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[PMID]:27773593
[Au] Autor:Shan L; Zhou X; Liu X; Wang Y; Su D; Hou Y; Yu N; Yang C; Liu B; Gao J; Duan Y; Yang J; Li W; Liang J; Sun L; Chen K; Xuan C; Shi L; Wang Y; Shang Y
[Ad] Endereço:Department of Biochemistry and Molecular Biology, 2011 Collaborative Innovation Center of Tianjin for Medical Epigenetics, Tianjin Key Laboratory of Medical Epigenetics, School of Basic Medical Sciences, Tianjin Medical University, 22 Qixiangtai Road, Tianjin 300070, China.
[Ti] Título:FOXK2 Elicits Massive Transcription Repression and Suppresses the Hypoxic Response and Breast Cancer Carcinogenesis.
[So] Source:Cancer Cell;30(5):708-722, 2016 Nov 14.
[Is] ISSN:1878-3686
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Although clinically associated with severe developmental defects, the biological function of FOXK2 remains poorly explored. Here we report that FOXK2 interacts with transcription corepressor complexes NCoR/SMRT, SIN3A, NuRD, and REST/CoREST to repress a cohort of genes including HIF1ß and EZH2 and to regulate several signaling pathways including the hypoxic response. We show that FOXK2 inhibits the proliferation and invasion of breast cancer cells and suppresses the growth and metastasis of breast cancer. Interestingly, FOXK2 is transactivated by ERα and transrepressed via reciprocal successive feedback by HIF1ß/EZH2. Significantly, the expression of FOXK2 is progressively lost during breast cancer progression, and low FOXK2 expression is strongly correlated with higher histologic grades, positive lymph nodes, and ERα /PR /HER2 status, all indicators of poor prognosis.
[Mh] Termos MeSH primário: Translocador Nuclear Receptor Aril Hidrocarboneto/genética
Neoplasias da Mama/patologia
Proteína Potenciadora do Homólogo 2 de Zeste/genética
Receptor alfa de Estrogênio/genética
Fatores de Transcrição Forkhead/metabolismo
Transcrição Genética
[Mh] Termos MeSH secundário: Animais
Neoplasias da Mama/genética
Neoplasias da Mama/metabolismo
Hipóxia Celular
Linhagem Celular Tumoral
Proliferação Celular
Regulação para Baixo
Feminino
Fatores de Transcrição Forkhead/genética
Regulação Neoplásica da Expressão Gênica
Seres Humanos
Camundongos
Invasividade Neoplásica
Prognóstico
Transdução de Sinais
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (ARNT protein, human); 0 (Estrogen Receptor alpha); 0 (Forkhead Transcription Factors); 0 (estrogen receptor alpha, human); 138391-32-9 (Aryl Hydrocarbon Receptor Nuclear Translocator); 143298-33-3 (interleukin binding factor); EC 2.1.1.43 (EZH2 protein, human); EC 2.1.1.43 (Enhancer of Zeste Homolog 2 Protein)
[Em] Mês de entrada:1706
[Cu] Atualização por classe:180131
[Lr] Data última revisão:
180131
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:161025
[St] Status:MEDLINE


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[PMID]:29261844
[Au] Autor:Duraisamy AJ; Mishra M; Kowluru RA
[Ad] Endereço:Kresge Eye Institute, Wayne State University, Detroit, Michigan, United States.
[Ti] Título:Crosstalk Between Histone and DNA Methylation in Regulation of Retinal Matrix Metalloproteinase-9 in Diabetes.
[So] Source:Invest Ophthalmol Vis Sci;58(14):6440-6448, 2017 Dec 01.
[Is] ISSN:1552-5783
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Purpose: Diabetes activates matrix metalloproteinase-9 (MMP-9), and MMP-9 via damaging retinal mitochondria, activates capillary cell apoptosis. MMP-9 promoter has binding sites for many transcription factors, and in diabetes its promoter undergoes epigenetic modifications, including histone modifications and DNA methylation. Enhancer of Zeste homolog 2 (Ezh2), which catalyzes dimethylation/trimethylation of histone 3 lysine 27 (H3K27me2 and me3), is also associated with DNA methylation. Our aim was to investigate link(s) between histone and DNA modifications in the regulation of MMP-9. Methods: Using human retinal endothelial cells, and also retinal microvessels from diabetic rats, effect of hyperglycemia on H3K27me3, and recruitment of Ezh2 at the MMP-9 promoter were quantified by chromatin-immunoprecipitation technique. Role of H3K27 trimethylation in regulating DNA methylation-transcription of MMP-9 was determined by regulating Ezh2 by its specific siRNA and also a pharmacologic inhibitor. Results: Hyperglycemia elevated H3K27me3 levels and the recruitment of Ezh2 at the MMP-9 promoter, and increased the enzyme activity of Ezh2. Inhibition of Ezh2 attenuated recruitment of both DNA methylating (Dnmt1) and hydroxymethylating (Tet2) enzymes and 5 hydroxymethyl cytosine at the same region of the MMP-9 promoter, and prevented increase in MMP-9 transcription and mitochondrial damage. Conclusions: Activation of Ezh2 in diabetes, via trimethylation of H3K27, facilitates recruitment of the enzymes responsible for regulation of DNA methylation of the MMP-9 promoter, resulting in its transcriptional activation. Thus, a close crosstalk between H3K27 trimethylation and DNA methylation in diabetes plays a critical role in the maintenance of cellular epigenetic integrity of MMP-9.
[Mh] Termos MeSH primário: Diabetes Mellitus Experimental
Retinopatia Diabética/genética
Regulação da Expressão Gênica
Histonas/metabolismo
Metaloproteinase 9 da Matriz/genética
Retina/metabolismo
[Mh] Termos MeSH secundário: Adulto
Idoso
Animais
Apoptose
Células Cultivadas
Metilação de DNA
Retinopatia Diabética/metabolismo
Retinopatia Diabética/patologia
Proteína Potenciadora do Homólogo 2 de Zeste/genética
Proteína Potenciadora do Homólogo 2 de Zeste/metabolismo
Epigênese Genética
Seres Humanos
Histona Desmetilases com o Domínio Jumonji/genética
Histona Desmetilases com o Domínio Jumonji/metabolismo
Metaloproteinase 9 da Matriz/biossíntese
Meia-Idade
Regiões Promotoras Genéticas
Ratos
Ratos Wistar
Reação em Cadeia da Polimerase em Tempo Real
Retina/patologia
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Histones); EC 1.14.11.- (Jumonji Domain-Containing Histone Demethylases); EC 1.5.- (Kdm6b protein, mouse); EC 2.1.1.43 (EZH2 protein, human); EC 2.1.1.43 (Enhancer of Zeste Homolog 2 Protein); EC 3.4.24.35 (Matrix Metalloproteinase 9)
[Em] Mês de entrada:1712
[Cu] Atualização por classe:171229
[Lr] Data última revisão:
171229
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171221
[St] Status:MEDLINE
[do] DOI:10.1167/iovs.17-22706


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[PMID]:29069576
[Au] Autor:Wen S; Wang J; Liu P; Li Y; Lu W; Hu Y; Liu J; He Z; Huang P
[Ad] Endereço:Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University, Guangzhou 510060, China; School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, China. Electronic address: wenshj@
[Ti] Título:Novel combination of histone methylation modulators with therapeutic synergy against acute myeloid leukemia in vitro and in vivo.
[So] Source:Cancer Lett;413:35-45, 2018 Jan 28.
[Is] ISSN:1872-7980
[Cp] País de publicação:Ireland
[La] Idioma:eng
[Ab] Resumo:Acute myeloid leukemia (AML) is a hematological malignancy with rapid disease progression and often becomes lethal without treatment. Development of effective new therapies is essential to improve the clinical outcome of AML patients. Enhancer of zeste homolog 2 (EZH2) and lysine specific demethylase 1 (LSD1) play important roles in epigenetic regulation and their altered expressions have been observed in cancer. Although EZH2 and LSD1 have opposite histone methylation functions, we found that both enzymes were paradoxically up-regulated in AML cells. Importantly, a combined inhibition of EZH2 and LSD1 resulted in a synergistic activity against AML in vitro and in vivo. Such synergy was mechanistically correlated with up-regulation of H3K4me1/2 and H3K9Ac and down-regulation of H3K27me3, leading to a decrease of anti-apoptotic protein Bcl-2. These epigenetic alterations also compromised the mitochondrial respiration capacity and glycolytic activity and resulted in ATP depletion, a key event contributing to the potent cytotoxic effect of the drug combination. Taken together, our work identified a novel therapeutic approach against AML by combining two small molecules that inhibit different histone methylation-modulating proteins with apparently opposite enzyme activities. Such a new drug combination strategy likely has significant clinical implications since epigenetic modulators are currently in clinical trials.
[Mh] Termos MeSH primário: Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia
Benzamidas/farmacologia
Proteína Potenciadora do Homólogo 2 de Zeste/antagonistas & inibidores
Inibidores Enzimáticos/farmacologia
Histona Desmetilases/antagonistas & inibidores
Histonas/metabolismo
Hidrazinas/farmacologia
Leucemia Mieloide Aguda/tratamento farmacológico
Piridonas/farmacologia
Sulfonamidas/farmacologia
[Mh] Termos MeSH secundário: Animais
Apoptose/efeitos dos fármacos
Relação Dose-Resposta a Droga
Sinergismo Farmacológico
Metabolismo Energético/efeitos dos fármacos
Proteína Potenciadora do Homólogo 2 de Zeste/genética
Proteína Potenciadora do Homólogo 2 de Zeste/metabolismo
Epigênese Genética/efeitos dos fármacos
Feminino
Células HL-60
Histona Desmetilases/genética
Histona Desmetilases/metabolismo
Seres Humanos
Leucemia Mieloide Aguda/enzimologia
Leucemia Mieloide Aguda/genética
Leucemia Mieloide Aguda/patologia
Metilação
Camundongos Endogâmicos BALB C
Camundongos Nus
Mitocôndrias/efeitos dos fármacos
Mitocôndrias/metabolismo
Proteínas Proto-Oncogênicas c-bcl-2/metabolismo
Fatores de Tempo
Células Tumorais Cultivadas
Regulação para Cima
Ensaios Antitumorais Modelo de Xenoenxerto
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (BCL2 protein, human); 0 (Benzamides); 0 (EPZ-6438); 0 (Enzyme Inhibitors); 0 (Histones); 0 (Hydrazines); 0 (Proto-Oncogene Proteins c-bcl-2); 0 (Pyridones); 0 (SP2509); 0 (Sulfonamides); EC 1.14.11.- (Histone Demethylases); EC 1.5.- (KDM1A protein, human); EC 2.1.1.43 (EZH2 protein, human); EC 2.1.1.43 (Enhancer of Zeste Homolog 2 Protein)
[Em] Mês de entrada:1712
[Cu] Atualização por classe:171204
[Lr] Data última revisão:
171204
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171026
[St] Status:MEDLINE


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[PMID]:29087384
[Au] Autor:Schlacher K
[Ad] Endereço:Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.
[Ti] Título:PARPi focus the spotlight on replication fork protection in cancer.
[So] Source:Nat Cell Biol;19(11):1309-1310, 2017 Oct 31.
[Is] ISSN:1476-4679
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:PARP inhibitors (PARPi) kill BRCA1/2-mutated cancers, which become resistant when DNA repair functions are restored. Now, MUS81 nuclease inhibition due to EZH2 downregulation is found to restore DNA replication fork protection but not repair, leading to PARPi-resistance in mutant BRCA2 cells and patients. This challenges the DNA repair dominance in synthetic lethality.
[Mh] Termos MeSH primário: Replicação do DNA/efeitos dos fármacos
Neoplasias/tratamento farmacológico
Neoplasias/genética
Inibidores de Poli(ADP-Ribose) Polimerases/farmacologia
Poli(ADP-Ribose) Polimerases/metabolismo
[Mh] Termos MeSH secundário: Proteína BRCA1/genética
Proteína BRCA2/genética
Dano ao DNA/efeitos dos fármacos
Dano ao DNA/genética
Reparo do DNA/efeitos dos fármacos
Reparo do DNA/genética
Replicação do DNA/genética
Regulação para Baixo/efeitos dos fármacos
Regulação para Baixo/genética
Proteína Potenciadora do Homólogo 2 de Zeste/genética
Seres Humanos
Neoplasias/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (BRCA1 Protein); 0 (BRCA1 protein, human); 0 (BRCA2 Protein); 0 (BRCA2 protein, human); 0 (Poly(ADP-ribose) Polymerase Inhibitors); EC 2.1.1.43 (EZH2 protein, human); EC 2.1.1.43 (Enhancer of Zeste Homolog 2 Protein); EC 2.4.2.30 (Poly(ADP-ribose) Polymerases)
[Em] Mês de entrada:1711
[Cu] Atualização por classe:171107
[Lr] Data última revisão:
171107
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171101
[St] Status:MEDLINE
[do] DOI:10.1038/ncb3638


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[PMID]:29048549
[Au] Autor:Yoshida K; Toden S; Ravindranathan P; Han H; Goel A
[Ad] Endereço:Center for Gastrointestinal Research, Center for Translational Genomics and Oncology, Baylor Scott and White Research Institute and Charles A. Sammons Cancer Center, Baylor University Medical Center, Dallas, TX 75246, USA.
[Ti] Título:Curcumin sensitizes pancreatic cancer cells to gemcitabine by attenuating PRC2 subunit EZH2, and the lncRNA PVT1 expression.
[So] Source:Carcinogenesis;38(10):1036-1046, 2017 Oct 01.
[Is] ISSN:1460-2180
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Development of resistance to chemotherapeutic drugs is a major challenge in the care of patients with pancreatic ductal adenocarcinoma (PDAC). Acquired resistance to chemotherapeutic agents in PDAC has been linked to a subset of cancer cells termed 'cancer stem cells' (CSCs). Therefore, an improved understanding of the molecular events underlying the development of pancreatic CSCs is required to identify new therapeutic targets to overcome chemoresistance. Accumulating evidence indicates that curcumin, a phenolic compound extracted from turmeric, can overcome de novo chemoresistance and re-sensitize tumors to various chemotherapeutic agents. However, the underlying mechanisms for curcumin-mediated chemosensitization remain unclear. The Enhancer of Zeste Homolog-2 (EZH2) subunit of Polycomb Repressive Complex 2 (PRC2) was recently identified as a key player regulating drug resistance. EZH2 mediates interaction with several long non-coding RNAs (lncRNAs) to modulate epithelial-mesenchymal transition and cancer stemness, phenomena commonly associated with drug resistance. Here, we report the re-sensitization of chemoresistant PDAC cells by curcumin through the inhibition of the PRC2-PVT1-c-Myc axis. Using gemcitabine-resistant PDAC cell lines, we found that curcumin sensitized chemoresistant cancer cells by inhibiting the expression of the PRC2 subunit EZH2 and its related lncRNA PVT1. Curcumin was also found to prevent the formation of spheroids, a hallmark of CSCs, and to down-regulate several self-renewal driving genes. In addition, we confirmed our in vitro findings in a xenograft mouse model where curcumin inhibited gemcitabine-resistant tumor growth. Overall, this study indicates clinical relevance for combining curcumin with chemotherapy to overcome chemoresistance in PDAC.
[Mh] Termos MeSH primário: Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia
Carcinoma Ductal Pancreático/tratamento farmacológico
Curcumina/farmacologia
Proteína Potenciadora do Homólogo 2 de Zeste/metabolismo
Neoplasias Pancreáticas/tratamento farmacológico
[Mh] Termos MeSH secundário: Animais
Apoptose/efeitos dos fármacos
Carcinoma Ductal Pancreático/genética
Carcinoma Ductal Pancreático/patologia
Pontos de Checagem do Ciclo Celular/efeitos dos fármacos
Linhagem Celular Tumoral
Curcumina/administração & dosagem
Desoxicitidina/administração & dosagem
Desoxicitidina/análogos & derivados
Resistência a Medicamentos Antineoplásicos/efeitos dos fármacos
Proteína Potenciadora do Homólogo 2 de Zeste/genética
Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos
Seres Humanos
Camundongos Nus
Células-Tronco Neoplásicas/efeitos dos fármacos
Neoplasias Pancreáticas/genética
Neoplasias Pancreáticas/patologia
RNA Longo não Codificante/genética
Ensaios Antitumorais Modelo de Xenoenxerto
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (PVT1 long-non-coding RNA, human); 0 (RNA, Long Noncoding); 0W860991D6 (Deoxycytidine); B76N6SBZ8R (gemcitabine); EC 2.1.1.43 (EZH2 protein, human); EC 2.1.1.43 (Enhancer of Zeste Homolog 2 Protein); IT942ZTH98 (Curcumin)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171030
[Lr] Data última revisão:
171030
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171020
[St] Status:MEDLINE
[do] DOI:10.1093/carcin/bgx065


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[PMID]:29035360
[Au] Autor:Rondinelli B; Gogola E; Yücel H; Duarte AA; van de Ven M; van der Sluijs R; Konstantinopoulos PA; Jonkers J; Ceccaldi R; Rottenberg S; D'Andrea AD
[Ad] Endereço:Department of Radiation Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts 02215, USA.
[Ti] Título:EZH2 promotes degradation of stalled replication forks by recruiting MUS81 through histone H3 trimethylation.
[So] Source:Nat Cell Biol;19(11):1371-1378, 2017 Nov.
[Is] ISSN:1476-4679
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:The emergence of resistance to poly-ADP-ribose polymerase inhibitors (PARPi) poses a threat to the treatment of BRCA1 and BRCA2 (BRCA1/2)-deficient tumours. Stabilization of stalled DNA replication forks is a recently identified PARPi-resistance mechanism that promotes genomic stability in BRCA1/2-deficient cancers. Dissecting the molecular pathways controlling genomic stability at stalled forks is critical. Here we show that EZH2 localizes at stalled forks where it methylates Lys27 on histone 3 (H3K27me3), mediating recruitment of the MUS81 nuclease. Low EZH2 levels reduce H3K27 methylation, prevent MUS81 recruitment at stalled forks and cause fork stabilization. As a consequence, loss of function of the EZH2/MUS81 axis promotes PARPi resistance in BRCA2-deficient cells. Accordingly, low EZH2 or MUS81 expression levels predict chemoresistance and poor outcome in patients with BRCA2-mutated tumours. Moreover, inhibition of Ezh2 in a murine Brca2 breast tumour model is associated with acquired PARPi resistance. Our findings identify EZH2 as a critical regulator of genomic stability at stalled forks that couples histone modifications to nuclease recruitment. Our data identify EZH2 expression as a biomarker of BRCA2-deficient tumour response to chemotherapy.
[Mh] Termos MeSH primário: Replicação do DNA/genética
Proteínas de Ligação a DNA/metabolismo
Endonucleases/metabolismo
Proteína Potenciadora do Homólogo 2 de Zeste/metabolismo
Histonas/metabolismo
[Mh] Termos MeSH secundário: Animais
Proteína BRCA1/metabolismo
Proteína BRCA2/metabolismo
Biomarcadores Tumorais/metabolismo
Neoplasias da Mama/genética
Neoplasias da Mama/metabolismo
Linhagem Celular
Linhagem Celular Tumoral
Replicação do DNA/efeitos dos fármacos
Resistência a Medicamentos Antineoplásicos/genética
Feminino
Instabilidade Genômica/efeitos dos fármacos
Instabilidade Genômica/genética
Células HEK293
Células HeLa
Seres Humanos
Metilação/efeitos dos fármacos
Camundongos
Camundongos Nus
Inibidores de Poli(ADP-Ribose) Polimerases/farmacologia
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (BRCA1 Protein); 0 (BRCA1 protein, human); 0 (BRCA2 Protein); 0 (BRCA2 protein, human); 0 (Biomarkers, Tumor); 0 (DNA-Binding Proteins); 0 (Histones); 0 (Poly(ADP-ribose) Polymerase Inhibitors); EC 2.1.1.43 (EZH2 protein, human); EC 2.1.1.43 (Enhancer of Zeste Homolog 2 Protein); EC 3.1.- (Endonucleases); EC 3.1.- (MUS81 protein, human)
[Em] Mês de entrada:1711
[Cu] Atualização por classe:171107
[Lr] Data última revisão:
171107
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171017
[St] Status:MEDLINE
[do] DOI:10.1038/ncb3626


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[PMID]:29033324
[Au] Autor:Wang AH; Juan AH; Ko KD; Tsai PF; Zare H; Dell'Orso S; Sartorelli V
[Ad] Endereço:Laboratory of Muscle Stem Cells and Gene Regulation, National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), NIH, Bethesda, MD 20829, USA.
[Ti] Título:The Elongation Factor Spt6 Maintains ESC Pluripotency by Controlling Super-Enhancers and Counteracting Polycomb Proteins.
[So] Source:Mol Cell;68(2):398-413.e6, 2017 Oct 19.
[Is] ISSN:1097-4164
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Spt6 coordinates nucleosome dis- and re-assembly, transcriptional elongation, and mRNA processing. Here, we report that depleting Spt6 in embryonic stem cells (ESCs) reduced expression of pluripotency factors, increased expression of cell-lineage-affiliated developmental regulators, and induced cell morphological and biochemical changes indicative of ESC differentiation. Selective downregulation of pluripotency factors upon Spt6 depletion may be mechanistically explained by its enrichment at ESC super-enhancers, where Spt6 controls histone H3K27 acetylation and methylation and super-enhancer RNA transcription. In ESCs, Spt6 interacted with the PRC2 core subunit Suz12 and prevented H3K27me3 accumulation at ESC super-enhancers and associated promoters. Biochemical as well as functional experiments revealed that Spt6 could compete for binding of the PRC2 methyltransferase Ezh2 to Suz12 and reduce PRC2 chromatin engagement. Thus, in addition to serving as a histone chaperone and transcription elongation factor, Spt6 counteracts repression by opposing H3K27me3 deposition at critical genomic regulatory regions.
[Mh] Termos MeSH primário: Regulação para Baixo
Elementos Facilitadores Genéticos
Proteína Potenciadora do Homólogo 2 de Zeste/metabolismo
Células-Tronco Embrionárias Murinas/metabolismo
Complexo Repressor Polycomb 2/metabolismo
Fatores de Transcrição/metabolismo
[Mh] Termos MeSH secundário: Acetilação
Animais
Linhagem Celular
Proteína Potenciadora do Homólogo 2 de Zeste/genética
Histonas/genética
Histonas/metabolismo
Camundongos
Complexo Repressor Polycomb 2/genética
Fatores de Transcrição/genética
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Histones); 0 (Supt6h protein, mouse); 0 (Suz12 protein, mouse); 0 (Transcription Factors); EC 2.1.1.43 (Enhancer of Zeste Homolog 2 Protein); EC 2.1.1.43 (Ezh2 protein, mouse); EC 2.1.1.43 (Polycomb Repressive Complex 2)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171031
[Lr] Data última revisão:
171031
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171017
[St] Status:MEDLINE


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[PMID]:28977589
[Au] Autor:Shoucri BM; Martinez ES; Abreo TJ; Hung VT; Moosova Z; Shioda T; Blumberg B
[Ad] Endereço:Department of Developmental and Cell Biology, University of California, Irvine, Irvine, California 92697-2300.
[Ti] Título:Retinoid X Receptor Activation Alters the Chromatin Landscape To Commit Mesenchymal Stem Cells to the Adipose Lineage.
[So] Source:Endocrinology;158(10):3109-3125, 2017 Oct 01.
[Is] ISSN:1945-7170
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Developmental exposure to environmental factors has been linked to obesity risk later in life. Nuclear receptors are molecular sensors that play critical roles during development and, as such, are prime candidates to explain the developmental programming of disease risk by environmental chemicals. We have previously characterized the obesogen tributyltin (TBT), which activates the nuclear receptors peroxisome proliferator-activated receptor γ (PPARγ) and retinoid X receptor (RXR) to increase adiposity in mice exposed in utero. Mesenchymal stem cells (MSCs) from these mice are biased toward the adipose lineage at the expense of the osteoblast lineage, and MSCs exposed to TBT in vitro are shunted toward the adipose fate in a PPARγ-dependent fashion. To address where in the adipogenic cascade TBT acts, we developed an in vitro commitment assay that permitted us to distinguish early commitment to the adipose lineage from subsequent differentiation. TBT and RXR activators (rexinoids) had potent effects in committing MSCs to the adipose lineage, whereas the strong PPARγ activator rosiglitazone was inactive. We show that activation of RXR is sufficient for adipogenic commitment and that rexinoids act through RXR to alter the transcriptome in a manner favoring adipogenic commitment. RXR activation alters expression of enhancer of zeste homolog 2 (EZH2) and modifies genome-wide histone 3 lysine 27 trimethylation (H3K27me3) in promoting adipose commitment and programming subsequent differentiation. These data offer insights into the roles of RXR and EZH2 in MSC lineage specification and shed light on how endocrine-disrupting chemicals such as TBT can reprogram stem cell fate.
[Mh] Termos MeSH primário: Adipócitos/citologia
Adipogenia/efeitos dos fármacos
Adipogenia/genética
Cromatina/efeitos dos fármacos
Células Mesenquimais Estromais/citologia
Receptores X Retinoide/fisiologia
[Mh] Termos MeSH secundário: Adipogenia/fisiologia
Animais
Diferenciação Celular/efeitos dos fármacos
Diferenciação Celular/genética
Cromatina/fisiologia
Disruptores Endócrinos/farmacologia
Proteína Potenciadora do Homólogo 2 de Zeste/genética
Epigênese Genética/efeitos dos fármacos
Expressão Gênica/efeitos dos fármacos
Técnicas de Silenciamento de Genes/veterinária
Camundongos
Camundongos Endogâmicos C57BL
Obesidade/etiologia
PPAR gama/fisiologia
Receptores X Retinoide/efeitos dos fármacos
Análise de Sequência de RNA/veterinária
Compostos de Trialquitina/farmacologia
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Chromatin); 0 (Endocrine Disruptors); 0 (PPAR gamma); 0 (Retinoid X Receptors); 0 (Trialkyltin Compounds); 4XDX163P3D (tributyltin); EC 2.1.1.43 (Enhancer of Zeste Homolog 2 Protein); EC 2.1.1.43 (Ezh2 protein, mouse)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171114
[Lr] Data última revisão:
171114
[Sb] Subgrupo de revista:AIM; IM
[Da] Data de entrada para processamento:171005
[St] Status:MEDLINE
[do] DOI:10.1210/en.2017-00348


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[PMID]:28976794
[Au] Autor:Ho TH; Kapur P; Eckel-Passow JE; Christie A; Joseph RW; Serie DJ; Cheville JC; Thompson RH; Homayoun F; Panwar V; Brugarolas J; Parker AS
[Ad] Endereço:Thai Huu Ho, Mayo Clinic, Phoenix, AZ; Jeanette E. Eckel-Passow, John C. Cheville, and R. Houston Thompson, Mayo Clinic, Rochester, MN; Payal Kapur, Alana Christie, Vandana Panwar, and James Brugarolas, University of Texas Southwestern Medical Center; Payal Kapur, Farrah Homayoun, and James Brugarol
[Ti] Título:Multicenter Validation of Enhancer of Zeste Homolog 2 Expression as an Independent Prognostic Marker in Localized Clear Cell Renal Cell Carcinoma.
[So] Source:J Clin Oncol;35(32):3706-3713, 2017 Nov 10.
[Is] ISSN:1527-7755
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Purpose Enhancer of zeste homolog 2 (EZH2), a chromatin remodeler, is implicated in the pathogenesis of clear cell renal cell carcinoma (ccRCC). However, the effect of EZH2 on outcomes in localized ccRCC is unclear, and molecular biomarkers are not currently integrated into prognostic models or adjuvant therapy trials. Methods We performed Cox regression to evaluate the association of tumor-based EZH2 gene and protein expression with survival in three independent cohorts: a cohort from The Cancer Genome Atlas (n = 532), a cohort from University of Texas Southwestern Medical Center (n = 122), and a cohort from Mayo Clinic (n = 1,338). Analyses were adjusted for the prognostic stage, size, grade, and necrosis (SSIGN) score as well as within low-, intermediate-, and high-risk SSIGN groups. Results Patients in The Cancer Genome Atlas cohort with EZH2-high gene expression were 1.5 times more likely to experience overall death than patients with EZH2-low expression (95% CI, 1.1 to 2.3; P = .028). Patients in the University of Texas Southwestern Medical Center cohort with EZH2-high protein expression were two times more likely to experience overall death than patients with EZH2-low expression (95% CI, 1.1 to 4.4; P = .034). Similarly, patients in the Mayo Clinic cohort with EZH2-high protein expression were 1.4 times more likely to experience overall death (95% CI, 1.2 to 1.7; P < .001). Patients in the Mayo Clinic cohort with EZH2-high protein expression were nearly two times more likely to experience RCC-specific death (95% CI, 1.5 to 2.6; P < .001); EZH2 protein expression was particularly prognostic among patients with low-risk SSIGN tumors (HR, 6.1; 95% CI, 3.4 to 11.1; P < .001). Conclusion EZH2 expression accurately predicts risk of RCC death beyond existing clinicopathologic models, particularly in low- and intermediate-risk SSIGN tumors. Further studies are required to incorporate molecular biomarkers into surveillance guidelines and adjuvant clinical trials.
[Mh] Termos MeSH primário: Carcinoma de Células Renais/metabolismo
Proteína Potenciadora do Homólogo 2 de Zeste/metabolismo
Neoplasias Renais/metabolismo
[Mh] Termos MeSH secundário: Adulto
Idoso
Idoso de 80 Anos ou mais
Biomarcadores Tumorais/metabolismo
Carcinoma de Células Renais/mortalidade
Carcinoma de Células Renais/patologia
Feminino
Seres Humanos
Neoplasias Renais/mortalidade
Neoplasias Renais/patologia
Masculino
Meia-Idade
Necrose
Gradação de Tumores
Estadiamento de Neoplasias
Prognóstico
Fatores de Risco
Taxa de Sobrevida
Estados Unidos
[Pt] Tipo de publicação:JOURNAL ARTICLE; MULTICENTER STUDY; VALIDATION STUDIES
[Nm] Nome de substância:
0 (Biomarkers, Tumor); EC 2.1.1.43 (Enhancer of Zeste Homolog 2 Protein)
[Em] Mês de entrada:1711
[Cu] Atualização por classe:171126
[Lr] Data última revisão:
171126
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171005
[St] Status:MEDLINE
[do] DOI:10.1200/JCO.2017.73.3238


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[PMID]:28923203
[Au] Autor:Kwon H; Song K; Han C; Zhang J; Lu L; Chen W; Wu T
[Ad] Endereço:Department of Pathology and Laboratory Medicine, Tulane University School of Medicine, New Orleans, Louisiana.
[Ti] Título:Epigenetic Silencing of miRNA-34a in Human Cholangiocarcinoma via EZH2 and DNA Methylation: Impact on Regulation of Notch Pathway.
[So] Source:Am J Pathol;187(10):2288-2299, 2017 Oct.
[Is] ISSN:1525-2191
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Aberrant expression and regulation of miRNAs have been implicated in multiple stages of tumorigenic processes. The current study was designed to explore the biological function and epigenetic regulation of miR-34a in human cholangiocarcinoma (CCA). Our data show that the expression of miR-34a is decreased significantly in CCA cells compared with non-neoplastic biliary epithelial cells. Forced overexpression of miR-34a in CCA cells inhibited their proliferation and clonogenic capacity in vitro, and suppressed tumor xenograft growth in severe combined immunodeficiency mice. We identified three key components of the Notch pathway, Notch1, Notch2, and Jagged 1, as direct targets of miR-34a. Our further studies show that down-regulation of miR-34a is caused by Enhancer of zeste homolog 2 (EZH2)-mediated H3 lysine 27 trimethylation as well as DNA methylation. Accordingly, treatment with the EZH2 inhibitor, selective S-adenosyl-methionine-competitive small-molecule (GSK126), or the DNA methylation inhibitor, 5-Aza-2'-deoxycytidine, partially restored miR-34a levels in human CCA cells. Immunohistochemical staining and Western blot analyses showed increased EZH2 expression in human CCA tissues and cell lines. We observed that GSK126 significantly reduced CCA cell growth in vitro and intrahepatic metastasis in vivo. Our findings provide novel evidence that miR-34a expression is silenced epigenetically by EZH2 and DNA methylation, which promotes CCA cell growth through activation of the Notch pathway. Consequently, these signaling cascades may represent potential therapeutic targets for effective treatment of human CCA.
[Mh] Termos MeSH primário: Neoplasias dos Ductos Biliares/genética
Colangiocarcinoma/genética
Metilação de DNA/genética
Proteína Potenciadora do Homólogo 2 de Zeste/metabolismo
Epigênese Genética
Inativação Gênica
MicroRNAs/metabolismo
Transdução de Sinais/genética
[Mh] Termos MeSH secundário: Animais
Sequência de Bases
Neoplasias dos Ductos Biliares/patologia
Linhagem Celular Tumoral
Proliferação Celular/efeitos dos fármacos
Proliferação Celular/genética
Colangiocarcinoma/patologia
Ilhas de CpG/genética
Metilação de DNA/efeitos dos fármacos
Proteína Potenciadora do Homólogo 2 de Zeste/genética
Epigênese Genética/efeitos dos fármacos
Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos
Inativação Gênica/efeitos dos fármacos
Histonas/metabolismo
Seres Humanos
Indóis/farmacologia
Lisina/metabolismo
Masculino
Camundongos Endogâmicos NOD
MicroRNAs/genética
Metástase Neoplásica
Piridonas/farmacologia
Receptores Notch/genética
Receptores Notch/metabolismo
Transdução de Sinais/efeitos dos fármacos
Ensaio Tumoral de Célula-Tronco
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (GSK126); 0 (Histones); 0 (Indoles); 0 (MIRN34 microRNA, human); 0 (MicroRNAs); 0 (Pyridones); 0 (Receptors, Notch); EC 2.1.1.43 (Enhancer of Zeste Homolog 2 Protein); K3Z4F929H6 (Lysine)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171122
[Lr] Data última revisão:
171122
[Sb] Subgrupo de revista:AIM; IM
[Da] Data de entrada para processamento:170920
[St] Status:MEDLINE



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