RESUMEN

Homeodomain-only protein homeobox (HOPX) mainly exerts its transcriptional repression by physically sequestering the serum co-repressor and recruiting histone deacetylase (HDAC), possessing important potential as a prognostic gene in acute myeloid leukemia (AML). HDACs play crucial roles in cell growth, gene regulation, and metabolism, and they are also important factors in promoting AML progression. Therefore, this project attempts to investigate whether HOPX affects AML progression by interacting with HDAC2 protein. Bioinformatics analysis was employed to identify potential prognostic genes in AML. Flow cytometry and MTT assays were performed to analyze the cellular biological functions of the AML prognostic marker HOPX. The interaction network of HOPX was analyzed using the Search Tool for the Retrieval of Interacting Genes database, and the interaction between HOPX and HDAC2 was observed using endogenous and exogenous immunoprecipitation. HOPX is highly expressed in AML cells. Further research uncovered that low expression of HOPX can repress the proliferation activity, anti-apoptotic ability, and differentiation blockage of AML cells. Moreover, mechanistically, HOPX induced AML differentiation blockage and malignant progression through interaction with HDAC. HOPX can serve as a prognostic marker for AML and can interact with HDAC2 to induce AML differentiation blockage and malignant progression.

Asunto(s)

Diferenciación Celular , Histona Desacetilasa 2 , Proteínas de Homeodominio , Leucemia Mieloide Aguda , Humanos , Leucemia Mieloide Aguda/metabolismo , Leucemia Mieloide Aguda/patología , Histona Desacetilasa 2/metabolismo , Proteínas de Homeodominio/metabolismo , Proteínas de Homeodominio/genética , Proliferación Celular , Regulación Leucémica de la Expresión Génica , Apoptosis , Línea Celular Tumoral , Pronóstico , Proteínas Supresoras de Tumor

RESUMEN

A differential diet with royal jelly (RJ) during early larval development in honeybees shapes the phenotype, which is probably mediated by epigenetic regulation of gene expression. Evidence indicates that small molecules in RJ can modulate gene expression in mammalian cells, such as the fatty acid 10-hydroxy-2-decenoic acid (10-HDA), previously associated with the inhibition of histone deacetylase enzymes (HDACs). Therefore, we combined computational (molecular docking simulations) and experimental approaches for the screening of potential HDAC inhibitors (HDACi) among 32 RJ-derived fatty acids. Biochemical assays and gene expression analyses (Reverse Transcriptase - quantitative Polymerase Chain Reaction) were performed to evaluate the functional effects of the major RJ fatty acids, 10-HDA and 10-HDAA (10-hydroxy-decanoic acid), in two human cancer cell lines (HCT116 and MDA-MB-231). The molecular docking simulations indicate that these fatty acids might interact with class I HDACs, specifically with the catalytic domain of human HDAC2, likewise well-known HDAC inhibitors (HDACi) such as SAHA (suberoylanilide hydroxamic acid) and TSA (Trichostatin A). In addition, the combined treatment with 10-HDA and 10-HDAA inhibits the activity of human nuclear HDACs and leads to a slight increase in the expression of HDAC-coding genes in cancer cells. Our findings indicate that royal jelly fatty acids collectively contribute to HDAC inhibition and that 10-HDA and 10-HDAA are weak HDACi that facilitate the acetylation of lysine residues of chromatin, triggering an increase in gene expression levels in cancer cells.

Asunto(s)

Ácidos Grasos , Inhibidores de Histona Desacetilasas , Simulación del Acoplamiento Molecular , Humanos , Inhibidores de Histona Desacetilasas/farmacología , Inhibidores de Histona Desacetilasas/química , Ácidos Grasos/metabolismo , Abejas , Línea Celular Tumoral , Animales , Ácidos Grasos Monoinsaturados/farmacología , Ácidos Grasos Monoinsaturados/química , Histona Desacetilasa 2/metabolismo , Histona Desacetilasa 2/genética , Histona Desacetilasa 2/antagonistas & inhibidores , Células HCT116

RESUMEN

Bone cancer pain (BCP) represents a prevalent symptom among cancer patients with bone metastases, yet its underlying mechanisms remain elusive. This study investigated the transcriptional regulation mechanism of Kv7(KCNQ)/M potassium channels in DRG neurons and its involvement in the development of BCP in rats. We show that HDAC2-mediated transcriptional repression of kcnq2/kcnq3 genes, which encode Kv7(KCNQ)/M potassium channels in dorsal root ganglion (DRG), contributes to the sensitization of DRG neurons and the pathogenesis of BCP in rats. Also, HDAC2 requires the formation of a corepressor complex with MeCP2 and Sin3A to execute transcriptional regulation of kcnq2/kcnq3 genes. Moreover, EREG is identified as an upstream signal molecule for HDAC2-mediated kcnq2/kcnq3 genes transcription repression. Activation of EREG/EGFR-ERK-Runx1 signaling, followed by the induction of HDAC2-mediated transcriptional repression of kcnq2/kcnq3 genes in DRG neurons, leads to neuronal hyperexcitability and pain hypersensitivity in tumor-bearing rats. Consequently, the activation of EREG/EGFR-ERK-Runx1 signaling, along with the subsequent transcriptional repression of kcnq2/kcnq3 genes by HDAC2 in DRG neurons, underlies the sensitization of DRG neurons and the pathogenesis of BCP in rats. These findings uncover a potentially targetable mechanism contributing to bone metastasis-associated pain in cancer patients.

Asunto(s)

Neoplasias Óseas , Dolor en Cáncer , Receptores ErbB , Ganglios Espinales , Histona Desacetilasa 2 , Canal de Potasio KCNQ2 , Animales , Histona Desacetilasa 2/metabolismo , Histona Desacetilasa 2/genética , Canal de Potasio KCNQ2/genética , Canal de Potasio KCNQ2/metabolismo , Ganglios Espinales/metabolismo , Ganglios Espinales/patología , Neoplasias Óseas/genética , Neoplasias Óseas/metabolismo , Neoplasias Óseas/secundario , Neoplasias Óseas/patología , Ratas , Dolor en Cáncer/genética , Dolor en Cáncer/metabolismo , Dolor en Cáncer/patología , Receptores ErbB/metabolismo , Receptores ErbB/genética , Canal de Potasio KCNQ3/genética , Canal de Potasio KCNQ3/metabolismo , Transcripción Genética , Proteína 2 de Unión a Metil-CpG/genética , Proteína 2 de Unión a Metil-CpG/metabolismo , Complejo Correpresor Histona Desacetilasa y Sin3/genética , Transducción de Señal/genética , Subunidad alfa 2 del Factor de Unión al Sitio Principal/genética , Subunidad alfa 2 del Factor de Unión al Sitio Principal/metabolismo , Humanos , Femenino , Quinasas MAP Reguladas por Señal Extracelular/metabolismo , Proteínas Represoras/genética , Proteínas Represoras/metabolismo , Ratas Sprague-Dawley , Sistema de Señalización de MAP Quinasas/genética

RESUMEN

ArfGAP with coiled-coil, ankyrin repeat and PH domains 3 (ACAP3) level has been confirmed to be downregulated in papillary thyroid carcinoma (PTC). Histone deacetylase inhibitors (HDACIs) have therapeutic effects on PTC. Accordingly, this study probed into the potential relation of histone deacetylase 2 (HDAC2) and ACAP3 in PTC. Expressions of ACAP3 and HDAC2 in PTC were investigated by quantitative real-time polymerase chain reaction (qRT-PCR). The relationship between HDAC2 and ACAP3 was predicted by Pearson analysis. Cell functional assays (cell counting kit-8, transwell, wound healing and flow cytometry assays) and rescue assay were carried out to determine the effects of HDAC2/ACAP3 axis on biological behaviors of PTC cells. Expressions of apoptosis-, epithelial-mesenchymal transition-, Protein Kinase B (AKT)-, and P53-related proteins were measured by Western blot. ACAP3 level was downregulated in PTC tissues and cells. ACAP3 overexpression (oe-ACAP3) suppressed viability, proliferation, migration and invasion of PTC cells, facilitated apoptosis, downregulated the expressions of Protein Kinase B (Bcl-2) and N-cadherin, upregulated the expressions of Bcl-2 associated protein X (Bax) and E-cadherin, diminished the p-AKT/AKT ratio and elevated the p-p53/p53 ratio; however, ACAP3 silencing or HDAC2 overexpression (oe-HDAC2) did the opposite. HDAC2 negatively correlated with ACAP3. The tumor-suppressing effect of oe-ACAP3 in PTC was reversed by oe-HDAC2. Collectively, ACAP3 negatively regulated by HDAC2 suppresses the proliferation and metastasis while facilitating apoptosis of PTC cells.

Asunto(s)

Apoptosis , Proliferación Celular , Proteínas Activadoras de GTPasa , Histona Desacetilasa 2 , Cáncer Papilar Tiroideo , Neoplasias de la Tiroides , Humanos , Apoptosis/efectos de los fármacos , Línea Celular Tumoral , Movimiento Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Transición Epitelial-Mesenquimal/efectos de los fármacos , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Proteínas Activadoras de GTPasa/metabolismo , Proteínas Activadoras de GTPasa/genética , Histona Desacetilasa 2/metabolismo , Histona Desacetilasa 2/genética , Histona Desacetilasa 2/antagonistas & inhibidores , Cáncer Papilar Tiroideo/patología , Cáncer Papilar Tiroideo/genética , Cáncer Papilar Tiroideo/metabolismo , Neoplasias de la Tiroides/patología , Neoplasias de la Tiroides/metabolismo , Neoplasias de la Tiroides/genética

RESUMEN

ADORA3 is mainly expressed in intestinal tract, and has the potential to promote the expression of mucin 2 (MUC2), the function-related factor of goblet cells, under asthma conditions. This study aims to confirm the induction and mechanisms of ADORA3 activation on goblet cells in ulcerative colitis (UC). A significant decrease in ADORA3 expression was found in mucosal biopsies from UC patients and in the colons of colitis mice. This reduction correlated negatively with disease severity and positively with goblet cell number. ADORA3 activation mitigated dextran sulfate sodium (DSS)-induced colitis and facilitated ATOH1-mediated goblet cell differentiation in both in vivo and in vitro. Metabolomics analysis unveiled that ADORA3 activation bolstered ketogenesis, leading to elevated levels of the metabolite BHB. Subsequently, BHB heightened the activity of HDAC1/2, augmenting histone acetylation at the H3K9ac site within the promoter region of the ATOH1 gene. Furthermore, the reason for ADORA3 activation to enhance ketogenesis was attributed to controlling the competitive binding among ß-arrestin2, SHP1 and PPARγ. This results in the non-ligand-dependent activation of PPARγ, thereby promoting the transcription of HMGCS2. The exact mechanisms by which ADORA3 promoted goblet cell differentiation and alleviated UC were elucidated using MRS1191 and shHMGCS2 plasmid. Collectively, ADORA3 activation promoted goblet cell differentiation and alleviated UC by enhancing ketogenesis via the "BHB-HDAC1/2-H3K9ac" pathway.

Asunto(s)

Diferenciación Celular , Colitis Ulcerosa , Células Caliciformes , Hidroximetilglutaril-CoA Sintasa , Adulto , Animales , Femenino , Humanos , Masculino , Ratones , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/metabolismo , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/genética , Ácido Butírico/farmacología , Colitis Ulcerosa/patología , Colitis Ulcerosa/metabolismo , Colon/patología , Colon/metabolismo , Sulfato de Dextran , Células Caliciformes/patología , Células Caliciformes/metabolismo , Histona Desacetilasa 1/metabolismo , Histona Desacetilasa 1/genética , Histona Desacetilasa 2/metabolismo , Histona Desacetilasa 2/genética , Hidroximetilglutaril-CoA Sintasa/metabolismo , Hidroximetilglutaril-CoA Sintasa/genética , Ratones Endogámicos C57BL , PPAR gamma/metabolismo , PPAR gamma/genética

RESUMEN

Cerebral arteriovenous malformations represent the most common form of vascular malformations and can cause recurrent bleeding and hemorrhagic stroke. The current issue of the JCI features an article by Zhao et al. describing a mouse model of cerebral arteriovenous malformations. Endothelial cells lacking matrix Gla protein, a BMP inhibitor, underwent epigenetic changes characteristic of an endothelial-to-mesenchymal fate transition. The authors uncovered a two-step process for this transition controlled by the epigenetic regulator histone deacetylase 2 (HDAC2), which controls endothelial cell differentiation, and by enhancer of zeste homolog 1 (EZH1), which suppressed mesenchymal fate. This discovery provides a promising entry point for preventive pharmacological interventions.

Asunto(s)

Epigénesis Genética , Histona Desacetilasa 2 , Animales , Ratones , Humanos , Histona Desacetilasa 2/metabolismo , Histona Desacetilasa 2/genética , Células Endoteliales/metabolismo , Células Endoteliales/patología , Malformaciones Arteriovenosas Intracraneales/genética , Malformaciones Arteriovenosas Intracraneales/metabolismo , Malformaciones Arteriovenosas Intracraneales/patología , Proteínas de Unión al Calcio/genética , Proteínas de Unión al Calcio/metabolismo , Modelos Animales de Enfermedad , Diferenciación Celular , Proteínas de la Matriz Extracelular/metabolismo , Proteínas de la Matriz Extracelular/genética

RESUMEN

Hepatocellular carcinoma (HCC) is a significant global health challenge. The activation of autophagy plays an essential role in promoting the proliferation and survival of cancer cells. However, the upstream regulatory network and mechanisms governing autophagy in HCC remain unclear. This study demonstrated that histone deacetylase 2 (HDAC2) regulates autophagy in HCC. Its expression was elevated in HCC tissues, and high HDAC2 expression was strongly associated with poor prognosis in individuals with HCC. Integrated in vitro and in vivo investigations confirmed that HDAC2 promotes autophagy and autophagy-related malignant progression in HCC. Mechanistically, HDAC2 bound specifically to the lysosome-associated protein transmembrane 4-ß (LAPTM4B) promoter at four distinct binding sites, enhancing its transcriptional activation and driving autophagy-related malignant progression in HCC. These findings establish LAPTM4B as a direct target gene of HDAC2. Furthermore, the selective inhibitor of HDAC2 effectively alleviated the malignant development of HCC. In addition, multivariate Cox regression analysis of 105 human HCC samples revealed that HDAC2 expression is an independent predictor of HCC prognosis. This study underscores the crucial role of the HDAC2-LAPTM4B axis in regulating autophagy in the malignant evolution of HCC and highlights the potential of targeting HDAC2 to prevent and halt the malignant progression of HCC.

Asunto(s)

Autofagia , Carcinoma Hepatocelular , Progresión de la Enfermedad , Histona Desacetilasa 2 , Neoplasias Hepáticas , Proteínas de la Membrana , Humanos , Carcinoma Hepatocelular/patología , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/metabolismo , Histona Desacetilasa 2/metabolismo , Histona Desacetilasa 2/genética , Autofagia/genética , Neoplasias Hepáticas/patología , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/metabolismo , Proteínas de la Membrana/metabolismo , Proteínas de la Membrana/genética , Masculino , Animales , Regulación Neoplásica de la Expresión Génica , Femenino , Línea Celular Tumoral , Ratones , Ratones Desnudos , Activación Transcripcional/genética , Persona de Mediana Edad , Ratones Endogámicos BALB C , Pronóstico , Proliferación Celular/genética , Regiones Promotoras Genéticas/genética , Proteínas Oncogénicas

RESUMEN

Dysregulation of histone deacetylases (HDACs) is closely associated with cancer development and progression. Here, we comprehensively analyzed the association between all HDAC family members and several clinicopathological and molecular traits of solid tumors across 22 distinct tumor types, focusing primarily on cancer stemness and immunity. To this end, we used publicly available TCGA data and several bioinformatic tools (i.e., GEPIA2, TISIDB, GSCA, Enrichr, GSEA). Our analyses revealed that class I and class II HDAC proteins are associated with distinct cancer phenotypes. The transcriptomic profiling indicated that class I HDAC members, including HDAC2, are positively associated with cancer stemness, while class IIA HDAC proteins, represented by HDAC7, show a negative correlation to cancer stem cell-like phenotypes in solid tumors. In contrast to tumors with high amounts of HDAC7 proteins, the transcriptome signatures of HDAC2-overexpressing cancers are significantly enriched with biological terms previously determined as stemness-associated genes. Moreover, high HDAC2-expressing tumors are depleted with immune-related processes, and HDAC2 expression correlates with tumor immunosuppressive microenvironments. On the contrary, HDAC7 upregulation is significantly associated with enhanced immune responses, followed by enriched infiltration of CD4+ and CD8+ T cells. This is the first comprehensive report demonstrating robust and versatile associations between specific HDAC family members, cancer dedifferentiation, and anti-tumor immune statuses in solid tumors.

Asunto(s)

Epigénesis Genética , Regulación Neoplásica de la Expresión Génica , Histona Desacetilasa 2 , Histona Desacetilasas , Neoplasias , Células Madre Neoplásicas , Humanos , Histona Desacetilasa 2/genética , Histona Desacetilasa 2/metabolismo , Neoplasias/genética , Neoplasias/patología , Neoplasias/inmunología , Células Madre Neoplásicas/metabolismo , Células Madre Neoplásicas/patología , Histona Desacetilasas/genética , Histona Desacetilasas/metabolismo , Microambiente Tumoral/genética , Microambiente Tumoral/inmunología , Perfilación de la Expresión Génica , Transcriptoma

RESUMEN

The histone deacetylase 2 (HDAC2), an enzyme involved in gene regulation, is a potent drug target for the treatment of colon cancer. Phytocompounds having anticancer properties show the ability to interact with HDAC2 enzyme. Among the compounds, docking scores of caffeic acid (CA) and p-coumaric acid (pCA) with HDAC2 showed good binding efficacy of -5.46 kcal/mol and -5.16 kcal/mol, respectively, with small inhibition constants. The higher binding efficacy of CA compared to pCA can be credited to the presence of an extra oxygen atom in the CA molecule, which forms an additional hydrogen bond with Tyr297. The HDAC2 in complex with these molecules was found to be stable by analyzing RMSD, RMSF, Rg, and SASA values obtained through MD simulations. Furthermore, CA and pCA exhibited low MM/GBSA free energies of -16.32 ± 2.62 kcal/mol and -17.01 ± 2.87 kcal/mol, respectively. The HOMO and LUMO energy gaps, dipole moments, global reactivity descriptor values, and MEP surfaces showed the reactivity of the molecules. The favourable physicochemical and pharmacokinetic properties, along with absence of toxicity of the molecules determined using ADMET analysis, suggested both the acids to be regarded as effective drugs in the treatment of colon cancer.

Asunto(s)

Neoplasias del Colon , Histona Desacetilasa 2 , Simulación del Acoplamiento Molecular , Simulación de Dinámica Molecular , Neoplasias del Colon/tratamiento farmacológico , Neoplasias del Colon/patología , Humanos , Histona Desacetilasa 2/antagonistas & inhibidores , Histona Desacetilasa 2/metabolismo , Histona Desacetilasa 2/química , Inhibidores de Histona Desacetilasas/química , Inhibidores de Histona Desacetilasas/farmacología , Ácidos Cafeicos/química , Ácidos Cafeicos/farmacología , Propionatos/química , Propionatos/farmacología , Ácidos Cumáricos/química , Ácidos Cumáricos/farmacología , Enlace de Hidrógeno , Teoría Funcional de la Densidad

RESUMEN

The human immunodeficiency virus type 1 (HIV-1) reservoir consists of latently infected cells which present a major obstacle to achieving a functional cure for HIV-1. The formation and maintenance of HIV-1 latency have been extensively studied, and latency-reversing agents (LRAs) that can reactivate latent HIV-1 by targeting the involved host factors are developed; however, their clinical efficacies remain unsatisfactory. Therefore, it is imperative to identify novel targets for more potential candidates or better combinations for LRAs. In this study, we utilized CRISPR affinity purification in situ of regulatory elements system to screen for host factors associated with the HIV-1 long terminal repeat region that could potentially be involved in HIV-1 latency. We successfully identified that origin recognition complex 1 (ORC1), the largest subunit of the origin recognition complex, contributes to HIV-1 latency in addition to its function in DNA replication initiation. Notably, ORC1 is enriched on the HIV-1 promoter and recruits a series of repressive epigenetic elements, including DNMT1 and HDAC1/2, and histone modifiers, such as H3K9me3 and H3K27me3, thereby facilitating the establishment and maintenance of HIV-1 latency. Moreover, the reactivation of latent HIV-1 through ORC1 depletion has been confirmed across various latency cell models and primary CD4+ T cells from people living with HIV-1. Additionally, we comprehensively validated the properties of liquid-liquid phase separation (LLPS) of ORC1 from multiple perspectives and identified the key regions that promote the formation of LLPS. This property is important for the recruitment of ORC1 to the HIV-1 promoter. Collectively, these findings highlight ORC1 as a potential novel target implicated in HIV-1 latency and position it as a promising candidate for the development of novel LRAs. IMPORTANCE: Identifying host factors involved in maintaining human immunodeficiency virus type 1 (HIV-1) latency and understanding their mechanisms prepares the groundwork to discover novel targets for HIV-1 latent infection and provides further options for the selection of latency-reversing agents in the "shock" strategy. In this study, we identified a novel role of the DNA replication factor origin recognition complex 1 (ORC1) in maintaining repressive chromatin structures surrounding the HIV-1 promoter region, thereby contributing to HIV-1 latency. This discovery expands our understanding of the non-replicative functions of the ORC complex and provides a potential therapeutic strategy for HIV-1 cure.

Asunto(s)

Epigénesis Genética , Infecciones por VIH , Duplicado del Terminal Largo de VIH , VIH-1 , Complejo de Reconocimiento del Origen , Regiones Promotoras Genéticas , Latencia del Virus , Latencia del Virus/genética , Humanos , VIH-1/genética , VIH-1/fisiología , Duplicado del Terminal Largo de VIH/genética , Infecciones por VIH/virología , Infecciones por VIH/genética , Infecciones por VIH/metabolismo , Complejo de Reconocimiento del Origen/metabolismo , Complejo de Reconocimiento del Origen/genética , Linfocitos T CD4-Positivos/virología , Células HEK293 , ADN (Citosina-5-)-Metiltransferasa 1/metabolismo , ADN (Citosina-5-)-Metiltransferasa 1/genética , Histona Desacetilasa 1/metabolismo , Histona Desacetilasa 1/genética , Histona Desacetilasa 2/metabolismo , Histona Desacetilasa 2/genética , Regulación Viral de la Expresión Génica , Replicación Viral , Histonas/metabolismo , Histonas/genética

RESUMEN

Access to DNA is the first level of control in regulating gene transcription, a control that is also critical for maintaining DNA integrity. Cellular senescence is characterized by profound transcriptional rearrangements and accumulation of DNA lesions. Here, we discovered an epigenetic complex between HDAC4 and HDAC1/HDAC2 that is involved in the erase of H2BK120 acetylation. The HDAC4/HDAC1/HDAC2 complex modulates the efficiency of DNA repair by homologous recombination, through dynamic deacetylation of H2BK120. Deficiency of HDAC4 leads to accumulation of H2BK120ac, impaired recruitment of BRCA1 and CtIP to the site of lesions, accumulation of damaged DNA and senescence. In senescent cells this complex is disassembled because of increased proteasomal degradation of HDAC4. Forced expression of HDAC4 during RAS-induced senescence reduces the genomic spread of γH2AX. It also affects H2BK120ac levels, which are increased in DNA-damaged regions that accumulate during RAS-induced senescence. In summary, degradation of HDAC4 during senescence causes the accumulation of damaged DNA and contributes to the activation of the transcriptional program controlled by super-enhancers that maintains senescence.

Asunto(s)

Daño del ADN , Histona Desacetilasa 1 , Histona Desacetilasa 2 , Histona Desacetilasas , Histonas , Humanos , Acetilación , Proteína BRCA1/metabolismo , Proteína BRCA1/genética , Línea Celular , Senescencia Celular , Histona Desacetilasa 1/metabolismo , Histona Desacetilasa 1/genética , Histona Desacetilasa 2/metabolismo , Histona Desacetilasa 2/genética , Histona Desacetilasas/metabolismo , Histona Desacetilasas/genética , Histonas/metabolismo , Reparación del ADN por Recombinación , Proteínas Represoras/metabolismo , Proteínas Represoras/genética

RESUMEN

Diabetic encephalopathy (DE) is a severe complication of the central nervous system associated with diabetes. In this study, we investigated the regulatory role of mammalian target of rapamycin (mTOR) on nuclear factor κB (NF-κB) in mice with DE, and the neuroprotective effect and therapeutic mechanisms of luteolin, a natural flavonoid compound with anti-inflammatory, antioxidant, and neuroprotective properties. The results indicated that treatment with luteolin improved the degree of cognitive impairment in mice with DE. It also decreased the levels of phosphorylated mTOR, phosphorylated NF-κB, and histone deacetylase 2 (HDAC2) and increased the expression of brain-derived neurotrophic factor and synaptic-related proteins. Furthermore, protein-protein interaction and the Gene Ontology analysis revealed that luteolin was involved in the regulatory network of HDAC2 expression through the mTOR/NF-κB signaling cascade. Our bioinformatics and molecular docking results indicated that luteolin may also directly target HDAC2, as an HDAC2 inhibitor, to alleviate DE, complementing mTOR/NF-κB signaling inhibition. Analysis of luteolin's target proteins and their interactions suggest an effect on HDAC2 and cognition. In conclusion, HDAC2 and tau hyperphosphorylation are regulated by the mTOR/NF-κB signaling cascade in DE, and luteolin is found to reverse these effects, demonstrating its protective role in DE.

Asunto(s)

Histona Desacetilasa 2 , Luteolina , FN-kappa B , Proteínas tau , Luteolina/farmacología , Luteolina/uso terapéutico , Animales , Histona Desacetilasa 2/metabolismo , FN-kappa B/metabolismo , Ratones , Proteínas tau/metabolismo , Fosforilación/efectos de los fármacos , Masculino , Serina-Treonina Quinasas TOR/metabolismo , Transducción de Señal/efectos de los fármacos , Encefalopatías/metabolismo , Encefalopatías/tratamiento farmacológico , Fármacos Neuroprotectores/farmacología , Fármacos Neuroprotectores/uso terapéutico , Simulación del Acoplamiento Molecular , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Experimental/tratamiento farmacológico , Complicaciones de la Diabetes/tratamiento farmacológico , Complicaciones de la Diabetes/metabolismo , Disfunción Cognitiva/metabolismo , Disfunción Cognitiva/tratamiento farmacológico , Ratones Endogámicos C57BL , Factor Neurotrófico Derivado del Encéfalo/metabolismo

RESUMEN

Embryonic stem cells (ESCs) can differentiate into all cell types of the embryonic germ layers. ESCs can also generate totipotent 2C-like cells and trophectodermal cells. However, these latter transitions occur at low frequency due to epigenetic barriers, the nature of which is not fully understood. Here, we show that treating mouse ESCs with sodium butyrate (NaB) increases the population of 2C-like cells and enables direct reprogramming of ESCs into trophoblast stem cells (TSCs) without a transition through a 2C-like state. Mechanistically, NaB inhibits histone deacetylase activities in the LSD1-HDAC1/2 corepressor complex. This increases acetylation levels in the regulatory regions of both 2C- and TSC-specific genes, promoting their expression. In addition, NaB-treated cells acquire the capacity to generate blastocyst-like structures that can develop beyond the implantation stage in vitro and form deciduae in vivo. These results identify how epigenetics restrict the totipotent and trophectoderm fate in mouse ESCs.

Asunto(s)

Diferenciación Celular , Inhibidores de Histona Desacetilasas , Células Madre Embrionarias de Ratones , Trofoblastos , Animales , Trofoblastos/citología , Trofoblastos/metabolismo , Trofoblastos/efectos de los fármacos , Ratones , Células Madre Embrionarias de Ratones/metabolismo , Células Madre Embrionarias de Ratones/citología , Células Madre Embrionarias de Ratones/efectos de los fármacos , Inhibidores de Histona Desacetilasas/farmacología , Diferenciación Celular/efectos de los fármacos , Reprogramación Celular/efectos de los fármacos , Histona Demetilasas/metabolismo , Histona Desacetilasa 1/metabolismo , Histona Desacetilasa 2/metabolismo , Epigénesis Genética , Femenino , Acetilación/efectos de los fármacos , Histona Desacetilasas/metabolismo , Ácido Butírico/farmacología

RESUMEN

BACKGROUND: Vascular endothelial growth factor (VEGF) is one of the most powerful proangiogenic factors and plays an important role in multiple diseases. Increased glycolytic rates and lactate accumulation are associated with pathological angiogenesis. RESULTS: Here, we show that a feedback loop between H3K9 lactylation (H3K9la) and histone deacetylase 2 (HDAC2) in endothelial cells drives VEGF-induced angiogenesis. We find that the H3K9la levels are upregulated in endothelial cells in response to VEGF stimulation. Pharmacological inhibition of glycolysis decreases H3K9 lactylation and attenuates neovascularization. CUT& Tag analysis reveals that H3K9la is enriched at the promoters of a set of angiogenic genes and promotes their transcription. Interestingly, we find that hyperlactylation of H3K9 inhibits expression of the lactylation eraser HDAC2, whereas overexpression of HDAC2 decreases H3K9 lactylation and suppresses angiogenesis. CONCLUSIONS: Collectively, our study illustrates that H3K9la is important for VEGF-induced angiogenesis, and interruption of the H3K9la/HDAC2 feedback loop may represent a novel therapeutic method for treating pathological neovascularization.

Asunto(s)

Retroalimentación Fisiológica , Histona Desacetilasa 2 , Histonas , Neovascularización Fisiológica , Factor A de Crecimiento Endotelial Vascular , Histona Desacetilasa 2/metabolismo , Histona Desacetilasa 2/genética , Factor A de Crecimiento Endotelial Vascular/metabolismo , Histonas/metabolismo , Humanos , Animales , Neovascularización Fisiológica/efectos de los fármacos , Células Endoteliales/metabolismo , Ratones , Células Endoteliales de la Vena Umbilical Humana/metabolismo , Glucólisis , Neovascularización Patológica/metabolismo , Angiogénesis

RESUMEN

Dendritic cell (DC) progenitors adapt their transcriptional program during development, generating different subsets. How chromatin modifications modulate these processes is unclear. Here, we investigate the impact of histone deacetylation on DCs by genetically deleting histone deacetylase 1 (HDAC1) or HDAC2 in hematopoietic progenitors and CD11c-expressing cells. While HDAC2 is not critical for DC development, HDAC1 deletion impairs pro-pDC and mature pDC generation and affects ESAM+cDC2 differentiation from tDCs and pre-cDC2s, whereas cDC1s are unchanged. HDAC1 knockdown in human hematopoietic cells also impairs cDC2 development, highlighting its crucial role across species. Multi-omics analyses reveal that HDAC1 controls expression, chromatin accessibility, and histone acetylation of the transcription factors IRF4, IRF8, and SPIB required for efficient development of cDC2 subsets. Without HDAC1, DCs switch immunologically, enhancing tumor surveillance through increased cDC1 maturation and interleukin-12 production, driving T helper 1-mediated immunity and CD8+ T cell recruitment. Our study reveals the importance of histone acetylation in DC development and anti-tumor immunity, suggesting DC-targeted therapeutic strategies for immuno-oncology.

Asunto(s)

Diferenciación Celular , Células Dendríticas , Histona Desacetilasa 1 , Células Dendríticas/metabolismo , Células Dendríticas/inmunología , Histona Desacetilasa 1/metabolismo , Animales , Humanos , Ratones , Ratones Endogámicos C57BL , Acetilación , Neoplasias/inmunología , Neoplasias/patología , Histonas/metabolismo , Linfocitos T CD8-positivos/inmunología , Linfocitos T CD8-positivos/metabolismo , Histona Desacetilasa 2/metabolismo , Interleucina-12/metabolismo

RESUMEN

Subclinical hypothyroidism (SCH) in pregnancy is the most common form of thyroid dysfunction in pregnancy, which can affect fetal nervous system development and increase the risk of neurodevelopmental disorders after birth. However, the mechanism of the effect of maternal subclinical hypothyroidism on fetal brain development and behavioral phenotypes is still unclear and requires further study. In this study, we constructed a mouse model of maternal subclinical hypothyroidism by exposing dams to drinking water containing 50 ppm propylthiouracil (PTU) during pregnancy and found that its offspring were accompanied by severe cognitive deficits by behavioral testing. Mechanistically, gestational SCH resulted in the upregulation of protein expression and activity of HDAC1/2/3 in the hippocampus of the offspring. ChIP analysis revealed that H3K9ac on the neurogranin (Ng) promoter was reduced in the hippocampus of the offspring of SCH, with a significant reduction in Ng protein, leading to reduced expression levels of synaptic plasticity markers PSD95 (a membrane-associated protein in the postsynaptic density) and SYN (synaptophysin, a specific marker for presynaptic terminals), and impaired synaptic plasticity. In addition, administration of MS-275 (an HDAC1/2/3-specific inhibitor) to SCH offspring alleviated impaired synaptic plasticity and cognitive dysfunction in offspring. Thus, our study suggests that maternal subclinical hypothyroidism may mediate offspring cognitive dysfunction through the HDAC1/2/3-H3K9ac-Ng pathway. Our study contributes to the understanding of the signaling mechanisms underlying maternal subclinical hypothyroidism-mediated cognitive impairment in the offspring.

Asunto(s)

Disfunción Cognitiva , Histona Desacetilasa 1 , Histona Desacetilasa 2 , Hipotiroidismo , Neurogranina , Efectos Tardíos de la Exposición Prenatal , Animales , Neurogranina/metabolismo , Neurogranina/genética , Hipotiroidismo/metabolismo , Femenino , Embarazo , Ratones , Disfunción Cognitiva/metabolismo , Disfunción Cognitiva/etiología , Histona Desacetilasa 2/metabolismo , Histona Desacetilasa 2/genética , Efectos Tardíos de la Exposición Prenatal/metabolismo , Histona Desacetilasa 1/metabolismo , Histona Desacetilasa 1/genética , Regulación hacia Abajo , Hipocampo/metabolismo , Masculino , Histona Desacetilasas/metabolismo , Histona Desacetilasas/genética , Ratones Endogámicos C57BL , Plasticidad Neuronal

RESUMEN

BACKGROUND: Elevated evidence suggests that the SENPs family plays an important role in tumor progression. However, the role of SENPs in AML remains unclear. METHODS: We evaluated the expression pattern of SENP1 based on RNA sequencing data obtained from OHSU, TCGA, TARGET, and MILE datasets. Clinical samples were used to verify the expression of SENP1 in the AML cells. Lentiviral vectors shRNA and sgRNA were used to intervene in SENP1 expression in AML cells, and the effects of SENP1 on AML proliferation and anti-apoptosis were detected using in vitro and in vivo models. Chip-qPCR, MERIP-qPCR, CO-IP, RNA pulldown, and dual-luciferase reporter gene assays were used to explore the regulatory mechanisms of SNEP1 in AML. RESULTS: SENP1 was significantly upregulated in high-risk AML patients and closely related to poor prognosis. The AKT/mTOR signaling pathway is a key downstream pathway that mediates SENP1's regulation of AML proliferation and anti-apoptosis. Mechanistically, the CO-IP assay revealed binding between SENP1 and HDAC2. SUMO and Chip-qPCR assays suggested that SENP1 can desumoylate HDAC2, which enhances EGFR transcription and activates the AKT pathway. In addition, we found that IGF2BP3 expression was upregulated in high-risk AML patients and was positively correlated with SENP1 expression. MERIP-qPCR and RIP-qPCR showed that IGF2BP3 binds SENP1 3-UTR in an m6A manner, enhances SENP1 expression, and promotes AKT pathway conduction. CONCLUSIONS: Our findings reveal a distinct mechanism of SENP1-mediated HDAC2-AKT activation and establish the critical role of the IGF2BP3/SENP1signaling axis in AML development.

Asunto(s)

Adenosina , Proliferación Celular , Cisteína Endopeptidasas , Histona Desacetilasa 2 , Leucemia Mieloide Aguda , Proteínas Proto-Oncogénicas c-akt , Proteínas de Unión al ARN , Sumoilación , Animales , Femenino , Humanos , Masculino , Ratones , Adenosina/análogos & derivados , Adenosina/metabolismo , Apoptosis , Biomarcadores de Tumor/metabolismo , Biomarcadores de Tumor/genética , Línea Celular Tumoral , Cisteína Endopeptidasas/metabolismo , Cisteína Endopeptidasas/genética , Progresión de la Enfermedad , Regulación Leucémica de la Expresión Génica , Histona Desacetilasa 2/metabolismo , Histona Desacetilasa 2/genética , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/metabolismo , Leucemia Mieloide Aguda/patología , Pronóstico , Proteínas Proto-Oncogénicas c-akt/metabolismo , Proteínas de Unión al ARN/metabolismo , Proteínas de Unión al ARN/genética , Transducción de Señal , Ensayos Antitumor por Modelo de Xenoinjerto

RESUMEN

BACKGROUND: Metabolic-associated fatty liver disease (MAFLD) is a leading cause of chronic liver disease worldwide. Autophagy plays a pivotal role in lipid metabolism; however, the mechanism underlying the reduced autophagic activity in MAFLD remains elusive. METHODS: Autophagy was monitored by TUNEL assay and immunofluorescence staining of LC3. The expression of autophagy-related proteins, PPARα, HDAC2, and HRD1 was detected by Western blot. The association between HDAC2 and PPARα promoter was assessed by chromatin immunoprecipitation (ChIP) and dual-luciferase assays, and the HRD1-mediated ubiquitin-proteasomal degradation of HDAC2 was detected by co-immunoprecipitation (co-IP). The in vitro findings were validated in a hypoxia-induced MAFLD mouse model. Histological changes, fibrosis, and apoptosis in liver tissues were detected by hematoxylin and eosin staining, Masson's trichrome staining, and TUNEL assay. The immunoreactivities of key molecules were examined by IHC analysis. RESULTS: Hypoxia-suppressed autophagy in hepatocytes. Hypoxic exposure downregulated HRD1 and PPARα, while upregulating HDAC2 in hepatocytes. Overexpression of PPARα promoted hepatic autophagy, while knocking down HDAC2 or overexpressing HRD1 reduced hypoxia-suppressed autophagy in hepatocytes. Mechanistically, HDAC2 acted as a transcriptional repressor of PPARα, and HRD1 mediated the degradation of HDAC2 through the ubiquitin-proteasome pathway. Functional studies further showed that hypoxia-suppressed hepatic autophagy via the HRD1/HDAC2/PPARα axis in vitro and in vivo. CONCLUSION: HRD1-mediated ubiquitination of HDAC2 regulates PPARα-mediated autophagy and ameliorates hypoxia-induced MAFLD.

Asunto(s)

Autofagia , Histona Desacetilasa 2 , PPAR alfa , Ubiquitina-Proteína Ligasas , Ubiquitinación , PPAR alfa/metabolismo , PPAR alfa/genética , Animales , Histona Desacetilasa 2/metabolismo , Histona Desacetilasa 2/genética , Ratones , Ubiquitina-Proteína Ligasas/metabolismo , Ubiquitina-Proteína Ligasas/genética , Humanos , Masculino , Hepatocitos/metabolismo , Hepatocitos/patología , Ratones Endogámicos C57BL , Enfermedad del Hígado Graso no Alcohólico/metabolismo , Enfermedad del Hígado Graso no Alcohólico/patología , Enfermedad del Hígado Graso no Alcohólico/genética , Modelos Animales de Enfermedad

RESUMEN

Porcine reproductive and respiratory syndrome virus (PRRSV), a member of the Arteriviridae family, represents a persistent menace to the global pig industry, causing reproductive failure and respiratory disease in pigs. In this study, we delved into the role of histone deacetylases (HDAC2) during PRRSV infection. Our findings revealed that HDAC2 expression is downregulated upon PRRSV infection. Notably, suppressing HDAC2 activity through specific small interfering RNA led to an increase in virus production, whereas overexpressing HDAC2 effectively inhibited PRRSV replication by boosting the expression of IFN-regulated antiviral molecules. Furthermore, we identified the virus's nonstructural protein 11 (nsp11) as a key player in reducing HDAC2 levels. Mutagenic analyses of PRRSV nsp11 revealed that its antagonistic effect on the antiviral activity of HDAC2 is dependent on its endonuclease activity. In summary, our research uncovered a novel immune evasion mechanism employed by PRRSV, providing crucial insights into the pathogenesis of this virus and guiding the development of innovative prevention strategies against PRRSV infection.

Asunto(s)

Endorribonucleasas , Histona Desacetilasa 2 , Evasión Inmune , Inmunidad Innata , Síndrome Respiratorio y de la Reproducción Porcina , Virus del Síndrome Respiratorio y Reproductivo Porcino , Animales , Humanos , Línea Celular , Endorribonucleasas/metabolismo , Endorribonucleasas/genética , Histona Desacetilasa 2/metabolismo , Histona Desacetilasa 2/genética , Síndrome Respiratorio y de la Reproducción Porcina/virología , Síndrome Respiratorio y de la Reproducción Porcina/inmunología , Virus del Síndrome Respiratorio y Reproductivo Porcino/inmunología , Virus del Síndrome Respiratorio y Reproductivo Porcino/genética , Porcinos , Proteínas no Estructurales Virales/metabolismo , Proteínas no Estructurales Virales/genética , Replicación Viral

RESUMEN

BACKGROUND: Although numerous studies have indicated that activated pyroptosis can enhance the efficacy of antitumour therapy in several tumours, the precise mechanism of pyroptosis in colorectal cancer (CRC) remains unclear. METHODS: Pyroptosis in CRC cells treated with antitumour agents was assessed using various techniques, including Western blotting, lactate dehydrogenase release assay and microscopy analysis. To uncover the epigenetic mechanisms that regulate NLRP3, chromatin changes and NLRP3 promoter histone modifications were assessed using Assay for Transposase-Accessible Chromatin using sequencing and RNA sequencing. Chromatin immunoprecipitation‒quantitative polymerase chain reaction was used to investigate the NLRP3 transcriptional regulatory mechanism. Additionally, xenograft and patient-derived xenograft models were constructed to validate the effects of the drug combinations. RESULTS: As the core molecule of the inflammasome, NLRP3 expression was silenced in CRC, thereby limiting gasdermin D (GSDMD)-mediated pyroptosis. Supplementation with NLRP3 can rescue pyroptosis induced by antitumour therapy. Overexpression of HDAC2 in CRC silences NLRP3 via epigenetic regulation. Mechanistically, HDAC2 suppressed chromatin accessibility by eliminating H3K27 acetylation. HDAC2 knockout promotes H3K27ac-mediated recruitment of the BRD4-p-P65 complex to enhance NLRP3 transcription. Inhibiting HDAC2 by Santacruzamate A in combination with classic antitumour agents (5-fluorouracil or regorafenib) in CRC xenograft-bearing animals markedly activated pyroptosis and achieved a significant therapeutic effect. Clinically, HDAC2 is inversely correlated with H3K27ac/p-P65/NLRP3 and is a prognostic factor for CRC patients. CONCLUSION: Collectively, our data revealed a crucial role for HDAC2 in inhibiting NLRP3/GSDMD-mediated pyroptosis in CRC cells and highlighted HDAC2 as a potential therapeutic target for antitumour therapy. HIGHLIGHTS: Silencing of NLRP3 limits the GSDMD-dependent pyroptosis in colorectal cancer. HDAC2-mediated histone deacetylation leads to epigenetic silencing of NLRP3. HDAC2 suppresses the NLRP3 transcription by inhibiting the formation of H3K27ac/BRD4/p-P65 complex. Targeting HDAC2 activates pyroptosis and enhances therapeutic effect.

Asunto(s)

Neoplasias Colorrectales , Gasderminas , Histona Desacetilasa 2 , Proteína con Dominio Pirina 3 de la Familia NLR , Piroptosis , Animales , Humanos , Ratones , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Línea Celular Tumoral , Neoplasias Colorrectales/tratamiento farmacológico , Neoplasias Colorrectales/genética , Neoplasias Colorrectales/metabolismo , Gasderminas/metabolismo , Histona Desacetilasa 2/metabolismo , Histona Desacetilasa 2/genética , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Péptidos y Proteínas de Señalización Intracelular/genética , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismo , Proteína con Dominio Pirina 3 de la Familia NLR/genética , Proteínas de Unión a Fosfato , Piroptosis/efectos de los fármacos , Piroptosis/genética