RESUMEN
The role of histone deacetylases (HDACs) in lung cancer has been extensively studied. Inhibition of HDAC activities have been used as a new cancer treatment strategy. To date, many HDAC inhibitors have been shown to induce apoptosis and inhibit tumorigenesis. Chidamide (CS055) is a new member of HDAC inhibitors. In China, Chidamide has been approved for the treatment of relapsed or refractory peripheral T-cell lymphoma. However, the efficacy of Chidamide in non-small cell lung cancer remains unclear. In this study, we used lung cancer primary cells and investigated the effects of Chidamide combined with paclitaxel on lung cancer. We found that Chidamide combined with paclitaxel effectively inhibited the expression and activity of HDAC in primary lung cancer cells, induced their apoptosis and blocked cell cycle. Chidamide combined with paclitaxel may therefore provide a new promising therapeutic treatment for lung cancer.
Asunto(s)
Aminopiridinas/farmacología , Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Benzamidas/farmacología , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Inhibidores de Histona Desacetilasas/farmacología , Neoplasias Pulmonares/tratamiento farmacológico , Paclitaxel/farmacología , Aminopiridinas/administración & dosificación , Apoptosis/efectos de los fármacos , Benzamidas/administración & dosificación , Carcinoma de Pulmón de Células no Pequeñas/enzimología , Carcinoma de Pulmón de Células no Pequeñas/patología , Ciclo Celular/efectos de los fármacos , Histona Desacetilasa 6/biosíntesis , Histona Desacetilasa 6/metabolismo , Inhibidores de Histona Desacetilasas/administración & dosificación , Histona Desacetilasas/biosíntesis , Histona Desacetilasas/metabolismo , Humanos , Neoplasias Pulmonares/enzimología , Neoplasias Pulmonares/patología , Paclitaxel/administración & dosificación , Proteínas Proto-Oncogénicas c-myc/antagonistas & inhibidores , Proteínas Proto-Oncogénicas c-myc/biosíntesis , Células Tumorales CultivadasRESUMEN
Epigenetic processes play important roles in brain responses to ischemic injury. We studied effects of photothrombotic stroke (PTS, a model of ischemic stroke) on the intracellular level and cellular localization of histone deacetylases HDAC3, HDAC4 and HDAC6 in the rat brain cortex, and tested the potential neuroprotector ability of their inhibitors. The background level of HDAC3, HDAC4 and HDAC6 in the rat cerebral cortex was relatively low. HDAC3 localized in the nuclei of some neurons and few astrocytes. HDAC4 was found in the neuronal cytoplasm. After PTS, their levels in penumbra did not change, but HDAC4 appeared in the nuclei of some cells. Its level in the cytoplasmic, but not nuclear fraction of penumbra decreased at 24, but not 4 h after PTS. HDAC6 was upregulated in neurons and astrocytes in the PTS-induced penumbra, especially in the nuclear fraction. Unlike HDAC3 and HDAC4, HDAC6 co-localized with TUNEL-positive apoptotic cells. Inhibitory analysis confirmed the involvement of HDAC6, but not HDAC3 and HDAC4 in neurodegeneration. HDAC6 inhibitor HPOB, HDAC2/8 inhibitor α-phenyl tropolone, and non-specific histone deacetylase inhibitor sodium valproate, but not HDAC3 inhibitor BRD3308, or HDAC4 inhibitor LMK235, decreased PTS-induced infarction volume in the mouse brain, reduced apoptosis, and recovered the motor behavior. HPOB also restored PTS-impaired acetylation of α-tubulin. α-phenyl tropolone restored acetylation of histone H4 in penumbra cells. These results suggest that histone deacetylases HDAC6 and HDAC2 are the possible molecular targets for anti-ischemic therapy, and their inhibitors α-phenyl tropolone, HBOP and sodium valproate can be considered as promising neuroprotectors.
Asunto(s)
Corteza Cerebral/enzimología , Histona Desacetilasa 6/biosíntesis , Inhibidores de Histona Desacetilasas/farmacología , Trombosis Intracraneal/enzimología , Accidente Cerebrovascular/enzimología , Tropolona/farmacología , Ácido Valproico/farmacología , Animales , Corteza Cerebral/efectos de los fármacos , Corteza Cerebral/patología , Expresión Génica , Inhibidores de Histona Desacetilasas/uso terapéutico , Histona Desacetilasas/biosíntesis , Trombosis Intracraneal/patología , Trombosis Intracraneal/prevención & control , Láseres de Semiconductores/efectos adversos , Masculino , Ratones , Fármacos Neuroprotectores/farmacología , Fármacos Neuroprotectores/uso terapéutico , Ratas , Accidente Cerebrovascular/patología , Accidente Cerebrovascular/prevención & control , Tropolona/uso terapéutico , Ácido Valproico/uso terapéuticoRESUMEN
The present study aimed to explore the effects of histone deacetylase 6 (HDAC6) on brain injury in rats induced by apolipoprotein E4 (APOE4) and amyloid ß protein alloform 140 (Aß140) copolymerization. The rats were randomly divided into four groups: Control group, sham group, APOE4 + Aß140 coinjection group (model group) and HDAC6 inhibitor group (HDAC6 group). The brain injury model was established by coinjection of APOE4 + Aß140. Morris water maze experiment was used to observe the spatial memory and learning the ability of rats. Histological changes of the hippocampus were observed by hematoxylin and eosin staining. The mRNA expression levels of choline acetyltransferase (ChAT) and HDAC6 were detected by reverse transcriptionquantitative PCR. Immunohistochemistry was used to detect the protein expression of HDAC6. Western blotting was used to detect the protein expression levels of HDAC6, microtubuleassociated protein tau and glycogen synthase kinase 3ß (GSK3ß). APOE4 and Aß140 coaggregation decreased the shortterm spatial memory and learning ability of rats, whereas inhibition of HDAC6 activity attenuated the injury. Inhibition of HDAC6 activity resulted in an attenuation of the APOE4 and Aß140 coaggregationinduced increase in the number of dysplastic hippocampal cells. Further experiments demonstrated that APOE4 and Aß140 coaggregation decreased the expression levels of ChAT mRNA, and the phosphorylation levels of tau GSK3ß protein in the hippocampus, whereas inhibition of HDAC6 activity resulted in increased expression of ChAT mRNA, tau protein and GSK3ß phosphorylation. The inhibition of HDAC6 activity was also demonstrated to reduce brain injury induced by APOE4 and Aß140 coaggregation in model rats.
Asunto(s)
Péptidos beta-Amiloides/metabolismo , Apolipoproteína E4/metabolismo , Lesiones Encefálicas/metabolismo , Regulación Enzimológica de la Expresión Génica/efectos de los fármacos , Hipocampo/metabolismo , Histona Desacetilasa 6/biosíntesis , Inhibidores de Histona Desacetilasas/farmacología , Fragmentos de Péptidos/metabolismo , Agregación Patológica de Proteínas/metabolismo , Animales , Lesiones Encefálicas/patología , Lesiones Encefálicas/fisiopatología , Colina O-Acetiltransferasa/biosíntesis , Hipocampo/patología , Hipocampo/fisiopatología , Histona Desacetilasa 6/antagonistas & inhibidores , Masculino , Aprendizaje por Laberinto/efectos de los fármacos , Agregación Patológica de Proteínas/patología , Agregación Patológica de Proteínas/fisiopatología , Ratas , Ratas Sprague-Dawley , Memoria Espacial/efectos de los fármacos , Proteínas tau/metabolismoRESUMEN
OCT4 is a key regulator in maintaining the pluripotency and self-renewal of embryonic stem cells (ESCs). Human OCT4 gene has three mRNA isoforms, termed OCT4A, OCT4B and OCT4B1. The 190-amino-acid protein isoform (OCT4B-190) is one of the major products of OCT4B mRNA, the biological function of which is still not well defined. Recent evidence suggests that OCT4B-190 may function in the cellular stress response. The glycogen synthase kinase-3ß (GSK-3ß) and histone deacetylase 6 (HDAC6) are also key stress modulators that play critical roles in the ischemic cascades of stroke. Hence, we here further investigated the effects of OCT4B-190 in the experimental stroke, and explored the underlying roles of GSK-3ß and HDAC6. We found that OCT4B-190 overexpression enhanced neuronal viability at 24â¯h after oxygen-glucose deprivation (OGD) treatment. Moreover, in male C57BL/6 mice subjected to transit middle cerebral artery occlusion (MCAO), OCT4B-190 overexpression reduced infarct volume and improved neurological function after stroke. Notably, we found spatio-temporal alterations of GSK-3ß and HDAC6 in the ischemic cortex and striatum, which were affected by adenovirus-mediated OCT4B-190 overexpression. OCT4B-190 demonstrated similar impacts on neuronal cultures in vitro, downregulating OGD-induced GSK-3ß activity and HDAC6 expression. In addition, we found that GSK-3ß and HDAC6 were co-expressed in the cytoplasm of neurons, and OCT4B-190 had an effect on interactions between GSK-3ß and HDAC6 in neuronal cultures subjected to OGD treatment. These findings suggest that OCT4B-190 exerts neuroprotection in the experimental stroke potentially by regulating actions of GSK-3ß and HDAC6 simultaneously, which may be an attractive therapeutic strategy for ischemic stroke.
Asunto(s)
Isquemia Encefálica/genética , Isquemia Encefálica/metabolismo , Glucógeno Sintasa Quinasa 3 beta/metabolismo , Histona Desacetilasa 6/metabolismo , Factor 3 de Transcripción de Unión a Octámeros/genética , Accidente Cerebrovascular/genética , Accidente Cerebrovascular/metabolismo , Animales , Isquemia Encefálica/patología , Células Cultivadas , Corteza Cerebral/metabolismo , Corteza Cerebral/patología , Citoplasma/metabolismo , Glucógeno Sintasa Quinasa 3 beta/biosíntesis , Glucógeno Sintasa Quinasa 3 beta/genética , Histona Desacetilasa 6/biosíntesis , Histona Desacetilasa 6/genética , Hipoxia Encefálica/tratamiento farmacológico , Hipoxia Encefálica/patología , Infarto de la Arteria Cerebral Media/patología , Masculino , Ratones , Ratones Endogámicos C57BL , Neostriado/efectos de los fármacos , Neostriado/metabolismo , Enfermedades del Sistema Nervioso/etiología , Enfermedades del Sistema Nervioso/psicología , Neuronas/metabolismo , Factor 3 de Transcripción de Unión a Octámeros/biosíntesis , Accidente Cerebrovascular/patologíaRESUMEN
Inhibition of bromodomain and extra terminal (BET) protein family members, including BRD4, decreases the expression of c-MYC and other key oncogenic factors and also significantly induces histone deacetylase 6 (HDAC6) expression. On the basis of the role of HDAC6 in malignant pathogenesis, we hypothesized that rational cotargeting of HDAC6 and BET family proteins may represent a novel approach that yields synergistic antimyeloma activity. We used genetic and pharmacologic approaches to selectively impair HDAC6 and BET function and evaluated the consequential impact on myeloma pathogenesis. These studies identified HDAC6 upregulation as an efficacy reducing mechanism for BET inhibitors because antagonizing HDAC6 activity synergistically enhanced the activity of JQ1 in a panel of multiple myeloma (MM) cell lines and primary CD138+ cells obtained from patients with MM. The synergy of this therapeutic combination was linked to significant reductions in c-MYC expression and increases in apoptosis induction. Administration of the clinical HDAC6 inhibitor ricolinostat was very well tolerated and significantly augmented the in vivo antimyeloma activity of JQ1. Ex vivo pharmacodynamic analyses demonstrated that the combination of JQ1 and ricolinostat led to significantly lower MM cell proliferation and increased apoptosis and diminished expression of c-MYC and BCL-2. These data demonstrate that cotargeting of HDAC6 and BET family members is a novel and clinically actionable approach to augment the efficacy of both classes of agents that warrants further investigation.
Asunto(s)
Sistemas de Liberación de Medicamentos , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Histona Desacetilasa 6/antagonistas & inhibidores , Ácidos Hidroxámicos/farmacología , Mieloma Múltiple/tratamiento farmacológico , Proteínas/metabolismo , Pirimidinas/farmacología , Animales , Línea Celular Tumoral , Femenino , Histona Desacetilasa 6/biosíntesis , Humanos , Ratones , Ratones SCID , Mieloma Múltiple/metabolismo , Mieloma Múltiple/patología , Proteínas Proto-Oncogénicas c-myc/biosíntesisRESUMEN
Previous studies have investigated the role of histone deacetylase 6 (HDAC6) in the regulation of androgen receptor (AR) in prostate cancer; however, the role of HDAC6 has not yet been clearly identified in breast cancer. The aim of this study was to examine the expression of HDAC6 and AR, determine the correlation between HDAC6 and AR, and assess the prognostic value of HDAC6 and AR in breast cancer. A total of 228 cases of invasive breast cancer were randomly selected. The expression of HDAC6 and AR was analyzed by immunohistochemistry. χ2 Tests were performed to determine the association between conventional clinicopathological factors and HDAC6, AR, and HDAC6/AR co-expression. Spearman correlation methods were performed to determine the correlation between HDAC6 and AR, and Kaplan-Meier analyses were performed to determine the prognostic impact of HDAC6, AR and HDAC6/AR co-expression; 58.8% (134/228) patients exhibited high expression of HDAC6. High HDAC6 expression was significantly associated with high histologic grade (G3) (P<.001) and p53 overexpression (P=.002). HDAC6 and AR expression levels were significantly associated (r=0.382, P<.01). In estrogen receptor (ER)-negative samples, high expression of HDAC6 was more common in the AR+ groups (P<.001) and correlated with high histologic grade (G3) (P=.009), as well as higher HER2 (P=.006) and p53 levels (P=.012). Higher expression of AR and HDAC6 and HDAC6/AR co-expression had a worse clinical prognosis. The expression levels of HDAC6 and AR are correlated in breast cancer; moreover, HDAC6 and AR have prognostic value in predicting the overall survival (OS) of ER-negative breast cancer patients.
Asunto(s)
Biomarcadores de Tumor/análisis , Neoplasias de la Mama/patología , Histona Desacetilasa 6/biosíntesis , Receptores Androgénicos/biosíntesis , Adulto , Anciano , Anciano de 80 o más Años , Neoplasias de la Mama/mortalidad , Femenino , Histona Desacetilasa 6/análisis , Humanos , Inmunohistoquímica , Estimación de Kaplan-Meier , Persona de Mediana Edad , Pronóstico , Receptores Androgénicos/análisisRESUMEN
Rabies virus (RABV) is the cause of rabies, and is associated with severe neurological symptoms, high mortality rate, and a serious threat to human health. Although cellular tubulin has recently been identified to be incorporated into RABV particles, the effects of RABV infection on the microtubule cytoskeleton remain poorly understood. In this study, we show that RABV infection induces microtubule depolymerization as observed by confocal microscopy, which is closely associated with the formation of the filamentous network of the RABV M protein. Depolymerization of microtubules significantly increases viral RNA synthesis, while the polymerization of microtubules notably inhibits viral RNA synthesis and prevents the viral M protein from inducing the formation of the filamentous network. Furthermore, the histone deacetylase 6 (HDAC6) expression level progressively increases during RABV infection, and the inhibition of HDAC6 deacetylase activity significantly decreases viral RNA synthesis. In addition, the expression of viral M protein alone was found to significantly upregulate HDAC6 expression, leading to a substantial reduction in its substrate, acetylated α-tubulin, eventually resulting in microtubule depolymerization. These results demonstrate that HDAC6 plays a positive role in viral transcription and replication by inducing microtubule depolymerization during RABV infection.
Asunto(s)
Histona Desacetilasa 6/metabolismo , Microtúbulos/metabolismo , ARN Viral/biosíntesis , Virus de la Rabia/metabolismo , Rabia/virología , Regulación hacia Arriba , Acetilación , Animales , Línea Celular , Supervivencia Celular , Cricetinae , Citoesqueleto , Dimetilsulfóxido/farmacología , Regulación Viral de la Expresión Génica , Células HEK293 , Histona Desacetilasa 6/biosíntesis , Humanos , Ratones , Microscopía Confocal , Inhibidores de la Síntesis del Ácido Nucleico/farmacología , Paclitaxel/farmacología , Virus de la Rabia/genética , Virus de la Rabia/patogenicidad , Activación Transcripcional , Tubulina (Proteína) , Proteínas de la Matriz Viral/genética , Proteínas de la Matriz Viral/metabolismoRESUMEN
OBJECTIVE: The goal of the study was to investigate the role of histone deacetylases (HDACs) in adipocyte function associated with obesity and hypoxia. METHODS: Total proteins and RNA were prepared from human visceral adipose tissues (VAT) of human obese and normal weight subjects and from white adipose tissue (WAT) of C57Bl6-Rj mice fed a normal or high fat diet (HFD) for 16 weeks. HDAC activity was measured by colorimetric assay whereas the gene and protein expression were monitored by real-time PCR and by western blotting, respectively. RNA interference (RNAi) was used to silence the expression of genes in 3T3-L1 adipocytes. RESULTS: Total HDAC activity was decreased in VAT and WAT from obese individuals and from mice fed a HFD, respectively. The HDAC activity reduction was associated with decreased HDAC5/Hdac5 and HDAC6/Hdac6 expression in human and mice adipocyte fraction. Similarly, hypoxia hampered total Hdac activity and reduced the expression of Hdac5 and Hdac6 in 3T3-L1 adipocytes. The decrease of both Hdac5 and Hdac6 by hypoxia was associated with altered expression of adipokines and of the inducible cAMP early repressor (Icer), a key repressor that is defective in human and mice obesity. Silencing of Icer in adipocytes reproduced the changes in adipokine levels under hypoxia and obesity, suggesting a causative effect. Finally, modeling the defect of the two Hdacs in adipocytes by RNAi or selective inhibitors mimicked the effects of hypoxia on the expression of Icer, leading to impairment of insulin-induced glucose uptake. CONCLUSION: Hdac5 and Hdac6 expression are required for the adequate expression of Icer and adipocyte function. Altered adipose expression of the two Hdacs in obesity by hypoxia may contribute to the development of metabolic abnormalities.