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1.
BMC Cancer ; 21(1): 979, 2021 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-34465286

RESUMO

BACKGROUND: Ubiquitously transcribed tetratricopeptide repeat on chromosome X (UTX) has been identified as a histone 3 lysine 27 (H3K27) demethylase and acted as a tumor suppressor gene or oncogenic function. The current study was to explore the significance of UTX in oral tongue squamous cell carcinoma (OTSCC) patients who received surgical resection. METHODS: A total of 148 OTSCC patients who underwent surgical resection were identified, including 64 patients (43%) with overexpression of UTX and 84 patients (57%) harboring low expression of UTX. We also used two OTSCC cell lines, SAS and Cal 27, to determine the modulation of cancer. Chi-square test was used to investigate the difference of categorical variables between the groups; survival outcome was analyzed using the Kaplan-Meier method in univariate analysis, and a Cox regression model was performed for multivariate analyses. RESULTS: Univariate and multivariate analyses showed overexpression of UTX were significantly related to worse disease-free survival (P = 0.028) and overall survival (P = 0.029). The two OTSCC cell lines were treated with GSK-J4, a potent inhibitor of UTX, and transwell migration and invasion assays showed an inhibitory effect with a dose-dependent manner. In addition, western blot analyses also revealed the inhibition of cell cycle and epithelial-mesenchymal transition. CONCLUSION: Our study suggests that UTX plays an important role in the process of OTSCC and overexpression of UTX may predict poor prognosis in OTSCC patients who received surgical resection.


Assuntos
Biomarcadores Tumorais/metabolismo , Carcinoma de Células Escamosas/patologia , Histona Desmetilases/metabolismo , Neoplasias Bucais/patologia , Neoplasias da Língua/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Carcinoma de Células Escamosas/metabolismo , Carcinoma de Células Escamosas/cirurgia , Progressão da Doença , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasias Bucais/metabolismo , Neoplasias Bucais/cirurgia , Prognóstico , Estudos Retrospectivos , Taxa de Sobrevida , Neoplasias da Língua/metabolismo , Neoplasias da Língua/cirurgia
2.
J Immunol ; 207(9): 2223-2234, 2021 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-34588217

RESUMO

The pathogenesis of allergic contact dermatitis (ACD) requires the activation of Ag-specific T cells, including effector and regulatory T cells. The differentiation and function of these T cells is epigenetically regulated through DNA methylation and histone modifications. However, the roles of altered histone H3K27 methylation in T cells in the development of ACD remain unknown. Two types of histone H3K27 demethylases, Utx and Jmjd3, have been reported in mammals. To determine the role of the histone H3K27 demethylase expression of T cells in the development of ACD, we generated T cell-specific, Utx-deficient (Utx KO) mice or Jmjd3-deficient (Jmjd3 KO) mice. Unlike control mice, Utx KO mice had severer symptoms of ACD, whereas Jmjd3 KO mice showed symptoms identical to those in control mice. In Utx KO mice with ACD, the massive infiltration of myeloid cells, including neutrophils and dendritic cells, has been observed. In addition, the expression of proinflammatory cytokines in CD4+ T cells of the draining lymph nodes (LNs) and in CD8+ T cells of the skin was increased in Utx KO mice, whereas the ratio of Foxp3+ regulatory CD4+ T cells to Foxp3- conventional CD4+ T cells was decreased in both the draining LNs and the skin of Utx KO mice with ACD. Furthermore, Foxp3+ regulatory CD4+ T cells of Utx KO mice with ACD expressed a decreased level of CCR4 (a skin-tropic chemokine receptor) in comparison with control. Thus, in CD4+ T cells, Utx could potentially be involved in the regulation of the pathogenesis of ACD.


Assuntos
Dermatite de Contato/imunologia , Histona Desmetilases/metabolismo , Histonas/metabolismo , Histona Desmetilases com o Domínio Jumonji/metabolismo , Pele/imunologia , Subpopulações de Linfócitos T/imunologia , Linfócitos T Reguladores/imunologia , Animais , Citocinas/metabolismo , Modelos Animais de Doenças , Fatores de Transcrição Forkhead/metabolismo , Histona Desmetilases/genética , Histonas/genética , Humanos , Mediadores da Inflamação/metabolismo , Histona Desmetilases com o Domínio Jumonji/genética , Camundongos , Camundongos Knockout , Receptores CCR4/metabolismo
3.
Cells ; 10(9)2021 09 18.
Artigo em Inglês | MEDLINE | ID: mdl-34572113

RESUMO

The increased level of hydrogen peroxide accompanies some modes of macrophage specification and is linked to ROS-based antimicrobial activity of these phagocytes. In this study, we show that activation of toll-like receptors with bacterial components such as LPS is accompanied by the decline in transcription of hydrogen peroxide decomposing enzyme-catalase, suppression of which facilitates the polarization of human macrophages towards the pro-inflammatory phenotype. The chromatin remodeling at the CAT promoter involves LSD1 and HDAC1, but activity of the first enzyme defines abundance of the two proteins on chromatin, histone acetylation status and the CAT transcription. LSD1 inhibition prior to macrophage activation with LPS prevents CAT repression by enhancing the LSD1 and interfering with the HDAC1 recruitment to the gene promoter. The maintenance of catalase level with LSD1 inhibitors during M1 polarization considerably limits LPS-triggered expression of some pro-inflammatory cytokines and markers such as IL1ß, TNFα, COX2, CD14, TLR2, and IFNAR, but the effect of LSD1 inhibitors is lost upon catalase deficiency. Summarizing, activity of LSD1 allows for the CAT repression in LPS stimulated macrophages, which negatively controls expression of some key pro-inflammatory markers. LSD1 inhibitors can be considered as possible immunosuppressive drugs capable of limiting macrophage M1 specialization.


Assuntos
Catalase/antagonistas & inibidores , Histona Desacetilase 1/metabolismo , Histona Desmetilases/metabolismo , Ativação de Macrófagos/imunologia , Macrófagos/imunologia , Receptores Toll-Like/metabolismo , Catalase/genética , Catalase/metabolismo , Diferenciação Celular , Citocinas/metabolismo , Histona Desacetilase 1/genética , Histona Desmetilases/genética , Humanos , Lipopolissacarídeos/farmacologia , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Transdução de Sinais , Receptores Toll-Like/genética , Fator de Necrose Tumoral alfa/metabolismo
4.
PLoS Pathog ; 17(9): e1009918, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34529741

RESUMO

Under RNA virus infection, retinoic acid-inducible gene I (RIG-I) in host cells recognizes viral RNA and activates the expression of type I IFN. To investigate the roles of protein methyltransferases and demethylases in RIG-I antiviral signaling pathway, we screened all the known related enzymes with a siRNA library and identified LSD1 as a positive regulator for RIG-I signaling. Exogenous expression of LSD1 enhances RIG-I signaling activated by virus stimulation, whereas its deficiency restricts it. LSD1 interacts with RIG-I, promotes its K63-linked polyubiquitination and interaction with VISA/MAVS. Interestingly, LSD1 exerts its function in antiviral response not dependent on its demethylase activity but through enhancing the interaction between RIG-I with E3 ligases, especially TRIM25. Furthermore, we provide in vivo evidence that LSD1 increases antiviral gene expression and inhibits viral replication. Taken together, our findings demonstrate that LSD1 is a positive regulator of signaling pathway triggered by RNA-virus through mediating RIG-I polyubiquitination.


Assuntos
Regulação da Expressão Gênica/fisiologia , Histona Desmetilases/metabolismo , Infecções por Vírus de RNA/metabolismo , Receptores de Superfície Celular/metabolismo , Animais , Chlorocebus aethiops , Células HEK293 , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Ubiquitinação , Células Vero
5.
Theranostics ; 11(16): 7970-7983, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34335974

RESUMO

The novel ß-coronavirus, SARS-CoV-2, the causative agent of coronavirus disease 2019 (COVID-19), has infected more than 177 million people and resulted in 3.84 million death worldwide. Recent epidemiological studies suggested that some environmental factors, such as air pollution, might be the important contributors to the mortality of COVID-19. However, how environmental exposure enhances the severity of COVID-19 remains to be fully understood. In the present report, we provided evidence showing that mdig, a previously reported environmentally-induced oncogene that antagonizes repressive trimethylation of histone proteins, is an important regulator for SARS-CoV-2 receptors neuropilin-1 (NRP1) and NRP2, cathepsins, glycan metabolism and inflammation, key determinants for viral infection and cytokine storm of the patients. Depletion of mdig in bronchial epithelial cells by CRISPR-Cas-9 gene editing resulted in a decreased expression of NRP1, NRP2, cathepsins, and genes involved in protein glycosylation and inflammation, largely due to a substantial enrichment of lysine 9 and/or lysine 27 trimethylation of histone H3 (H3K9me3/H3K27me3) on these genes as determined by ChIP-seq. Meanwhile, we also validated that environmental factor arsenic is able to induce mdig, NRP1 and NRP2, and genetic disruption of mdig lowered expression of NRP1 and NRP2. Furthermore, mdig may coordinate with the Neanderthal variants linked to an elevated mortality of COVID-19. These data, thus, suggest that mdig is a key mediator for the severity of COVID-19 in response to environmental exposure and targeting mdig may be the one of the effective strategies in ameliorating the symptom and reducing the mortality of COVID-19.


Assuntos
COVID-19/metabolismo , COVID-19/virologia , Dioxigenases/metabolismo , Histona Desmetilases/metabolismo , Neuropilina-1/metabolismo , Proteínas Nucleares/metabolismo , Polissacarídeos/metabolismo , SARS-CoV-2/metabolismo , Células Epiteliais Alveolares/metabolismo , Animais , COVID-19/epidemiologia , Catepsinas/metabolismo , Linhagem Celular , Células Cultivadas , Dioxigenases/biossíntese , Dioxigenases/genética , Exposição Ambiental , Histona Desmetilases/biossíntese , Histona Desmetilases/genética , Histonas/metabolismo , Humanos , Proteínas Nucleares/biossíntese , Proteínas Nucleares/genética , Pandemias , Ratos , SARS-CoV-2/patogenicidade , Glicoproteína da Espícula de Coronavírus/metabolismo
6.
J Immunol ; 207(6): 1599-1615, 2021 09 15.
Artigo em Inglês | MEDLINE | ID: mdl-34408010

RESUMO

GFI1 is a DNA-binding transcription factor that regulates hematopoiesis by repressing target genes through its association with complexes containing histone demethylases such as KDM1A (LSD1) and histone deacetylases (HDACs). To study the consequences of the disruption of the complex between GFI1 and histone-modifying enzymes, we have used knock-in mice harboring a P2A mutation in GFI1 coding region that renders it unable to bind LSD1 and associated histone-modifying enzymes such as HDACs. GFI1P2A mice die prematurely and show increased numbers of memory effector and regulatory T cells in the spleen accompanied by a severe systemic inflammation with high serum levels of IL-6, TNF-α, and IL-1ß and overexpression of the gene encoding the cytokine oncostatin M (OSM). We identified lung alveolar macrophages, CD8 T cell from the spleen and thymic eosinophils, and monocytes as the sources of these cytokines in GFI1P2A mice. Chromatin immunoprecipitation showed that GFI1/LSD1 complexes occupy sites at the Osm promoter and an intragenic region of the Tnfα gene and that a GFI1P2A mutant still remains bound at these sites even without LSD1. Methylation and acetylation of histone H3 at these sites were enriched in cells from GFI1P2A mice, the H3K27 acetylation being the most significant. These data suggest that the histone modification facilitated by GFI1 is critical to control inflammatory pathways in different cell types, including monocytes and eosinophils, and that a disruption of GFI1-associated complexes can lead to systemic inflammation with fatal consequences.


Assuntos
Proteínas de Ligação a DNA/deficiência , Histona Desmetilases/metabolismo , Proteínas Mutantes/metabolismo , Transdução de Sinais/genética , Síndrome de Resposta Inflamatória Sistêmica/sangue , Fatores de Transcrição/deficiência , Animais , Transplante de Medula Óssea/métodos , Linfócitos T CD8-Positivos/imunologia , Citocinas/sangue , Citocinas/genética , Proteínas de Ligação a DNA/genética , Feminino , Expressão Gênica , Técnicas de Introdução de Genes , Histonas/metabolismo , Macrófagos/imunologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Mutação , Ligação Proteica , Síndrome de Resposta Inflamatória Sistêmica/genética , Síndrome de Resposta Inflamatória Sistêmica/imunologia , Fatores de Transcrição/genética
7.
Development ; 148(17)2021 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-34373913

RESUMO

Neutrophils are the most abundant vertebrate leukocytes and they are essential to host defense. Despite extensive investigation, the molecular network controlling neutrophil differentiation remains incompletely understood. GFI1 is associated with several myeloid disorders, but its role and the role of its co-regulators in granulopoiesis and pathogenesis are far from clear. Here, we demonstrate that zebrafish gfi1aa deficiency induces excessive neutrophil progenitor proliferation, accumulation of immature neutrophils from the embryonic stage, and some phenotypes similar to myelodysplasia syndrome in adulthood. Both genetic and epigenetic analyses demonstrate that immature neutrophil accumulation in gfi1aa-deficient mutants is due to upregulation of cebpa transcription. Increased transcription was associated with Lsd1-altered H3K4 methylation of the cebpa regulatory region. Taken together, our results demonstrate that Gfi1aa, Lsd1 and cebpa form a regulatory network that controls neutrophil development, providing a disease progression-traceable model for myelodysplasia syndrome. Use of this model could provide new insights into the molecular mechanisms underlying GFI1-related myeloid disorders as well as a means by which to develop targeted therapeutic approaches for treatment.


Assuntos
Proteínas Estimuladoras de Ligação a CCAAT/metabolismo , Proteínas de Ligação a DNA/metabolismo , Hematopoese/genética , Histona Desmetilases/metabolismo , Neutrófilos/citologia , Proteínas de Peixe-Zebra/metabolismo , Animais , Proteínas Estimuladoras de Ligação a CCAAT/genética , Diferenciação Celular , Proliferação de Células , Proteínas de Ligação a DNA/deficiência , Embrião não Mamífero , Epigênese Genética , Células Precursoras de Granulócitos/citologia , Células Precursoras de Granulócitos/metabolismo , Histona Desmetilases/genética , Neutrófilos/metabolismo , Peixe-Zebra , Proteínas de Peixe-Zebra/deficiência , Proteínas de Peixe-Zebra/genética
8.
Biochim Biophys Acta Gen Subj ; 1865(11): 129990, 2021 11.
Artigo em Inglês | MEDLINE | ID: mdl-34390793

RESUMO

BACKGROUND: Histone lysine-specific demethylase 1 (LSD1) has become a potential anticancer target for the novel drug discovery. Recent reports have shown that SP2509 and its derivatives strongly inhibit LSD1 as allosteric inhibitors. However, the binding mechanism of these allosteric inhibitors in the allosteric site of LSD1 is not known yet. METHODS: The stability and binding mechanism of allosteric inhibitors in the binding site of LSD1 were evaluated by molecular docking, ligand-based pharmacophore, molecular dynamics (MD) simulations, molecular mechanics generalized born surface area (MM/GBSA) analysis, quantum mechanics/molecular mechanics (QM/MM) calculation and Hirshfeld surface analysis. RESULTS: The conformational geometry and the intermolecular interactions of allosteric inhibitors showed high binding affinity towards allosteric site of LSD1 with the neighboring amino acids (Gly358, Cys360, Leu362, Asp375 and Glu379). Meanwhile, MD simulations and MM/GBSA analysis were performed on selected allosteric inhibitors in complex with LSD1 protein, which confirmed the high stability and binding affinity of these inhibitors in the allosteric site of LSD1. CONCLUSION: The simulation results revealed the crucial factors accounting for allosteric inhibitors of LSD1, including different protein-ligand interactions, the positions and conformations of key residues, and the ligands flexibilities. Meanwhile, a halogen bond interaction between chlorine atom of ligand and key residues Trp531 and His532 was recurrent in our analysis confirming its importance. GENERAL SIGNIFICANCE: Overall, our research analyzed in depth the binding modes of allosteric inhibitors with LSD1 and could provide useful information for the design of novel allosteric inhibitors.


Assuntos
Inibidores Enzimáticos/farmacologia , Histona Desmetilases/antagonistas & inibidores , Hidrazinas/farmacologia , Sulfonamidas/farmacologia , Regulação Alostérica/efeitos dos fármacos , Inibidores Enzimáticos/química , Histona Desmetilases/metabolismo , Humanos , Hidrazinas/química , Modelos Moleculares , Estrutura Molecular , Sulfonamidas/química
9.
Nat Commun ; 12(1): 4319, 2021 07 14.
Artigo em Inglês | MEDLINE | ID: mdl-34262032

RESUMO

Despite the genetic inactivation of SMARCA4, a core component of the SWI/SNF-complex commonly found in cancer, there are no therapies that effectively target SMARCA4-deficient tumours. Here, we show that, unlike the cells with activated MYC oncogene, cells with SMARCA4 inactivation are refractory to the histone deacetylase inhibitor, SAHA, leading to the aberrant accumulation of H3K27me3. SMARCA4-mutant cells also show an impaired transactivation and significantly reduced levels of the histone demethylases KDM6A/UTX and KDM6B/JMJD3, and a strong dependency on these histone demethylases, so that its inhibition compromises cell viability. Administering the KDM6 inhibitor GSK-J4 to mice orthotopically implanted with SMARCA4-mutant lung cancer cells or primary small cell carcinoma of the ovary, hypercalcaemic type (SCCOHT), had strong anti-tumour effects. In this work we highlight the vulnerability of KDM6 inhibitors as a characteristic that could be exploited for treating SMARCA4-mutant cancer patients.


Assuntos
Antineoplásicos/uso terapêutico , DNA Helicases/deficiência , Histona Desmetilases/antagonistas & inibidores , Histona Desmetilases com o Domínio Jumonji/antagonistas & inibidores , Neoplasias/tratamento farmacológico , Proteínas Nucleares/deficiência , Fatores de Transcrição/deficiência , Animais , Antineoplásicos/farmacologia , Benzazepinas/farmacologia , Benzazepinas/uso terapêutico , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , DNA Helicases/metabolismo , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Expressão Gênica , Inibidores de Histona Desacetilases/farmacologia , Inibidores de Histona Desacetilases/uso terapêutico , Histona Desmetilases/genética , Histona Desmetilases/metabolismo , Histonas/metabolismo , Humanos , Histona Desmetilases com o Domínio Jumonji/genética , Histona Desmetilases com o Domínio Jumonji/metabolismo , Camundongos , Neoplasias/metabolismo , Proteínas Nucleares/metabolismo , Pirimidinas/farmacologia , Pirimidinas/uso terapêutico , Fatores de Transcrição/metabolismo , Ativação Transcricional
10.
J Enzyme Inhib Med Chem ; 36(1): 1563-1572, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-34281464

RESUMO

A series of tertiary sulphonamide derivatives were synthesised and evaluated for their antiproliferative activity against liver cancer cell lines (SNU-475, HepG-2, and Bel-7402). Among these tertiary sulphonamides, compound 17a displayed the best anti-liver cancer activity against Bel-7402 cells with an IC50 value of 0.32 µM. Compound 17a could effectively inhibit tubulin polymerisation with an IC50 value of 1.27 µM. Meanwhile, it selectively suppressed LSD1 with an IC50 value of 63 nM. It also concentration-dependently inhibited migration against Bel-7402 cells. Importantly, tertiary sulphonamide 17a exhibited the potent antitumor activity in vivo. All these findings revealed that compound 17a might be a tertiary sulphonamide-based dual inhibitor of tubulin polymerisation and LSD1 to treat liver cancer.


Assuntos
Antineoplásicos/farmacologia , Inibidores Enzimáticos/farmacologia , Histona Desmetilases/antagonistas & inibidores , Neoplasias Hepáticas/tratamento farmacológico , Bibliotecas de Moléculas Pequenas/farmacologia , Sulfonamidas/farmacologia , Moduladores de Tubulina/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Histona Desmetilases/metabolismo , Humanos , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patologia , Estrutura Molecular , Polimerização/efeitos dos fármacos , Bibliotecas de Moléculas Pequenas/síntese química , Bibliotecas de Moléculas Pequenas/química , Relação Estrutura-Atividade , Sulfonamidas/síntese química , Sulfonamidas/química , Tubulina (Proteína)/metabolismo , Moduladores de Tubulina/síntese química , Moduladores de Tubulina/química
11.
J Cancer Res Clin Oncol ; 147(10): 2867-2877, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34218325

RESUMO

OBJECTIVE: It has been studied that mesenchymal stem cells (MSCs)-derived exosomes could suppress tumor growth in nasopharyngeal carcinoma (NPC) and microRNA-181a (miR-181a) could mediate drug resistance in NPC. Focused on this work, the mechanism of human umbilical cord MSCs (hUC-MSCs)-derived exosomal miR-181a was explored in NPC cell progression. METHODS: NPC tissues and normal tissues were obtained from patients, and miR-181a and KDM5C expression was examined. hUC-MSCs-derived exosomes were extracted, identified and co-cultured with NPC cells (C666-1 and SUNE1). C666-1 cell progression in vitro and/or tumor growth in vivo were examined after incubation with exosomes, miR-181a or lysine-specific demethylase 5C (KDM5C). miR-181a and KDM5C expression were examined in NPC. RESULTS: miR-181a expression was reduced while KDM5C expression was elevated in NPC. hUC-MSCs-derived exosomes restrained NPC cell growth in vivo and in vitro. Depleting or restoring exosomal miR-181a promoted or delayed NPC cell progression. KDM5C silencing suppressed NPC cell progression. CONCLUSION: This study concluded that hUC-MSCs-derived exosomal miR-181a retards NPC development via negatively modulating KDM5C, serving as a candidate reference for the therapy of NPC.


Assuntos
Exossomos/genética , Regulação Neoplásica da Expressão Gênica , Histona Desmetilases/metabolismo , Transplante de Células-Tronco Mesenquimais/métodos , Células-Tronco Mesenquimais/citologia , MicroRNAs/genética , Neoplasias Nasofaríngeas/prevenção & controle , Adulto , Idoso , Idoso de 80 Anos ou mais , Animais , Apoptose , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Movimento Celular , Proliferação de Células , Feminino , Histona Desmetilases/genética , Humanos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Pessoa de Meia-Idade , Neoplasias Nasofaríngeas/genética , Neoplasias Nasofaríngeas/metabolismo , Neoplasias Nasofaríngeas/patologia , Prognóstico , Células Tumorais Cultivadas , Cordão Umbilical/citologia , Ensaios Antitumorais Modelo de Xenoenxerto
12.
BMC Cancer ; 21(1): 819, 2021 Jul 16.
Artigo em Inglês | MEDLINE | ID: mdl-34266408

RESUMO

BACKGROUND: Cell division cycle 25A (CDC25A) is a well-recognized regulator of cell cycle progression and is involved in cancer development. This work focused on the function of CDC25A in cervical cancer cell growth and the molecules involved. METHODS: A GEO dataset GSE63514 comprising data of cervical squamous cell carcinoma (CSCC) tissues was used to screen the aberrantly expressed genes in cervical cancer. The CDC25A expression in cancer and normal tissues was predicted in the GEPIA database and that in CSCC and normal cells was determined by RT-qPCR and western blot assays. Downregulation of CDC25A was introduced in CSCC cells to explore its function in cell growth and the cell cycle progression. The potential regulators of CDC25A activity and the possible involved signaling were explored. RESULTS: CDC25A was predicted to be overexpressed in CSCC, and high expression of CDC25A was observed in CSCC cells. Downregulation of CDC25A in ME180 and C33A cells reduced cell proliferation and blocked cell cycle progression, and it increased cell apoptosis. ALX3 was a positive regulator of CDC25A through transcription promotion. It recruited a histone demethylase, lysine demethylase 2B (KDM2B), to the CDC25A promoter, which enhanced CDC25A expression through demethylation of H3k4me3. Overexpression of ALX3 in cells blocked the inhibitory effects of CDC25A silencing. CDC25A was found as a positive regulator of the PI3K/Akt signaling pathway. CONCLUSION: This study suggested that the ALX3 increased CDC25A expression through KDM2B-mediated demethylation of H3K4me3, which induced proliferation and cell cycle progression of cervical cancer cells.


Assuntos
Histona Desmetilases/metabolismo , Proteínas de Homeodomínio/metabolismo , Neoplasias do Colo do Útero/metabolismo , Animais , Proliferação de Células/fisiologia , Feminino , Humanos , Camundongos , Camundongos Nus , Transfecção , Neoplasias do Colo do Útero/genética , Neoplasias do Colo do Útero/patologia
13.
PLoS Genet ; 17(7): e1009715, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-34329293

RESUMO

Histone methylation is dynamically regulated to shape the epigenome and adjust central nuclear processes including transcription, cell cycle control and DNA repair. Lysine-specific histone demethylase 2 (LSD2) has been implicated in multiple types of human cancers. However, its functions remain poorly understood. This study investigated the histone demethylase LSD2 homolog AMX-1 in C. elegans and uncovered a potential link between H3K4me2 modulation and DNA interstrand crosslink (ICL) repair. AMX-1 is a histone demethylase and mainly localizes to embryonic cells, the mitotic gut and sheath cells. Lack of AMX-1 expression resulted in embryonic lethality, a decreased brood size and disorganized premeiotic tip germline nuclei. Expression of AMX-1 and of the histone H3K4 demethylase SPR-5 is reciprocally up-regulated upon lack of each other and the mutants show increased H3K4me2 levels in the germline, indicating that AMX-1 and SPR-5 regulate H3K4me2 demethylation. Loss of AMX-1 function activates the CHK-1 kinase acting downstream of ATR and leads to the accumulation of RAD-51 foci and increased DNA damage-dependent apoptosis in the germline. AMX-1 is required for the proper expression of mismatch repair component MutL/MLH-1 and sensitivity against ICLs. Interestingly, formation of ICLs lead to ubiquitination-dependent subcellular relocalization of AMX-1. Taken together, our data suggest that AMX-1 functions in ICL repair in the germline.


Assuntos
Reparo do DNA/genética , Histona Desmetilases/metabolismo , Animais , Animais Geneticamente Modificados , Caenorhabditis elegans , Proteínas de Caenorhabditis elegans , Núcleo Celular/metabolismo , Dano ao DNA/genética , Reparo do DNA/fisiologia , Células Germinativas/metabolismo , Histona Desmetilases/fisiologia , Histonas/genética , Metilação , Processamento de Proteína Pós-Traducional/genética , Ubiquitinação
14.
Exp Hematol ; 99: 32-43.e13, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-34126175

RESUMO

Histone methylases and demethylases regulate gene expression programs in hematopoiesis. The molecular function of the demethylase KDM6A in normal hematopoiesis and, in particular, for the hematopoietic stem and progenitor cell (HSPC) compartment remains only partially understood. Female but not male Kdm6a-/- HSPCs were functionally impaired in adoptive transfer experiments as well as upon proliferative stress induced by 5-fluorouracil. Loss of Kdm6a affected primarily early B cells and erythroid and myeloid progenitor cells with respect to both number and function. Global gene expression analyses revealed a shared altered gene signature in Kdm6a-/- pro-B and pre-B cells that is also present in HSPCs, supporting that altered B-cell differentiation in Kdm6a-/- animals is already initiated in HSPCs. Interestingly, loss of KDM6A did not affect the global level of methylation of H3K27, its presumed target, in hematopoietic cells. Our data indicate a critical role for KDM6A in the regulation of hematopoietic differentiation and differentiation-specific gene expression programs, with a prominent role in early B-cell differentiation that is likely independent of H3K27 methylation status.


Assuntos
Diferenciação Celular , Hematopoese , Histona Desmetilases/metabolismo , Histonas/metabolismo , Células Precursoras de Linfócitos B/enzimologia , Estresse Fisiológico , Animais , Histona Desmetilases/genética , Histonas/genética , Metilação , Camundongos , Camundongos Knockout
15.
Cell Death Dis ; 12(7): 633, 2021 06 19.
Artigo em Inglês | MEDLINE | ID: mdl-34148069

RESUMO

Colorectal cancer (CRC) stem cells are resistant to cancer therapy and are therefore responsible for tumour progression after conventional therapy fails. However, the molecular mechanisms underlying the maintenance of stemness are poorly understood. In this study, we identified PCGF1 as a crucial epigenetic regulator that sustains the stem cell-like phenotype of CRC. PCGF1 expression was increased in CRC and was significantly correlated with cancer progression and poor prognosis in CRC patients. PCGF1 knockdown inhibited CRC stem cell proliferation and CRC stem cell enrichment. Importantly, PCGF1 silencing impaired tumour growth in vivo. Mechanistically, PCGF1 bound to the promoters of CRC stem cell markers and activated their transcription by increasing the H3K4 histone trimethylation (H3K4me3) marks and decreasing the H3K27 histone trimethylation (H3K27me3) marks on their promoters by increasing expression of the H3K4me3 methyltransferase KMT2A and the H3K27me3 demethylase KDM6A. Our findings suggest that PCGF1 is a potential therapeutic target for CRC treatment.


Assuntos
Neoplasias Colorretais/enzimologia , Metilação de DNA , Epigênese Genética , Células-Tronco Neoplásicas/enzimologia , Complexo Repressor Polycomb 1/metabolismo , Animais , Proliferação de Células , Neoplasias Colorretais/genética , Neoplasias Colorretais/patologia , Feminino , Regulação Neoplásica da Expressão Gênica , Células HCT116 , Histona Desmetilases/genética , Histona Desmetilases/metabolismo , Histona-Lisina N-Metiltransferase/genética , Histona-Lisina N-Metiltransferase/metabolismo , Humanos , Camundongos Endogâmicos BALB C , Camundongos Nus , Proteína de Leucina Linfoide-Mieloide/genética , Proteína de Leucina Linfoide-Mieloide/metabolismo , Células-Tronco Neoplásicas/patologia , Fenótipo , Complexo Repressor Polycomb 1/genética , Carga Tumoral , Microambiente Tumoral
16.
Acta Biochim Biophys Sin (Shanghai) ; 53(8): 1098-1105, 2021 Jul 28.
Artigo em Inglês | MEDLINE | ID: mdl-34169322

RESUMO

Hyperactivation of Janus kinase (JAK)/signal transducer and activator of transcription (STAT) signaling promotes tumorigenesis and cancer progression. STAT3 participates in the essential processes of cell proliferation, survival, and differentiation in many types of tumors. In the present study, SP2509 was identified as a potent inhibitor of the JAK/STAT3 signaling pathway by high-throughput drug screening based on a STAT3-driven luciferase expression system. Our results indicated that SP2509 inhibits constitutive STAT3 activation and the expression of STAT3-driven downstream genes. Bcl-xL, c-Myc, and Cyclin D1 were downregulated after treatment with SP2509. In addition, SP2509 specifically inhibits JAK activity, which could cause cell cycle arrest, inhibit cell growth, and induce apoptosis of various cancer cells. These results confirmed that SP2509 inhibits tumor progression by suppressing the expression of JAK/STAT3 signaling and STAT3-related downstream genes. Moreover, we demonstrated that SP2509 inhibits tumor growth in vivo and induces cell death in vitro. SP2509-mediated inhibition of STAT3 phosphorylation is dependent on its original target lysine-specific demethylase 1 in cancer cells. In summary, our results indicate that SP2509 is a novel inhibitor of JAK/STAT3 signaling.


Assuntos
Antineoplásicos/farmacologia , Histona Desmetilases/antagonistas & inibidores , Hidrazinas/farmacologia , Proteínas de Neoplasias , Neoplasias/tratamento farmacológico , Fator de Transcrição STAT3/metabolismo , Transdução de Sinais/efeitos dos fármacos , Sulfonamidas/farmacologia , Células A549 , Histona Desmetilases/genética , Histona Desmetilases/metabolismo , Humanos , Janus Quinases/genética , Proteínas de Neoplasias/antagonistas & inibidores , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/metabolismo , Neoplasias/genética , Neoplasias/metabolismo , Neoplasias/patologia , Fator de Transcrição STAT3/genética , Transdução de Sinais/genética
17.
Mutat Res Rev Mutat Res ; 787: 108362, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34083050

RESUMO

Radiotherapy is one of the primary modalities for cancer treatment, and its efficiency usually relies on cellular radiosensitivity. DNA damage repair is a core content of cellular radiosensitivity, and the primary mechanism of which includes non-homologous end-joining (NHEJ) and homologous recombination (HR). By affecting DNA damage repair, histone methylation regulated by histone methyltransferases (HMTs) and histone demethylases (HDMs) participates in the regulation of cellular radiosensitivity via three mechanisms: (a) recruiting DNA repair-related proteins, (b) regulating the expressions of DNA repair genes, and (c) mediating the dynamic change of chromatin. Interestingly, both aberrantly high and low levels of histone methylation could impede DNA repair processes. Here we reviewed the mechanisms of the dual effects of histone methylation on cell response to radiation. Since some inhibitors of HMTs and HDMs are reported to increase cellular radiosensitivity, understanding their molecular mechanisms may be helpful in developing new drugs for the therapy of radioresistant tumors.


Assuntos
Histona Desmetilases/metabolismo , Histona Metiltransferases/metabolismo , Histonas/metabolismo , Reparo do DNA/genética , Reparo do DNA/fisiologia , Feminino , Histona Desmetilases/genética , Histona Metiltransferases/genética , Histonas/genética , Humanos , Masculino , Tolerância a Radiação
18.
Development ; 148(12)2021 06 15.
Artigo em Inglês | MEDLINE | ID: mdl-34081130

RESUMO

Epigenetic factors have been shown to play a crucial role in X-linked intellectual disability (XLID). Here, we investigate the contribution of the XLID-associated histone demethylase PHF8 to astrocyte differentiation and function. Using genome-wide analyses and biochemical assays in mouse astrocytic cultures, we reveal a regulatory crosstalk between PHF8 and the Notch signaling pathway that balances the expression of the master astrocytic gene Nfia. Moreover, PHF8 regulates key synaptic genes in astrocytes by maintaining low levels of H4K20me3. Accordingly, astrocytic-PHF8 depletion has a striking effect on neuronal synapse formation and maturation in vitro. These data reveal that PHF8 is crucial in astrocyte development to maintain chromatin homeostasis and limit heterochromatin formation at synaptogenic genes. Our studies provide insights into the involvement of epigenetics in intellectual disability.


Assuntos
Astrócitos/metabolismo , Diferenciação Celular , Regulação da Expressão Gênica , Histona Desmetilases/genética , Fatores de Transcrição/genética , Animais , Astrócitos/citologia , Sítios de Ligação , Biomarcadores , Diferenciação Celular/genética , Proliferação de Células , Perfilação da Expressão Gênica , Histona Desmetilases/metabolismo , Histonas/metabolismo , Camundongos , Modelos Biológicos , Neurogênese , Neurônios/metabolismo , Ligação Proteica , Sinapses/metabolismo , Fatores de Transcrição/metabolismo , Transcrição Genética
19.
J Biomed Sci ; 28(1): 41, 2021 Jun 04.
Artigo em Inglês | MEDLINE | ID: mdl-34082769

RESUMO

Lysine-specific demethylase 1 (LSD1) targets mono- or di-methylated histone H3K4 and H3K9 as well as non-histone substrates and functions in the regulation of gene expression as a transcriptional repressor or activator. This enzyme plays a pivotal role in various physiological processes, including development, differentiation, inflammation, thermogenesis, neuronal and cerebral physiology, and the maintenance of stemness in stem cells. LSD1 also participates in pathological processes, including cancer as the most representative disease. It promotes oncogenesis by facilitating the survival of cancer cells and by generating a pro-cancer microenvironment. In this review, we discuss the role of LSD1 in several aspects of cancer, such as hypoxia, epithelial-to-mesenchymal transition, stemness versus differentiation of cancer stem cells, as well as anti-tumor immunity. Additionally, the current understanding of the involvement of LSD1 in various other pathological processes is discussed.


Assuntos
Histona Desmetilases/genética , Homeostase/genética , Neoplasias/genética , Animais , Diferenciação Celular/genética , Transição Epitelial-Mesenquimal/genética , Histona Desmetilases/imunologia , Histona Desmetilases/metabolismo , Homeostase/imunologia , Humanos , Hipóxia/enzimologia , Hipóxia/genética , Hipóxia/imunologia , Camundongos , Neoplasias/enzimologia , Neoplasias/imunologia , Células-Tronco Neoplásicas/fisiologia , Evasão Tumoral/genética
20.
Cell Death Dis ; 12(6): 573, 2021 06 03.
Artigo em Inglês | MEDLINE | ID: mdl-34083515

RESUMO

Epigenomic dysregulation is a common pathological feature in human hematological malignancies. H3K9me3 emerges as an important epigenomic marker in acute myeloid leukemia (AML). Its associated methyltransferases, such as SETDB1, suppress AML leukemogenesis, whilst H3K9me3 demethylases KDM4C is required for mixed-lineage leukemia rearranged AML. However, the specific role and molecular mechanism of action of another member of the KDM4 family, KDM4A has not previously been clearly defined. In this study, we delineated and functionally validated the epigenomic network regulated by KDM4A. We show that selective loss of KDM4A is sufficient to induce apoptosis in a broad spectrum of human AML cells. This detrimental phenotype results from a global accumulation of H3K9me3 and H3K27me3 at KDM4A targeted genomic loci thereby causing downregulation of a KDM4A-PAF1 controlled transcriptional program essential for leukemogenesis, distinct from that of KDM4C. From this regulatory network, we further extracted a KDM4A-9 gene signature enriched with leukemia stem cell activity; the KDM4A-9 score alone or in combination with the known LSC17 score, effectively stratifies high-risk AML patients. Together, these results establish the essential and unique role of KDM4A for AML self-renewal and survival, supporting further investigation of KDM4A and its targets as a potential therapeutic vulnerability in AML.


Assuntos
Autorrenovação Celular/genética , Sobrevivência Celular/genética , Epigenômica/métodos , Histona Desmetilases/metabolismo , Leucemia Mieloide Aguda/genética , Animais , Apoptose , Humanos , Camundongos
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