RESUMO
Oxide ceramics are considered promising candidates as solid electrolytes (SEs) for sodium metal batteries. However, the high sintering temperature induced boundaries and pores between angular grains lead to high grain boundary resistance and pathways for dendrite growth. Herein, we report a grain boundary modification strategy, which in situ generates an amorphous matrix among Na5SmSi4O12 oxide grains via tuning the chemical composition. The mechanical properties as well as electron mitigating capability of modified SE have been significantly enhanced. As a result, the SE achieves a room-temperature total ionic conductivity of 5.61 mS cm-1, the highest value for sodium-based oxide SEs. The Na|SE|Na symmetric cell achieves a high critical current density of 2.5 mA cm-2 and excellent cycle life over more than 2800 h at 0.15 mA cm-2 without dendrite formation. The full cell with Na3V2(PO4)3 as the cathode demonstrates impressive cycling performance, maintaining stability over 3000 cycles at 5C without observable loss of capacity.
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BACKGROUND: Metabolic reprogramming and epigenetic alterations contribute to the aggressiveness of pancreatic ductal adenocarcinoma (PDAC). Lactate-dependent histone modification is a new type of histone mark, which links glycolysis metabolite to the epigenetic process of lactylation. However, the role of histone lactylation in PDAC remains unclear. METHODS: The level of histone lactylation in PDAC was identified by western blot and immunohistochemistry, and its relationship with the overall survival was evaluated using a Kaplan-Meier survival plot. The participation of histone lactylation in the growth and progression of PDAC was confirmed through inhibition of histone lactylation by glycolysis inhibitors or lactate dehydrogenase A (LDHA) knockdown both in vitro and in vivo. The potential writers and erasers of histone lactylation in PDAC were identified by western blot and functional experiments. The potential target genes of H3K18 lactylation (H3K18la) were screened by CUT&Tag and RNA-seq analyses. The candidate target genes TTK protein kinase (TTK) and BUB1 mitotic checkpoint serine/threonine kinase B (BUB1B) were validated through ChIP-qPCR, RT-qPCR and western blot analyses. Next, the effects of these two genes in PDAC were confirmed by knockdown or overexpression. The interaction between TTK and LDHA was identified by Co-IP assay. RESULTS: Histone lactylation, especially H3K18la level was elevated in PDAC, and the high level of H3K18la was associated with poor prognosis. The suppression of glycolytic activity by different kinds of inhibitors or LDHA knockdown contributed to the anti-tumor effects of PDAC in vitro and in vivo. E1A binding protein p300 (P300) and histone deacetylase 2 were the potential writer and eraser of histone lactylation in PDAC cells, respectively. H3K18la was enriched at the promoters and activated the transcription of mitotic checkpoint regulators TTK and BUB1B. Interestingly, TTK and BUB1B could elevate the expression of P300 which in turn increased glycolysis. Moreover, TTK phosphorylated LDHA at tyrosine 239 (Y239) and activated LDHA, and subsequently upregulated lactate and H3K18la levels. CONCLUSIONS: The glycolysis-H3K18la-TTK/BUB1B positive feedback loop exacerbates dysfunction in PDAC. These findings delivered a new exploration and significant inter-relationship between lactate metabolic reprogramming and epigenetic regulation, which might pave the way toward novel lactylation treatment strategies in PDAC therapy.
Assuntos
Carcinoma Ductal Pancreático , Regulação Neoplásica da Expressão Gênica , Glicólise , Histonas , L-Lactato Desidrogenase , Neoplasias Pancreáticas , Carcinoma Ductal Pancreático/metabolismo , Carcinoma Ductal Pancreático/patologia , Carcinoma Ductal Pancreático/genética , Humanos , Histonas/metabolismo , Animais , Linhagem Celular Tumoral , Neoplasias Pancreáticas/metabolismo , Neoplasias Pancreáticas/patologia , Neoplasias Pancreáticas/genética , Camundongos , Retroalimentação Fisiológica , Epigênese Genética , Carcinogênese/metabolismo , Carcinogênese/genética , Prognóstico , Proliferação de Células , FemininoRESUMO
The byproduct formation in environmental catalysis is strongly influenced by the chemical state and coordination of catalysts. Herein, two Pd/CeO2 catalysts (PdCe-350 and PdCe-800) with varying oxygen vacancies (Ov) and coordination numbers (CN) of Pd were prepared to investigate the mechanism of N2O and NH3 formation during NO reduction by CO. PdCe-350 exhibits a higher density of Ov and Pd sites with higher CN, leading to an enhanced metal-support interaction by electron transformation from the support to Pd. Consequently, PdCe-350 displayed increased levels of byproduct formation. In situ spectroscopies under dry and wet conditions revealed that at low temperatures, the N2O formation strongly correlated with the Ov density through the decomposition of chelating nitro species on PdCe-350. Conversely, at high temperatures, it was linked to the reactivity of Pd species, primarily facilitated by monodentate nitrates on PdCe-800. In terms of NH3 formation, its occurrence was closely associated with the activation of H2O and C3H6, since a water-gas shift or hydrocarbon reforming could provide hydrogen. Both bridging and monodentate nitrates showed activity in NH3 formation, while hyponitrites were identified as key intermediates for both catalysts. The insights provide a fundamental understanding of the intricate relationship among the local coordination of Pd, surface Ov, and byproduct distribution.
Assuntos
Oxigênio , Água , Oxirredução , Análise Espectral , Nitratos/química , CatáliseRESUMO
The impact of water on catalyst activity remains inconclusive due to its dependence on the specific reaction environment. To maximize the exploitation of water's promoting effect, we employed ammonia selective catalytic reduction (NH3-SCR) as a probe reaction and proposed a phosphorus modification strategy for Cu-ZSM-5 catalysts. The objective of this approach was to construct water-adaptive microstructures through directional arrangement. To investigate the effect of phosphorus on the transformation of framework copper sites in humid environments, we conducted comprehensive characterizations and density functional theory calculation. Results reveal that water molecules cleave the oxygen bridges between phosphorus oxide and copper, leading to the formation of active isolated [Cu(OH)]+ groups and phosphate. The phosphate species weaken the interaction between exchanged Cu2+ groups and the zeolite framework, leading to the generation of highly migratory hydrated Cu2+ species. This work will potentially guide the rational design of water-adaptive catalysts for gas pollution abatement in a humid environment.
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Modulating vanadia-based metal oxides is one of the effective methods for designing difunctional catalysts for simultaneous control of NOx and chlorobenzene (CB) from the emissions of industrial sources. Excessive NH3 adsorption and polychlorinated species accumulation on the surface are the primary issues poisoning catalysts and reducing their lifetime. Herein, Sb is selected as an NH3 adsorption alleviator and polychlorinated species preventor dopant on V2O5-WO3/TiO2. The catalyst exhibits an excellent performance for total NOx and 90% CB conversions at 300-400 °C under a gas hourly space velocity (GHSV) of 60,000 mL g-1 h-1. The HCl and N2 selectivities are maintained at 90 and 98%, respectively. The anti-poisoning ability could be attributed to the generated V-O-Sb chains on the surface: the band gap of vanadium is narrowed and the electron capability is strengthened. The above variation weakens the Lewis acid sites and blocks the electrophilic chlorination reactions of the catalyst surface (formation of polychlorinated species). In addition, oxygen vacancies on Sb-O-Ti also increase: the ring opening of benzoates is accelerated and NH3 adsorption energy is weakened. The above variation lowers the energy barriers of C-Cl cleavage even under NH3 pre-adsorption models and enhances NOx reduction thermodynamically and kinetically.
Assuntos
Poluentes Ambientais , Titânio , Amônia , Óxidos , CatáliseRESUMO
Copper-loaded ceria (Cu/CeO2) catalysts have become promising for the catalytic oxidation of industrial CO emissions. Since their superior redox property mainly arises from the synergistic effect between Cu and the CeO2 support, the dispersion state of Cu species may dominate the catalytic performance of Cu/CeO2 catalysts: the extremely high or low dispersity is disadvantageous for the catalytic performance. The nanoparticle catalysts usually present few contact sites, while the single-atom catalysts tend to be passivated due to their relatively single valence state. To achieve a suitable dispersion state, we synthesized a superior Cu/CeO2 catalyst with Cu atomic clusters, realizing high atomic exposure and unit atomic activity simultaneously via favorable electron interaction and an anchoring effect. The catalyst reaches a 90% CO conversion at 130 °C, comparable to noble-metal catalysts. According to combined in situ spectroscopy and density functional theory calculations, the superior CO oxidation performance of the Cu atomic cluster catalyst results from the joint efforts of effective adsorption of CO at the electrophilic sites, the CO spillover phenomenon, and the efficient bicarbonate pathway triggered by hydroxyl. By providing a superior atomic cluster catalyst and uncovering the catalytic oxidation mechanism of Cu-Ce dual-active sites, our work may enlighten future research on industrial gaseous pollutant removal.
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Cobre , Elétrons , Oxirredução , Adsorção , CatáliseRESUMO
Loss of function/dysregulation of inhibitor of growth 4 (ING4) and hyperactivation of NF-κB are frequent events in many types of human malignancies. However, the molecular mechanisms underlying these remarkable aberrations are not understood. Here, we report that ING4 is physically associated with JFK. We demonstrated that JFK targets ING4 for ubiquitination and degradation through assembly of an Skp1-Cul1-F-box (SCF) complex. We showed that JFK-mediated ING4 destabilization leads to the hyperactivation of the canonical NF-κB pathway and promotes angiogenesis and metastasis of breast cancer. Significantly, the expression of JFK is markedly up-regulated in breast cancer, and the level of JFK is negatively correlated with that of ING4 and positively correlated with an aggressive clinical behavior of breast carcinomas. Our study identified SCF(JFK) as a bona fide E3 ligase for ING4 and unraveled the JFK-ING4-NF-κB axis as an important player in the development and progression of breast cancer, supporting the pursuit of JFK as a potential target for breast cancer intervention.
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Neoplasias da Mama/enzimologia , Neoplasias da Mama/fisiopatologia , Proteínas de Ciclo Celular/metabolismo , Proteínas F-Box/metabolismo , Proteínas de Homeodomínio/metabolismo , Neovascularização Patológica/enzimologia , Proteínas Supressoras de Tumor/metabolismo , Neoplasias da Mama/irrigação sanguínea , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Células MCF-7 , Complexos Multiproteicos , NF-kappa B/metabolismo , Metástase Neoplásica , Neovascularização Patológica/genética , Proteólise , Transdução de Sinais , UbiquitinaçãoRESUMO
In most of the world's building material industries, the control of flue gas pollutants mainly focuses on a single pollutant. However, given the large capacity and high contribution of China's building materials industry to global air pollution, the need to develop multi-pollutant emission reduction technology is urgent. Recently, China has focused on reducing the emissions of flue gas pollutants in the building materials industry, established many key research and development projects, and gradually implemented more stringent pollutant emission limits. This project focuses on the most recent advances in flue gas emission control technology in China's building materials industry, including denitration, dust removal, desulfurization, synergistic multi-pollutant emission reduction, and the construction of pilot research and demonstration projects for pollutant removal in several building material industries. On this basis, revised pollutant limits in flue gas emitted in China's building material industry are proposed.
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Poluentes Atmosféricos , Poluição do Ar , Poluentes Ambientais , Poluentes Atmosféricos/análise , Poluição do Ar/prevenção & controle , Poluição do Ar/análise , Materiais de Construção , ChinaRESUMO
Obstetric antiphospholipid syndrome (OAPS) is an autoimmune disorder with severe life-threatening complications shown during pregnancy. It has been reported that the increase in CD16+CD56dim natural killer (NK) cells in peripheral blood are risk factors for recurrent miscarriages, but this expression of CD16+CD56dim NK cells in OAPS patients has not been reported, and the mechanism is not clearly illustrated. In this study, we compared the distributional profiles of different NK cell subsets and the expressions of NK cell-activating receptors in peripheral blood of patients with OAPS and healthy women. Our results showed significantly increased NKG2A-NKG2D+ subset and decreased NKG2A+NKG2D- subset in CD3- CD16+CD56dim NK cells, CD3-CD16-CD56bright NK cells and CD56+T cells in OAPS patients compared with those in healthy control women. The CD27-CD11b+ subset significantly increased in CD3-CD16+CD56dim NK cells in OAPS patients compared with those in healthy control women. In addition, the NKG2A-NKG2D+ subset in CD3-CD16+CD56dim NK subset in triple positivity was higher than single positivity OAPS patients. At the optimal diagnostic threshold established by ROC analysis, using the cut-off of NKG2A-NKG2D+ and CD27-CD11b+ subset in CD3-CD16+CD56dim NK cells is 10.10% and 92.75%, the sensitivity of NKG2A-NKG2D+ and CD27-CD11b+ to detect patients with OAPS compared with healthy control results was 94.1% and 60.8%, and specificity was 84.2% and 89.5%, respectively, with an area under the curve (AUC) of 0.903 and 0.829, respectively. The NKG2A-NKG2D+ subset in CD3-CD16+CD56dim NK cells was positively correlated with the antiphospholipid antibodies lg anti-aCL IgG, lg anti-aCL IgM, lg anti-aCL IgA, lg anti-ß2GP1 IgM and Complement 4(C4), while the CD27+CD11b+ subset in CD3-CD16+CD56dim NK cells was correlated with lg anti-ß2GP1 IgG and lg anti-ß2GP1 IgA. These results suggested that the NK cytotoxic function enhanced in OAPS patients and unbalanced of NK activating receptors and inhibiting receptors may contribute to the immune pathogenesis of OAPS.
Assuntos
Síndrome Antifosfolipídica , Subfamília K de Receptores Semelhantes a Lectina de Células NK , Anticorpos Antifosfolipídeos , Síndrome Antifosfolipídica/diagnóstico , Antígeno CD56 , Feminino , Humanos , Células Matadoras Naturais , Gravidez , Receptores de IgGRESUMO
The V2O5/TiO2 (VTi) catalyst has been widely employed for the NH3 selective catalytic reduction (NH3-SCR) reaction, and sulfur (S) and alkali metals (K) were usually considered as poisons during this reaction. In this work, the synergistic effect of S and K over the VTi catalyst for the NH3-SCR reaction was analyzed and discussed. It is surprisingly observed that the synergistic effects of S and K exhibited a detoxification effect on the NH3-SCR reaction. That is, although the VTi catalyst exhibited moderate resistance to S poisoning and unsatisfactory resistance to K deactivation, the SCR activity was restored to close to fresh VTi when K and S coexisted. This detoxification effect also could occur between other alkali metals (e.g., Ca and Na) and sulfur. X-ray photoelectron spectroscopy and charge density difference studies both indicate that the introduction of K could significantly affect the electronic structure of V, but this toxic effect was recovered by the further addition of S because of the strong interaction between S and K. Therefore, this detoxification effect can occur in the practical reaction atmosphere, which alleviates the alkali metal poisoning of commercial catalysts.
Assuntos
Amônia , Metais Alcalinos , Amônia/química , Catálise , Enxofre , Titânio/químicaRESUMO
Catalytic combustion is an efficient method to eliminate CO and volatile organic compound (VOC) pollutants. CuMn2O4 spinel is a high-performance non-noble metal oxide catalyst for catalytic combustion and has the potential to replace noble metal catalysts. In order to further improve the catalytic activity of CuMn2O4 spinel, we propose a simple and low-cost approach to introduce numerous oxygen and metal vacancies simultaneously in situ on the CuMn2O4 spinel surface for the catalytic combustion of CO and VOCs. Alkali treatment was used to generate oxygen vacancies (VO), copper vacancies (VCu), and novel active sites (VO combines with Mn2O3 at the interface between Mn2O3(222) and CuMn2O4(311)) on the CuMn2O4 spinel surface. In the catalytic combustion of CO and VOCs, the vacancies and new active sites showed high activity and stability. The oxidation rate of CO increased by 4.13 times at 160 °C, and that of toluene increased by 11.63 times at 250 °C. Oxygen is easier to adsorb and dissociate on VO and novel sites, and the dissociated oxygen also more easily participates in the oxidation reaction. Furthermore, the lattice oxygen at VCu more readily participates in the oxidation reaction. This strategy is beneficial for the development of defect engineering on spinel surfaces and provides a new idea for improving the catalytic combustion activity of CuMn2O4 spinel.
RESUMO
Simultaneous catalytic elimination of nitrogen oxides (NOx, x = 1 and 2) and volatile organic compounds (VOCs) is of great importance for environmental preservation in China. In this work, the interactions of simultaneous removal of NOx and methylbenzene (PhCH3) were investigated on a CeO2-TiO2 mixed oxide catalyst, which demonstrated excellent bifunctional removal efficiencies for the two pollutants. The results indicated that NOx positively promotes PhCH3 oxidation, while NH3 negatively inhibits through competitive adsorption with PhCH3. The underlying mechanism is that a pseudo PhCH3-SCR reaction happened in this process is parallel to NH3-SCR. Combined with in situ diffuse reflectance infrared Fourier transform spectroscopy and quasi in situ X-ray photoelectron spectroscopy, the interaction mechanism between NOx and PhCH3 is proposed. Specifically, NOx is adsorbed on the catalyst surface to produce nitrate species, which reacts with the carboxylate generated during PhCH3 oxidation to form organic nitrogen intermediates that create N2 and CO2 in the following reactions. In the reaction process, the superoxide (O2-) generated by O2 activation on the catalyst surface is an important species for the propelling of oxidation reaction. This work could provide guidelines for the design of state-of-the-art catalysts for simultaneous catalytic removal of NOx and VOCs.
Assuntos
Óxidos , Tolueno , Amônia/química , Catálise , Óxidos de Nitrogênio/química , Oxirredução , Óxidos/química , TitânioRESUMO
Histone H3K4 demethylase LSD1 plays an important role in stem cell biology, especially in the maintenance of the silencing of differentiation genes. However, how the function of LSD1 is regulated and the differentiation genes are derepressed are not understood. Here, we report that elimination of LSD1 promotes embryonic stem cell (ESC) differentiation toward neural lineage. We showed that the destabilization of LSD1 occurs posttranscriptionally via the ubiquitin-proteasome pathway by an E3 ubiquitin ligase, Jade-2. We demonstrated that Jade-2 is a major LSD1 negative regulator during neurogenesis in vitro and in vivo in both mouse developing cerebral cortices and zebra fish embryos. Apparently, Jade-2-mediated degradation of LSD1 acts as an antibraking system and serves as a quick adaptive mechanism for re-establishing epigenetic landscape without more laborious transcriptional regulations. As a potential anticancer strategy, Jade-2-mediated LSD1 degradation could potentially be used in neuroblastoma cells to induce differentiation toward postmitotic neurons.
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Células-Tronco Embrionárias/metabolismo , Histona Desmetilases/metabolismo , Neuroblastoma/metabolismo , Neurogênese , Ubiquitina-Proteína Ligases/metabolismo , Animais , Diferenciação Celular , Linhagem Celular Tumoral , Epigênese Genética , Regulação da Expressão Gênica no Desenvolvimento , Células HeLa , Histona Desmetilases/genética , Humanos , Camundongos , Neuroblastoma/fisiopatologia , Oxirredutases N-Desmetilantes/genética , Oxirredutases N-Desmetilantes/metabolismo , Ubiquitina-Proteína Ligases/genética , Peixe-Zebra/embriologia , Peixe-Zebra/metabolismo , Proteínas de Peixe-Zebra/genética , Proteínas de Peixe-Zebra/metabolismoRESUMO
OBJECTIVE: To explore the genetic etiology of a patient with glycogen storage diseases. METHODS: Clinical data of child and his parents were collected. The genes associated with glycogen storage diseases were subjected to high-throughput sequencing to screen the variants. Candidate variant was validated by Sanger sequencing. Pathogenicity of the variant was predicted by bioinformatic analysis. RESULTS: High-throughput sequencing results showed that the boy has carried a hemizygous c.749C>T (p.S250L) variant of the PHKA2 gene. Sanger sequencing verified the results and confirmed that it was inherited from his mother. This variant was unreported previously and predicted to be pathogenic by bioinformatic analysis. CONCLUSION: The patient was diagnosed with glycogen storage disease type IXa due to a novel c.749C>T (p.S250L) hemizygous variant of the PHKA2 gene. High-throughput sequencing can facilitate timely and accurate differential diagnosis of glycogen storage disease type IXa.
Assuntos
Doença de Depósito de Glicogênio , Criança , Família , Testes Genéticos , Doença de Depósito de Glicogênio/diagnóstico , Doença de Depósito de Glicogênio/genética , Doença de Depósito de Glicogênio/patologia , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Humanos , Masculino , Mutação , Fosforilase Quinase/genéticaRESUMO
Catalytic combustion is an advanced technology to eliminate industrial volatile organic compounds such as toluene. In order to replace the expensive noble metal catalysts and avoid the aggregation phenomenon occurring in traditional heterogeneous interfaces, designing homogeneous interfaces can become an emerging methodology to enhance the catalytic combustion performance of metal oxide catalysts. A mesocrystalline CeO2 catalyst with abundant Ce-Ce homogeneous interfaces is synthesized via a self-flaming method which exhibits boosted catalytic performance for toluene combustion compared with traditional CeO2, leading to a â¼40 °C lower T90. The abundant Ce-Ce homogeneous interfaces formed by both highly ordered stacking and small grain size endow the CeO2 mesocrystal with superior redox property and oxygen storage capacity via forming various oxygen vacancies. Surface and bulk oxygen vacancies generate and activate crucial oxygen species, while interfacial oxygen vacancies further promote the reaction behavior of oxygen species (i.e., activation, regeneration, and migration), causing the splitting of redox property toward lower temperature. These properties facilitate aromatic ring decomposition, the important rate-determining step, thus contributing to toluene catalytic degradation to CO2. This work may shed insights into the catalytic effects of homogeneous interfaces in pollutant removal and provide a strategy of interfacial defect engineering for catalyst development.
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Cério , Tolueno , Catálise , Oxirredução , ÓxidosRESUMO
How chromatin dynamics is regulated to ensure efficient DNA repair remains to be understood. Here, we report that the ubiquitin-specific protease USP11 acts as a histone deubiquitinase to catalyze H2AK119 and H2BK120 deubiquitination. We showed that USP11 is physically associated with the chromatin remodeling NuRD complex and functionally involved in DNA repair process. We demonstrated that USP11-mediated histone deubiquitination and NuRD-associated histone deacetylation coordinate to allow timely termination of DNA repair and reorganization of the chromatin structure. As such, USP11 is involved in chromatin condensation, genomic stability, and cell survival. Together, these observations indicate that USP11 is a chromatin modifier critically involved in DNA damage response and the maintenance of genomic stability.
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Montagem e Desmontagem da Cromatina/genética , Reparo do DNA/genética , Enzimas Desubiquitinantes/genética , Tioléster Hidrolases/genética , Sobrevivência Celular/genética , Cromatina/genética , Quebras de DNA de Cadeia Dupla , Dano ao DNA/genética , Instabilidade Genômica/genética , Células HEK293 , Histonas/genética , Humanos , Complexo Mi-2 de Remodelação de Nucleossomo e Desacetilase/genética , Processamento de Proteína Pós-Traducional/genética , Ubiquitinação/genéticaRESUMO
Catalytic combustion technology is one of the effective methods to remove VOCs such as toluene from industrial emissions. The decomposition of an aromatic ring via catalyst oxygen vacancies is usually the rate-determining step of toluene oxidation into CO2. Series of CeO2 probe models were synthesized with different ratios of surface-to-bulk oxygen vacancies. Besides the devotion of the surface vacancies, a part of the bulk vacancies promotes the redox property of CeO2 in toluene catalytic combustion: surface vacancies tend to adsorb and activate gaseous O2 to form adsorbed oxygen species, whereas bulk vacancies improve the mobility and activity of lattice oxygen species via their transmission effect. Adsorbed oxygen mainly participates in the chemical adsorption and partial oxidation of toluene (mostly to phenolate). With the elevated temperatures, lattice oxygen of the catalysts facilitates the decomposition of aromatic rings and further improves the oxidation of toluene to CO2.
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Cério , Tolueno , Catálise , Oxirredução , OxigênioRESUMO
Zinc-figure protein 217 (ZNF217) is a C2H2 zinc finger transcription factor that works as a pivotal effector stimulating embryonic immortalization as well as oncogenicity during multiple cancer processes. Nevertheless, the expression of ZNF217 in hepatocellular carcinoma (HCC) and the underlying specific molecular mechanisms remains elusive. In the present study, we aimed to explore the potential role of ZNF217 in HCC cell proliferation and invasion, as well as the underlying mechanism. Here, we demonstrated that the expression of ZNF217 was higher in HCC patients and indicated worse overall survival times, which was confirmed by Oncomine datasets and The Cancer Genome Atlas (TCGA) HCC cohorts. Further research discovered that knockdown of ZNF217 inhibited the proliferation of HCC cells in vitro and in vivo. Enforced expression of ZNF217 could promote Epithelial-mesenchymal transition and thus the invasion of HCC cells. Mechanistically, we identified ZNF217 interacted with LSD1 in vivo and in vitro. Knockdown of ZNF217 was accompanied by a parallel increase in di-methyl histone 3 lysine4 levels on CDH1 promoter, which indicated ZNF217 could recruit LSD1 to affect CDH1 epigenetic expression from transcription level. Of note, bioinformatics analyses, a dual luciferase reporter assay, RT-qPCR and western blot analysis demonstrated that microRNA-101 (miR-101), a well-known tumor suppressor in HCC, acted as a negative regulator of ZNF217. The inhibition of HCC progression by miR-101 was counteracted by ZNF217 overexpression. Taken together, our study presents the regulation mechanism of miR-101/ZNF217/CDH1 axis for the first time and provides new evidences of ZNF217 as a potential therapeutic target for HCC patients.
Assuntos
Carcinoma Hepatocelular/genética , Histona Desmetilases/genética , Neoplasias Hepáticas/genética , MicroRNAs/genética , Transativadores/genética , Animais , Carcinoma Hepatocelular/patologia , Linhagem Celular Tumoral , Movimento Celular/genética , Proliferação de Células/genética , Progressão da Doença , Transição Epitelial-Mesenquimal/genética , Regulação Neoplásica da Expressão Gênica/genética , Células Hep G2 , Humanos , Neoplasias Hepáticas/patologia , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Transcrição Gênica/genéticaRESUMO
BACKGROUND: Melanoma, originated from melanocytes located on the basal membrane of the epithelial tissue, is the most aggressive form of skin cancer that accounts for 75% of skin cancer-related death. Although it is believed that BRAF mutation and the mitogen-activated protein kinase (MAPK) pathway play critical roles in the pathogenesis of melanoma, how the MAPK signaling is regulated in melanoma carcinogenesis is still not fully understood. METHODS: We characterized JMJD6 expression in melanoma tissue array by immunohistochemistry analysis. We used human melanoma A375, 451Lu and SK-MEL-1 cell lines for in vitro proliferation and invasion experiments, and xenograft transplanted mice using murine melanoma B16F10 cells by bioluminescence imaging for in vivo tumor growth and pulmonary metastasis assessments. Endothelial tube formation assay, chicken yolk sac membrane assay and matrigel plug assay were performed to test the effect of JMJD6 on the angiogenic potential in vitro and in vivo. RESULTS: Here we report that the jumonji C domain-containing demethylase/hydroxylase JMJD6 is markedly up-regulated in melanoma. We found that high expression of JMJD6 is closely correlated with advanced clinicopathologic stage, aggressiveness, and poor prognosis of melanoma. RNA-seq showed that knockdown of JMJD6 affects the alternative splicing of a panel of transcripts including that encoding for PAK1, a key component in MAPK signaling pathway. We demonstrated that JMJD6 enhances the MAPK signaling and promotes multiple cellular processes including melanogenesis, proliferation, invasion, and angiogenesis in melanoma cells. Interestingly, JMJD6 is transcriptionally activated by c-Jun, generating a feedforward loop to drive the development and progression of melanoma. CONCLUSIONS: Our results indicate that JMJD6 is critically involved in melanoma carcinogenesis, supporting the pursuit of JMJD6 as a potential biomarker for melanoma aggressiveness and a target for melanoma intervention.
Assuntos
Processamento Alternativo , Histona Desmetilases com o Domínio Jumonji/metabolismo , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/secundário , Melanoma/metabolismo , Quinases Ativadas por p21/genética , Animais , Linhagem Celular Tumoral , Proliferação de Células , Regulação Neoplásica da Expressão Gênica , Humanos , Histona Desmetilases com o Domínio Jumonji/genética , Medições Luminescentes , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Sistema de Sinalização das MAP Quinases , Melanoma/genética , Melanoma/patologia , Camundongos , Invasividade Neoplásica , Estadiamento de Neoplasias , Transplante de Neoplasias , Prognóstico , Quinases Ativadas por p21/metabolismoRESUMO
Jumonji domain-containing 6 (JMJD6) is a member of the Jumonji C domain-containing family of proteins. Compared to other members of the family, the cellular activity of JMJD6 is still not clearly defined and its biological function is still largely unexplored. Here we report that JMJD6 is physically associated with the tumor suppressor p53. We demonstrated that JMJD6 acts as an α-ketoglutarate- and Fe(II)-dependent lysyl hydroxylase to catalyze p53 hydroxylation. We found that p53 indeed exists as a hydroxylated protein in vivo and that the hydroxylation occurs mainly on lysine 382 of p53. We showed that JMJD6 antagonizes p53 acetylation, promotes the association of p53 with its negative regulator MDMX, and represses transcriptional activity of p53. Depletion of JMJD6 enhances p53 transcriptional activity, arrests cells in the G1 phase, promotes cell apoptosis, and sensitizes cells to DNA damaging agent-induced cell death. Importantly, knockdown of JMJD6 represses p53-dependent colon cell proliferation and tumorigenesis in vivo, and significantly, the expression of JMJD6 is markedly up-regulated in various types of human cancer especially in colon cancer, and high nuclear JMJD6 protein is strongly correlated with aggressive clinical behaviors of colon adenocarcinomas. Our results reveal a novel posttranslational modification for p53 and support the pursuit of JMJD6 as a potential biomarker for colon cancer aggressiveness and a potential target for colon cancer intervention.