. The antitumor efficacy of the triorganotin(IV) butyrates was tested in colon cancer cells and, among them, tributyltin(IV) butyrate (BT2) was selected as the most efficacious. BT2 induced G2/M cell cycle arrest, ER stress, and apoptotic cell death. These effects were obtained using low concentrations of BT2 up to 1 µM, whereas butyric acid alone was completely inefficacious, and the parent compound TBT was poorly effective at the same treatment conditions. To assess whether butyrate in the coordinated form maintains its epigenetic effects, histone acetylation was evaluated and a dramatic decrease in acetyl-H3 and -H4 histones was found. In contrast, butyrate alone stimulated histone acetylation at a higher concentration (5 mM). BT2 was also capable of preventing histone acetylation induced by SAHA, another potent HDAC inhibitor, thus suggesting that it may activate HDACs. These results support a potential use of BT2, a novel epigenetic modulator, in colon cancer treatment.


Assuntos
Apoptose/genética , Ácido Butírico/química , Neoplasias do Colo/patologia , Estresse do Retículo Endoplasmático/genética , Epigênese Genética/efeitos dos fármacos , Compostos de Trialquitina/química , Compostos de Trialquitina/farmacologia , Acetilação/efeitos dos fármacos , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Histona Desacetilases/metabolismo , Humanos , Processamento de Proteína Pós-Traducional/efeitos dos fármacos
7.
Pestic Biochem Physiol ; 178: 104908, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34446212

RESUMO

Histone acetylation plays important roles in eukaryotic chromatin modification and gene expression regulation. Acetylation levels are modulated by histone deacetylases (HDACs), which function as key epigenetic factors that regulate gene expression in response to various stresses. HDT701, a member of the HD2 subfamily of HDACs, plays crucial roles in plant responses to abiotic stress and pathogen infection. Here, we analysed the expression pattern of SbHDT701 in sorghum. Real-time fluorescence quantitative PCR (RT-qPCR) results showed that expression of SbHDT701 was tissue-specific, and up-regulated under drought (d-mannitol) and salt (NaCl) stresses. We also determined the optimal expression conditions for SbHDT701 protein accumulation, and successfully expressed and purified SbHDT701 protein. Besides, overexpression of SbHDT701 in could promote the growth of recombinant cells under abiotic stress. SbHDT701 expression in Escherichia coli also increased acetylation modification levels following treatment with 750 mM NaCl, and 100 mM or 300 mM d-mannitol. In summary, the sorghum HDAC SbHDT701 mediates stress responses by enhancing acetylation modification levels.


Assuntos
Histona Desacetilases , Sorghum , Acetilação , Secas , Regulação da Expressão Gênica de Plantas , Histona Desacetilases/genética , Histona Desacetilases/metabolismo , Sorghum/genética
8.
Int J Mol Sci ; 22(15)2021 Jul 26.
Artigo em Inglês | MEDLINE | ID: mdl-34360712

RESUMO

Histone deacetylase (HDAC) and histone acetyltransferase (HAT) regulate transcription and the most important functions of cells by acetylating/deacetylating histones and non-histone proteins. These proteins are involved in cell survival and death, replication, DNA repair, the cell cycle, and cell responses to stress and aging. HDAC/HAT balance in cells affects gene expression and cell signaling. There are very few studies on the effects of stroke on non-histone protein acetylation/deacetylation in brain cells. HDAC inhibitors have been shown to be effective in protecting the brain from ischemic damage. However, the role of different HDAC isoforms in the survival and death of brain cells after stroke is still controversial. HAT/HDAC activity depends on the acetylation site and the acetylation/deacetylation of the main proteins (c-Myc, E2F1, p53, ERK1/2, Akt) considered in this review, that are involved in the regulation of cell fate decisions. Our review aims to analyze the possible role of the acetylation/deacetylation of transcription factors and signaling proteins involved in the regulation of survival and death in cerebral ischemia.


Assuntos
Isquemia Encefálica/metabolismo , Histona Acetiltransferases/metabolismo , Histona Desacetilases/metabolismo , Modelos Neurológicos , Processamento de Proteína Pós-Traducional , Transdução de Sinais , Fatores de Transcrição/metabolismo , Acetilação , Animais , Humanos
9.
Int J Mol Sci ; 22(16)2021 Aug 05.
Artigo em Inglês | MEDLINE | ID: mdl-34445133

RESUMO

New chimeric inhibitors targeting the epidermal growth factor (EGFR) and histone deacetylases (HDACs) were synthesized and tested for antineoplastic efficiency in solid cancer (prostate and hepatocellular carcinoma) and leukemia/lymphoma cell models. The most promising compounds, 3BrQuin-SAHA and 3ClQuin-SAHA, showed strong inhibition of tumor cell growth at one-digit micromolar concentrations with IC50 values similar to or lower than those of clinically established reference compounds SAHA and gefitinib. Target-specific EGFR and HDAC inhibition was demonstrated in cell-free kinase assays and Western blot analyses, while unspecific cytotoxic effects could not be observed in LDH release measurements. Proapoptotic formation of reactive oxygen species and caspase-3 activity induction in PCa and HCC cell lines DU145 and Hep-G2 seem to be further aspects of the modes of action. Antiangiogenic potency was recognized after applying the chimeric inhibitors on strongly vascularized chorioallantoic membranes of fertilized chicken eggs (CAM assay). The novel combination of two drug pharmacophores against the EGFR and HDACs in one single molecule was shown to have pronounced antineoplastic effects on tumor growth in both solid and leukemia/lymphoma cell models. The promising results merit further investigations to further decipher the underlying modes of action of the novel chimeric inhibitors and their suitability for new clinical approaches in tumor treatment.


Assuntos
Antineoplásicos/farmacologia , Inibidores de Histona Desacetilases/farmacologia , Histona Desacetilases/metabolismo , Apoptose/efeitos dos fármacos , Carcinoma Hepatocelular/tratamento farmacológico , Carcinoma Hepatocelular/metabolismo , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Ensaios de Seleção de Medicamentos Antitumorais/métodos , Receptores ErbB/antagonistas & inibidores , Células Hep G2 , Humanos , Leucemia/tratamento farmacológico , Leucemia/metabolismo , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/metabolismo , Linfoma/tratamento farmacológico , Linfoma/metabolismo
10.
Int J Mol Sci ; 22(16)2021 Aug 11.
Artigo em Inglês | MEDLINE | ID: mdl-34445342

RESUMO

Epigenetic regulation by histone deacetylase (HDAC) is associated with synaptic plasticity and memory formation, and its aberrant expression has been linked to cognitive disorders, including Alzheimer's disease (AD). This study aimed to investigate the role of class IIa HDAC expression in AD and monitor it in vivo using a novel radiotracer, 6-(tri-fluoroacetamido)-1-hexanoicanilide ([18F]TFAHA). A human neural cell culture model with familial AD (FAD) mutations was established and used for in vitro assays. Positron emission tomography (PET) imaging with [18F]TFAHA was performed in a 3xTg AD mouse model for in vivo evaluation. The results showed a significant increase in HDAC4 expression in response to amyloid-ß (Aß) deposition in the cell model. Moreover, treatment with an HDAC4 selective inhibitor significantly upregulated the expression of neuronal memory-/synaptic plasticity-related genes. In [18F]TFAHA-PET imaging, whole brain or regional uptake was significantly higher in 3xTg AD mice compared with WT mice at 8 and 11 months of age. Our study demonstrated a correlation between class IIa HDACs and Aßs, the therapeutic benefit of a selective inhibitor, and the potential of using [18F]TFAHA as an epigenetic radiotracer for AD, which might facilitate the development of AD-related neuroimaging approaches and therapies.


Assuntos
Doença de Alzheimer/diagnóstico por imagem , Inibidores de Histona Desacetilases/farmacocinética , Histona Desacetilases/metabolismo , Doença de Alzheimer/genética , Doença de Alzheimer/metabolismo , Doença de Alzheimer/patologia , Animais , Encéfalo/diagnóstico por imagem , Encéfalo/metabolismo , Modelos Animais de Doenças , Epigênese Genética/efeitos dos fármacos , Epigênese Genética/fisiologia , Radioisótopos de Flúor/química , Radioisótopos de Flúor/farmacocinética , Regulação Enzimológica da Expressão Gênica/efeitos dos fármacos , Inibidores de Histona Desacetilases/química , Histona Desacetilases/classificação , Histona Desacetilases/genética , Humanos , Camundongos , Camundongos da Linhagem 129 , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Neuroimagem/métodos , Tomografia por Emissão de Pósitrons/métodos , Células Tumorais Cultivadas
11.
Phys Chem Chem Phys ; 23(32): 17576-17590, 2021 Aug 28.
Artigo em Inglês | MEDLINE | ID: mdl-34369509

RESUMO

The rational design of selective histone deacetylase 2 (HDAC2) inhibitors is beneficial for the therapeutic treatment of liver cancer, though HDAC2 is highly homologous to HDAC8, which may lead to undesired side effects due to the pan-inhibition towards HDAC2 and HDAC8. To clarify the structural basis of selective inhibition towards HDAC2 over HDAC8, we utilized multiple in silico strategies, including sequence alignment, structural comparison, molecular docking, molecular dynamics simulations, free energy calculations, alanine scanning mutagenesis, pharmacophore modeling, protein contacts atlas analysis and QM/MM calculations to study the binding patterns of HDAC2/8 selective inhibitors. Through the whole process described above, it is found that although HDAC2 has conserved GLY154 and PHE210 that also exist within HDAC8, namely GLY151 and PHE208, the two isoforms exhibit diverse binding modes towards their inhibitors. Typically, HDAC2 inhibitors interact with the Zn2+ ions through the core chelate group, while HDAC8 inhibitors adopt a bent conformation within the HDAC8 pocket that inclines to be in contact with the Zn2+ ions through the terminal hydroxamic acid group. In summary, our data comprehensively elucidate the selectivity mechanism towards HDAC2 over HDAC8, which would guide the rational design of selective HDAC2 inhibitors for liver cancer treatment.


Assuntos
Histona Desacetilase 2/antagonistas & inibidores , Histona Desacetilase 2/metabolismo , Inibidores de Histona Desacetilases/metabolismo , Sequência de Aminoácidos , Domínio Catalítico , Desenho de Fármacos , Histona Desacetilase 2/química , Histona Desacetilase 2/genética , Inibidores de Histona Desacetilases/química , Histona Desacetilases/química , Histona Desacetilases/metabolismo , Humanos , Neoplasias Hepáticas/tratamento farmacológico , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Mutagênese , Mutação , Ligação Proteica , Proteínas Repressoras/antagonistas & inibidores , Proteínas Repressoras/química , Proteínas Repressoras/metabolismo , Termodinâmica
12.
Cell Prolif ; 54(10): e13119, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34435400

RESUMO

OBJECTIVES: Histone deacetylase 8 (HDAC8) is one of the class I HDAC family proteins, which participates in the neuronal disorders, parasitic/viral infections, tumorigenesis and many other biological processes. However, its potential function during female germ cell development has not yet been fully understood. MATERIALS AND METHODS: HDAC8-targeting siRNA was microinjected into GV oocytes to deplete HDAC8. PCI-34051 was used to inhibit the enzyme activity of HDAC8. Immunostaining, immunoblotting and fluorescence intensity quantification were applied to assess the effects of HDAC8 depletion or inhibition on the oocyte meiotic maturation, spindle/chromosome structure, γ-tubulin dynamics and acetylation level of α-tubulin. RESULTS: We observed that HDAC8 was localized in the nucleus at GV stage and then translocated to the spindle apparatus from GVBD to M II stages in porcine oocytes. Depletion of HDAC8 led to the oocyte meiotic failure by showing the reduced polar body extrusion rate. In addition, depletion of HDAC8 resulted in aberrant spindle morphologies and misaligned chromosomes due to the defective recruitment of γ-tubulin to the spindle poles. Notably, these meiotic defects were photocopied by inhibition of HDAC8 activity using its specific inhibitor PCI-34051. However, inhibition of HDAC8 did not affect microtubule stability as assessed by the acetylation level of α-tubulin. CONCLUSIONS: Collectively, our findings demonstrate that HDAC8 acts as a regulator of spindle assembly during porcine oocyte meiotic maturation.


Assuntos
Histona Desacetilases/metabolismo , Meiose/fisiologia , Oócitos/metabolismo , Fuso Acromático/metabolismo , Acetilação/efeitos dos fármacos , Animais , Fenômenos Biológicos/efeitos dos fármacos , Cromossomos/efeitos dos fármacos , Cromossomos/metabolismo , Cromossomos/fisiologia , Feminino , Ácidos Hidroxâmicos/farmacologia , Indóis/farmacologia , Meiose/efeitos dos fármacos , Microtúbulos/efeitos dos fármacos , Microtúbulos/metabolismo , Microtúbulos/fisiologia , Oócitos/efeitos dos fármacos , Oócitos/fisiologia , Fuso Acromático/efeitos dos fármacos , Fuso Acromático/fisiologia , Suínos , Tubulina (Proteína)/metabolismo
13.
Toxicol Lett ; 351: 78-88, 2021 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-34454011

RESUMO

We previously found that prenatal ethanol exposure (PEE) induced adrenal dysplasia in offspring, which was related to intrauterine maternal glucocorticoid overexposure. This study investigated the intergenerational genetic effect and sex differences of PEE-induced changes in the synthetic function of adrenal corticosterone in offspring, and to clarify the intrauterine origin programming mechanism. Wistar pregnant rats were gavaged with ethanol (4 g/kg bw/d) from gestation day (GD) 9-20, and F1 generation was born naturally. The F1 generation female rats in the PEE group were mated with normal male rats to produce F2 generation. Serum and adrenal glands of fetal rats and F1/F2 adult rats were collected at GD20 and postnatal week 28. PEE increased the serum corticosterone level, while diminishing the expression of adrenal steroid synthases of fetal rats. Moreover, PEE enhanced the mRNA expression of GR and HDAC1, but inhibited the mRNA expression of SF1 and reduced the H3K9ac level of P450scc in the fetal adrenal gland. In PEE adult offspring of F1 and F2 generation the serum corticosterone level, the H3K9ac level of P450scc and its expression were decreased in males but were increased in females. In NCI-H295R cells, cortisol reduced the production of endogenous cortisol, down-regulated SF1, and up-regulated HDAC1 expression by activating GR, and decreased H3K9ac level and expression of P450scc. In conclusion, PEE could induce adrenal dysplasia in offspring with sex differences and intergenerational genetic effects, and the adrenal insufficiency in male offspring was related to the induction of low functional genetic programming of P450scc by intrauterine high corticosterone through the GR/SF1/HDAC1 pathway.


Assuntos
Glândulas Suprarrenais/efeitos dos fármacos , Glândulas Suprarrenais/metabolismo , Corticosterona/biossíntese , Etanol/toxicidade , Glândulas Suprarrenais/crescimento & desenvolvimento , Animais , Linhagem Celular , Feminino , Desenvolvimento Fetal/efeitos dos fármacos , Regulação da Expressão Gênica no Desenvolvimento/efeitos dos fármacos , Histona Desacetilases/genética , Histona Desacetilases/metabolismo , Hidrocortisona , Masculino , Gravidez , Efeitos Tardios da Exposição Pré-Natal , Fatores de Processamento de RNA/genética , Fatores de Processamento de RNA/metabolismo , Ratos , Ratos Wistar , Receptores de Glucocorticoides/genética , Receptores de Glucocorticoides/metabolismo , Fatores Sexuais , Organismos Livres de Patógenos Específicos
14.
Adv Clin Chem ; 104: 151-231, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34462055

RESUMO

Neuroepigenetics, a new branch of epigenetics, plays an important role in the regulation of gene expression. Neuroepigenetics is associated with holistic neuronal function and helps in formation and maintenance of memory and learning processes. This includes neurodevelopment and neurodegenerative defects in which histone modification enzymes appear to play a crucial role. These modifications, carried out by acetyltransferases and deacetylases, regulate biologic and cellular processes such as apoptosis and autophagy, inflammatory response, mitochondrial dysfunction, cell-cycle progression and oxidative stress. Alterations in acetylation status of histone as well as non-histone substrates lead to transcriptional deregulation. Histone deacetylase decreases acetylation status and causes transcriptional repression of regulatory genes involved in neural plasticity, synaptogenesis, synaptic and neural plasticity, cognition and memory, and neural differentiation. Transcriptional deactivation in the brain results in development of neurodevelopmental and neurodegenerative disorders. Mounting evidence implicates histone deacetylase inhibitors as potential therapeutic targets to combat neurologic disorders. Recent studies have targeted naturally-occurring biomolecules and micro-RNAs to improve cognitive defects and memory. Multi-target drug ligands targeting HDAC have been developed and used in cell-culture and animal-models of neurologic disorders to ameliorate synaptic and cognitive dysfunction. Herein, we focus on the implications of histone deacetylase enzymes in neuropathology, their regulation of brain function and plausible involvement in the pathogenesis of neurologic defects.


Assuntos
Histona Desacetilases/metabolismo , Doenças Neurodegenerativas/metabolismo , Animais , Epigênese Genética/genética , Humanos , Doenças Neurodegenerativas/genética
15.
Neoplasma ; 68(5): 1043-1051, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34427099

RESUMO

The present study aimed to explore how histone deacetylases 3 (HDAC3) regulated the resistance to cisplatin by inhibiting the transcription of lncRNA-LOC101928316 (LOC101928316) in gastric cancer (GC). We revealed that HDAC3 expression in cisplatin-resistant cell lines was significantly higher than that of GC parental cell lines. Besides, knockdown of HDAC3 inhibited the cell activity, cell invasion, and migration but promoted the apoptosis of GC cisplatin-resistant cell lines. To our surprise, silencing HDAC3 inhibited the transcription of LOC101928316 by promoting the level of acetylation of H3K4 on the LOC101928316 promoter, thus promoting the LOC101 expression in GC cisplatin-resistant cell lines. Together, the overexpression of HDAC3 mediated LOC101928316 to promote GC resistance to cisplatin by activating the PI3K-Akt-mTOR pathway. Therefore, HDAC3 may serve as a potential target of cisplatin resistance in GC.


Assuntos
Histona Desacetilases/metabolismo , RNA Longo não Codificante , Neoplasias Gástricas , Linhagem Celular Tumoral , Cisplatino/farmacologia , Resistencia a Medicamentos Antineoplásicos/genética , Regulação Neoplásica da Expressão Gênica , Histona Desacetilases/genética , Humanos , Fosfatidilinositol 3-Quinases/genética , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/genética , Proteínas Proto-Oncogênicas c-akt/metabolismo , RNA Longo não Codificante/genética , Transdução de Sinais , Neoplasias Gástricas/tratamento farmacológico , Neoplasias Gástricas/genética , Serina-Treonina Quinases TOR/genética , Serina-Treonina Quinases TOR/metabolismo
16.
Sheng Li Xue Bao ; 73(3): 527-534, 2021 Jun 25.
Artigo em Chinês | MEDLINE | ID: mdl-34230954

RESUMO

Oogenesis is the basic reproductive process of female mammals and is essential for fertilization and embryo development. Recent studies have shown that epigenetic modifications play an important role in the regulation of mammalian reproductive processes (such as oogenesis, spermatogenesis, preimplantation embryo development and sex differentiation). Taking histone acetylation as an instance, the dynamic changes of histone acetyltransferases (HATs) and deacetylases (HDACs) are involved in the regulation of gene activation and inactivation when numerous key physiological events occur during reproduction. Thereinto, HDAC1 and HDAC2, which are highly homologous in terms of both structure and function, play a pivotal role in murine oogenesis. HDAC1 and 2 jointly regulate the global transcription and the incidence of apoptosis of growing oocytes and affect its subsequent growth and development, which reflects their compensatory function. In addition, HDAC1 and 2 also play a specific part in oogenesis respectively. It has shown that HDAC2 is more critical than HDAC1 for oocyte development, which regulates de novo DNA methylation and chromosome segregation. Reciprocally, HDAC1 is more critical than HDAC2 for preimplantation development. Deficiency of HDAC1 causes the decreased proliferation of embryonic stem cells and the smaller embryoid bodies with irregular shape. In this review, we summarized the role and the current research progress of HDAC1/2 in murine oogenesis, to provide a reference for further understanding the relationship between epigenetic modifications and reproductive regulation.


Assuntos
Histona Desacetilase 1 , Histona Desacetilase 2 , Acetilação , Animais , Desenvolvimento Embrionário , Feminino , Histona Desacetilase 1/genética , Histona Desacetilase 1/metabolismo , Histona Desacetilase 2/genética , Histona Desacetilase 2/metabolismo , Histona Desacetilases/metabolismo , Masculino , Camundongos , Oócitos , Oogênese
17.
J Med Chem ; 64(13): 8827-8869, 2021 07 08.
Artigo em Inglês | MEDLINE | ID: mdl-34161101

RESUMO

The acetylation of histone and non-histone proteins has been implicated in several disease states. Modulation of such epigenetic modifications has therefore made histone deacetylases (HDACs) important drug targets. HDAC3, among various class I HDACs, has been signified as a potentially validated target in multiple diseases, namely, cancer, neurodegenerative diseases, diabetes, obesity, cardiovascular disorders, autoimmune diseases, inflammatory diseases, parasitic infections, and HIV. However, only a handful of HDAC3-selective inhibitors have been reported in spite of continuous efforts in design and development of HDAC3-selective inhibitors. In this Perspective, the roles of HDAC3 in various diseases as well as numerous potent and HDAC3-selective inhibitors have been discussed in detail. It will surely open up a new vista in the discovery of newer, more effective, and more selective HDAC3 inhibitors.


Assuntos
Inibidores de Histona Desacetilases/farmacologia , Histona Desacetilases/metabolismo , Neoplasias/tratamento farmacológico , Doenças Autoimunes/tratamento farmacológico , Doenças Autoimunes/metabolismo , Doenças Cardiovasculares/tratamento farmacológico , Doenças Cardiovasculares/metabolismo , Diabetes Mellitus/tratamento farmacológico , Diabetes Mellitus/metabolismo , Infecções por HIV/tratamento farmacológico , Infecções por HIV/metabolismo , Inibidores de Histona Desacetilases/química , Humanos , Neoplasias/metabolismo , Doenças Neurodegenerativas/tratamento farmacológico , Doenças Neurodegenerativas/metabolismo , Obesidade/tratamento farmacológico , Obesidade/metabolismo
18.
J Med Chem ; 64(12): 8447-8473, 2021 06 24.
Artigo em Inglês | MEDLINE | ID: mdl-34097389

RESUMO

Novel dual HDAC3/tubulin inhibitors were designed and efficiently synthesized by combining the pharmacophores of SMART (tubulin inhibitor) and MS-275 (HDAC inhibitor), among which compound 15c was found to be the most potent and balanced HDAC3/tubulin dual inhibitor with high HDAC3 activity (IC50 = 30 nM) and selectivity (SI > 1000) as well as excellent antiproliferative potency against various cancer cell lines, including an HDAC-resistant gastric cancer cell line (YCC3/7) with IC50 values in the range of 30-144 nM. Compound 15c inhibited B16-F10 cancer cell migration and colony formation. In addition, 15c demonstrated significant in vivo antitumor efficacy in a B16-F10 melanoma tumor model with a better TGI (70.00%, 10 mg/kg) than that of the combination of MS-275 and SMART. Finally, 15c presented a safe cardiotoxicity profile and did not cause nephro-/hepatotoxicity. Collectively, this work shows that compound 15c represents a novel tubulin/HDAC3 dual-targeting agent deserving further investigation as a potential anticancer agent.


Assuntos
Antineoplásicos/uso terapêutico , Inibidores de Histona Desacetilases/uso terapêutico , Neoplasias/tratamento farmacológico , Moduladores de Tubulina/uso terapêutico , Animais , Antineoplásicos/síntese química , Antineoplásicos/metabolismo , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Pontos de Checagem da Fase G2 do Ciclo Celular/efeitos dos fármacos , Inibidores de Histona Desacetilases/síntese química , Inibidores de Histona Desacetilases/metabolismo , Histona Desacetilases/metabolismo , Humanos , Camundongos Endogâmicos C57BL , Simulação de Acoplamento Molecular , Estrutura Molecular , Neoplasias/patologia , Ligação Proteica , Relação Estrutura-Atividade , Tubulina (Proteína)/metabolismo , Moduladores de Tubulina/síntese química , Moduladores de Tubulina/metabolismo
19.
FASEB J ; 35(7): e21368, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-34125448

RESUMO

In the current study, we sought to determine the roles of histone deacetylase 5 (HDAC5) on the promotion of intestinal sepsis in a mouse model. Dual luciferase reporter gene assay was used to determine the binding relationship between HDAC5 and Ghrelin. Cecal ligation and puncture (CLP) was used as an animal model of intestinal sepsis. The roles of HDAC5 on intestinal sepsis were determined by HDAC5 knockdown, overexpression, and inhibitor (LMK-235) in vivo. Mice intestinal permeability and intestinal epithelial damage were evaluated, and HE staining was used to evaluate the intestinal mucosal injury index. Lipopolysaccharide (LPS)-treated intestinal-derived macrophages served as a cell model of sepsis, followed by the loss-of-function and gain-of-function assays. ELISA was used to determine the levels of inflammatory factors, and TUNEL staining was used to detect intestinal cell apoptosis. HDAC5 was upregulated in the intestine of sepsis patients. This increased HDAC5 expression was positively correlated with the expression of inflammatory factors TNF-α, IL-1ß, IL-6, and HMGB1, as well as the intestinal dysfunction-related factors IFABP. In sepsis mice, the expression of inflammatory factors was reduced by HDAC5 knockdown. HDAC5 knockdown also improved survival, morphology of intestinal tissue, intestinal permeability, and epithelial damage. Ghrelin was bound and inhibited by HDAC5, but E2F1 expression was increased by Ghrelin overexpression, leading to inhibition of the NF-κB pathway. Ghrelin and E2F1 expression were increased by the treatment with HDAC5 inhibitor LMK-235, which inhibited the NF-κB pathway to improve intestinal dysfunction in the sepsis model. In conclusion, HDAC5 inhibits Ghrelin to reduce E2F1 and thus activate the NF-κB pathway, thereby promoting intestinal sepsis.


Assuntos
Fator de Transcrição E2F1/metabolismo , Grelina/metabolismo , Histona Desacetilases/metabolismo , Enteropatias/patologia , NF-kappa B/metabolismo , Sepse/patologia , Animais , Modelos Animais de Doenças , Fator de Transcrição E2F1/genética , Regulação da Expressão Gênica , Grelina/genética , Histona Desacetilases/genética , Humanos , Enteropatias/genética , Enteropatias/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , NF-kappa B/genética , Sepse/genética , Sepse/metabolismo
20.
Plant Cell Rep ; 40(9): 1603-1615, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34041586

RESUMO

Plants have developed sophisticated and complex epigenetic regulation-based mechanisms to maintain stable growth and development under diverse environmental conditions. Histone deacetylases (HDACs) are important epigenetic regulators in eukaryotes that are involved in the deacetylation of lysine residues of histone H3 and H4 proteins. Plants have developed a unique HDAC family, HD2, in addition to the RPD3 and Sir2 families, which are also present in other eukaryotes. HD2s are well conserved plant-specific HDACs, which were first identified as nucleolar phosphoproteins in maize. The HD2 family plays important roles not only in fundamental developmental processes, including seed germination, root and leaf development, floral transition, and seed development but also in regulating plant responses to biotic and abiotic stresses. Some of the HD2 members coordinate with each other to function. The HD2 family proteins also show functional association with RPD3-type HDACs and other transcription factors as a part of repression complexes in gene regulatory networks involved in environmental stress responses. This review aims to analyse and summarise recent research progress in the HD2 family, and to describe their role in plant growth and development and in response to different environmental stresses.


Assuntos
Histona Desacetilases/metabolismo , Fenômenos Fisiológicos Vegetais , Proteínas de Plantas/metabolismo , Estresse Fisiológico/fisiologia , Evolução Molecular , Regulação da Expressão Gênica de Plantas , Histona Desacetilases/genética , Lycopersicon esculentum/enzimologia , Lycopersicon esculentum/fisiologia , Oryza/enzimologia , Oryza/fisiologia , Fosfoproteínas/metabolismo , Desenvolvimento Vegetal , Proteínas de Plantas/genética , Solanum tuberosum/enzimologia , Solanum tuberosum/fisiologia
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