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[PMID]:29337058
[Au] Autor:Kim K; Son MY; Jung CR; Kim DS; Cho HS
[Ad] Endereço:Korea Research Institute of Bioscience and Biotechnology, Daejeon, 305-333, Republic of Korea.
[Ti] Título:EHMT2 is a metastasis regulator in breast cancer.
[So] Source:Biochem Biophys Res Commun;496(2):758-762, 2018 02 05.
[Is] ISSN:1090-2104
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Various modes of epigenetic regulation of breast cancer proliferation and metastasis have been investigated, but epigenetic mechanisms involved in breast cancer metastasis remain elusive. Thus, in this study, EHMT2 (a histone methyltransferase) was determined to be significantly overexpressed in breast cancer tissues and in Oncomine data. In addition, knockdown of EHMT2 reduced cell migration/invasion and regulated the expression of EMT-related markers (E-cadherin, Claudin 1, and Vimentin). Furthermore, treatment with BIX-01294, a specific inhibitor of EHMT2, affected migration/invasion in MDA-MB-231 cells. Therefore, our findings demonstrate functions of EHMT2 in breast cancer metastasis and suggest that targeting EHMT2 may be an effective therapeutic strategy for preventing breast cancer metastasis.
[Mh] Termos MeSH primário: Neoplasias da Mama/genética
Regulação Neoplásica da Expressão Gênica
Antígenos de Histocompatibilidade/genética
Histona-Lisina N-Metiltransferase/genética
Invasividade Neoplásica/genética
[Mh] Termos MeSH secundário: Mama/metabolismo
Mama/patologia
Neoplasias da Mama/patologia
Linhagem Celular Tumoral
Movimento Celular
Epigênese Genética
Feminino
Seres Humanos
Invasividade Neoplásica/patologia
Metástase Neoplásica/genética
Metástase Neoplásica/patologia
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Histocompatibility Antigens); EC 2.1.1.43 (EHMT2 protein, human); EC 2.1.1.43 (Histone-Lysine N-Methyltransferase)
[Em] Mês de entrada:1802
[Cu] Atualização por classe:180216
[Lr] Data última revisão:
180216
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:180117
[St] Status:MEDLINE


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[PMID]:29281720
[Au] Autor:Rodriguez-Madoz JR; San Jose-Eneriz E; Rabal O; Zapata-Linares N; Miranda E; Rodriguez S; Porciuncula A; Vilas-Zornoza A; Garate L; Segura V; Guruceaga E; Agirre X; Oyarzabal J; Prosper F
[Ad] Endereço:Cell Therapy Program, Center for Applied Medical Research (CIMA), University of Navarra, Pamplona, Spain.
[Ti] Título:Reversible dual inhibitor against G9a and DNMT1 improves human iPSC derivation enhancing MET and facilitating transcription factor engagement to the genome.
[So] Source:PLoS One;12(12):e0190275, 2017.
[Is] ISSN:1932-6203
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:The combination of defined factors with small molecules targeting epigenetic factors is a strategy that has been shown to enhance optimal derivation of iPSCs and could be used for disease modelling, high throughput screenings and/or regenerative medicine applications. In this study, we showed that a new first-in-class reversible dual G9a/DNMT1 inhibitor compound (CM272) improves the efficiency of human cell reprogramming and iPSC generation from primary cells of healthy donors and patient samples, using both integrative and non-integrative methods. Moreover, CM272 facilitates the generation of human iPSC with only two factors allowing the removal of the most potent oncogenic factor cMYC. Furthermore, we demonstrated that mechanistically, treatment with CM272 induces heterochromatin relaxation, facilitates the engagement of OCT4 and SOX2 transcription factors to OSKM refractory binding regions that are required for iPSC establishment, and enhances mesenchymal to epithelial transition during the early phase of cell reprogramming. Thus, the use of this new G9a/DNMT reversible dual inhibitor compound may represent an interesting alternative for improving cell reprogramming and human iPSC derivation for many different applications while providing interesting insights into reprogramming mechanisms.
[Mh] Termos MeSH primário: Reprogramação Celular
Genoma Humano
Histona-Lisina N-Metiltransferase/antagonistas & inibidores
Células-Tronco Pluripotentes Induzidas/citologia
Proteínas Repressoras/antagonistas & inibidores
Fatores de Transcrição/metabolismo
[Mh] Termos MeSH secundário: Células Cultivadas
Antígenos de Histocompatibilidade
Seres Humanos
Reação em Cadeia da Polimerase em Tempo Real
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (DMAP1 protein, human); 0 (Histocompatibility Antigens); 0 (Repressor Proteins); 0 (Transcription Factors); EC 2.1.1.43 (EHMT2 protein, human); EC 2.1.1.43 (Histone-Lysine N-Methyltransferase)
[Em] Mês de entrada:1802
[Cu] Atualização por classe:180206
[Lr] Data última revisão:
180206
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171228
[St] Status:MEDLINE
[do] DOI:10.1371/journal.pone.0190275


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[PMID]:28460359
[Au] Autor:Zhang J; Yao D; Jiang Y; Huang J; Yang S; Wang J
[Ad] Endereço:School of Traditional Chinese Materia Medica, Shenyang Pharmaceutical University, Shenyang 110016, China.
[Ti] Título:Synthesis and biological evaluation of benzimidazole derivatives as the G9a Histone Methyltransferase inhibitors that induce autophagy and apoptosis of breast cancer cells.
[So] Source:Bioorg Chem;72:168-181, 2017 06.
[Is] ISSN:1090-2120
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:G9a (also known as KMT1C or EHMT2) is initially identified as a H3K9 methyltransferase that specifically mono- and dimethylates 'Lys-9' of histone H3 (H3K9me1 and H3K9me2, respectively) in euchromatin. It is overexpressed in various human cancers and employed as a promising target in cancer therapy. We discovered a benzoxazole scaffold through virtual high-throughput screening, and designed, synthesized 24 derivatives and investigated for inhibition of G9a. After several rounds of kinase and anti-proliferative activity screening, we discovered a potent G9a antagonist (GA001) with an IC value of 1.32µM that could induce autophagy via AMPK in MCF7 cells. In addition, we found high concentration of GA001 could induce apoptosis via p21-Bim signal cascades in MCF7 cells. Our results highlight a new approach for the development of a novel drug targeting G9a with a potential to induce autophagy and apoptosis for future breast cancer therapy.
[Mh] Termos MeSH primário: Antineoplásicos/farmacologia
Autofagia/efeitos dos fármacos
Benzimidazóis/farmacologia
Neoplasias da Mama/tratamento farmacológico
Inibidores Enzimáticos/farmacologia
Histona-Lisina N-Metiltransferase/antagonistas & inibidores
[Mh] Termos MeSH secundário: Antineoplásicos/síntese química
Antineoplásicos/química
Benzimidazóis/síntese química
Benzimidazóis/química
Neoplasias da Mama/patologia
Sobrevivência Celular/efeitos dos fármacos
Relação Dose-Resposta a Droga
Ensaios de Seleção de Medicamentos Antitumorais
Inibidores Enzimáticos/síntese química
Inibidores Enzimáticos/química
Feminino
Antígenos de Histocompatibilidade/metabolismo
Histona-Lisina N-Metiltransferase/metabolismo
Seres Humanos
Células MCF-7
Modelos Moleculares
Estrutura Molecular
Relação Estrutura-Atividade
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Antineoplastic Agents); 0 (Benzimidazoles); 0 (Enzyme Inhibitors); 0 (Histocompatibility Antigens); E24GX49LD8 (benzimidazole); EC 2.1.1.43 (EHMT2 protein, human); EC 2.1.1.43 (Histone-Lysine N-Methyltransferase)
[Em] Mês de entrada:1706
[Cu] Atualização por classe:171214
[Lr] Data última revisão:
171214
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170502
[St] Status:MEDLINE


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[PMID]:28455378
[Au] Autor:Chi L; Ahmed A; Roy AR; Vuong S; Cahill LS; Caporiccio L; Sled JG; Caniggia I; Wilson MD; Delgado-Olguin P
[Ad] Endereço:Translational Medicine, The Hospital for Sick Children, Toronto, Ontario M5G 0A4, Canada.
[Ti] Título:G9a controls placental vascular maturation by activating the Notch Pathway.
[So] Source:Development;144(11):1976-1987, 2017 06 01.
[Is] ISSN:1477-9129
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Defective fetoplacental vascular maturation causes intrauterine growth restriction (IUGR). A transcriptional switch initiates placental maturation, during which blood vessels elongate. However, the cellular mechanisms and regulatory pathways involved are unknown. We show that the histone methyltransferase G9a, also known as Ehmt2, activates the Notch pathway to promote placental vascular maturation. Placental vasculature from embryos with G9a-deficient endothelial progenitor cells failed to expand owing to decreased endothelial cell proliferation and increased trophoblast proliferation. Moreover, G9a deficiency altered the transcriptional switch initiating placental maturation and caused downregulation of Notch pathway effectors including Importantly, Notch pathway activation in G9a-deficient endothelial progenitors extended embryonic life and rescued placental vascular expansion. Thus, G9a activates the Notch pathway to balance endothelial cell and trophoblast proliferation and coordinates the transcriptional switch controlling placental vascular maturation. Accordingly, and were downregulated in human placentae from IUGR-affected pregnancies, suggesting that G9a is an important regulator in placental diseases caused by defective vascular maturation.
[Mh] Termos MeSH primário: Antígenos de Histocompatibilidade/metabolismo
Histona-Lisina N-Metiltransferase/metabolismo
Placenta/irrigação sanguínea
Receptores Notch/metabolismo
Transdução de Sinais
[Mh] Termos MeSH secundário: Animais
Movimento Celular/genética
Proliferação Celular
Regulação para Baixo/genética
Embrião de Mamíferos/metabolismo
Embrião de Mamíferos/ultraestrutura
Desenvolvimento Embrionário/genética
Células Endoteliais/citologia
Células Endoteliais/metabolismo
Feminino
Retardo do Crescimento Fetal/genética
Regulação da Expressão Gênica no Desenvolvimento
Antígenos de Histocompatibilidade/genética
Histona-Lisina N-Metiltransferase/genética
Seres Humanos
Proteína de Ligação a Sequências Sinal de Recombinação J de Imunoglobina/genética
Proteína de Ligação a Sequências Sinal de Recombinação J de Imunoglobina/metabolismo
Camundongos
Organogênese/genética
Placenta/citologia
Placenta/ultraestrutura
Gravidez
Transdução de Sinais/genética
Células-Tronco/citologia
Células-Tronco/metabolismo
Transcrição Genética
Trofoblastos/citologia
Trofoblastos/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Histocompatibility Antigens); 0 (Immunoglobulin J Recombination Signal Sequence-Binding Protein); 0 (RBPJ protein, human); 0 (Receptors, Notch); EC 2.1.1.43 (EHMT2 protein, human); EC 2.1.1.43 (G9a protein, mouse); EC 2.1.1.43 (Histone-Lysine N-Methyltransferase)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:171126
[Lr] Data última revisão:
171126
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170430
[St] Status:MEDLINE
[do] DOI:10.1242/dev.148916


  5 / 10627 MEDLINE  
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[PMID]:28973434
[Au] Autor:O'Geen H; Ren C; Nicolet CM; Perez AA; Halmai J; Le VM; Mackay JP; Farnham PJ; Segal DJ
[Ad] Endereço:Genome Center and Department of Biochemistry and Molecular Medicine, University of California, Davis, CA 95616, USA.
[Ti] Título:dCas9-based epigenome editing suggests acquisition of histone methylation is not sufficient for target gene repression.
[So] Source:Nucleic Acids Res;45(17):9901-9916, 2017 Sep 29.
[Is] ISSN:1362-4962
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Distinct epigenomic profiles of histone marks have been associated with gene expression, but questions regarding the causal relationship remain. Here we investigated the activity of a broad collection of genomically targeted epigenetic regulators that could write epigenetic marks associated with a repressed chromatin state (G9A, SUV39H1, Krüppel-associated box (KRAB), DNMT3A as well as the first targetable versions of Ezh2 and Friend of GATA-1 (FOG1)). dCas9 fusions produced target gene repression over a range of 0- to 10-fold that varied by locus and cell type. dCpf1 fusions were unable to repress gene expression. The most persistent gene repression required the action of several effector domains; however, KRAB-dCas9 did not contribute to persistence in contrast to previous reports. A 'direct tethering' strategy attaching the Ezh2 methyltransferase enzyme to dCas9, as well as a 'recruitment' strategy attaching the N-terminal 45 residues of FOG1 to dCas9 to recruit the endogenous nucleosome remodeling and deacetylase complex, were both successful in targeted deposition of H3K27me3. Surprisingly, however, repression was not correlated with deposition of either H3K9me3 or H3K27me3. Our results suggest that so-called repressive histone modifications are not sufficient for gene repression. The easily programmable dCas9 toolkit allowed precise control of epigenetic information and dissection of the relationship between the epigenome and gene regulation.
[Mh] Termos MeSH primário: Cromatina/química
Endonucleases/genética
Epigenômica/métodos
Inativação Gênica
Histonas/genética
[Mh] Termos MeSH secundário: Cromatina/metabolismo
DNA (Citosina-5-)-Metiltransferases/genética
DNA (Citosina-5-)-Metiltransferases/metabolismo
Endonucleases/metabolismo
Edição de Genes
Células HCT116
Células HEK293
Antígenos de Histocompatibilidade/genética
Antígenos de Histocompatibilidade/metabolismo
Histona-Lisina N-Metiltransferase/genética
Histona-Lisina N-Metiltransferase/metabolismo
Histonas/metabolismo
Seres Humanos
Metilação
Metiltransferases/genética
Metiltransferases/metabolismo
Proteínas Nucleares/genética
Proteínas Nucleares/metabolismo
Regiões Promotoras Genéticas
RNA Mensageiro/genética
RNA Mensageiro/metabolismo
Receptor ErbB-2/genética
Receptor ErbB-2/metabolismo
Proteínas Recombinantes de Fusão/genética
Proteínas Recombinantes de Fusão/metabolismo
Proteínas Repressoras/genética
Proteínas Repressoras/metabolismo
Fatores de Transcrição/genética
Fatores de Transcrição/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Chromatin); 0 (Histocompatibility Antigens); 0 (Histones); 0 (Nuclear Proteins); 0 (RNA, Messenger); 0 (Recombinant Fusion Proteins); 0 (Repressor Proteins); 0 (Transcription Factors); 0 (ZFPM1 protein, human); 0 (ZNF350 protein, human); EC 2.1.1. (SUV39H1 protein, human); EC 2.1.1.- (Methyltransferases); EC 2.1.1.37 (DNA (Cytosine-5-)-Methyltransferases); EC 2.1.1.37 (DNA methyltransferase 3A); EC 2.1.1.43 (EHMT2 protein, human); EC 2.1.1.43 (Histone-Lysine N-Methyltransferase); EC 2.7.10.1 (ERBB2 protein, human); EC 2.7.10.1 (Receptor, ErbB-2); EC 3.1.- (Endonucleases)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171116
[Lr] Data última revisão:
171116
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171004
[St] Status:MEDLINE
[do] DOI:10.1093/nar/gkx578


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[PMID]:28953652
[Au] Autor:Lee J; Park BG; Jeong HS; Park YH; Kim S; Kim BS; Kim HJ; Huh KH; Jeong HJ; Kim YS
[Ad] Endereço:aDepartment of Transplantation Surgery, Severance Hospital, Yonsei University Health System bDepartment of Laboratory Medicine, Severance Hospital, Yonsei University Health System cDepartment of Pathology, Severance Hospital, Yonsei University Health System dDepartment of Nephrology, Severance Hospital, Yonsei University Health System eDepartment of Surgery, Yonsei University College of Medicine, Seoul, Republic of Korea.
[Ti] Título:Successful kidney transplantation across a positive complement-dependent cytotoxicity crossmatch by using C1q assay-directed, bortezomib-assisted desensitization: A case report.
[So] Source:Medicine (Baltimore);96(39):e8145, 2017 Sep.
[Is] ISSN:1536-5964
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:RATIONALE: Human leukocyte antigen (HLA) is the major immunologic barrier in kidney transplantation (KT). Various desensitization protocols to overcome the HLA barrier have increased the opportunity for transplantation in sensitized patients. In addition, technological advances in solid-phase assays have permitted more comprehensive assessment of donor-specific antibodies. Although various desensitization therapies and immunologic techniques have been developed, the final transplantation decision is still based on the classic complement-dependent cytotoxicity (CDC) crossmatch (XM) technique. Some patients who fail to achieve negative XM have lost their transplant opportunities, even after receiving sufficient desensitization therapies. PATIENT CONCERNS: A 57-year-old male with end-stage renal disease secondary to chronic glomerulonephritis was scheduled to have a second transplant from his son, but CDC XM was positive. DIAGNOSES: Initial CDC XM (Initial T-AHG 1:32) and flow-cytometry XM were positive. Anti-HLA-B59 donor specific antibody was detected by Luminex single antigen assay. INTERVENTIONS: Herein, we report a successful case of KT across a positive CDC XM (T-AHG 1:8 at the time of transplantation) by using C1q assay-directed, bortezomib-assisted desensitization. After confirming a negative conversion in the C1q donor-specific antibody, we decided to perform KT accepting a positive AHG-CDC XM of 1:8 at the time of transplantation. OUTCOMES: The posttransplant course was uneventful and a protocol biopsy at 3 months showed no evidence of rejection. The patient had excellent graft function at 12 months posttransplant. LESSONS: The results of XM test and solid-phase assay should be interpreted in the context of the individual patient.
[Mh] Termos MeSH primário: Dessensibilização Imunológica/métodos
Rejeição de Enxerto
Antígenos HLA-B/análise
Teste de Histocompatibilidade/métodos
Falência Renal Crônica
Transplante de Rim
[Mh] Termos MeSH secundário: Rejeição de Enxerto/imunologia
Rejeição de Enxerto/prevenção & controle
Antígenos de Histocompatibilidade/análise
Seres Humanos
Falência Renal Crônica/imunologia
Falência Renal Crônica/cirurgia
Transplante de Rim/efeitos adversos
Transplante de Rim/métodos
Masculino
Meia-Idade
Cuidados Pré-Operatórios/métodos
Resultado do Tratamento
[Pt] Tipo de publicação:CASE REPORTS; JOURNAL ARTICLE
[Nm] Nome de substância:
0 (HLA-B Antigens); 0 (HLA-B59 antigen); 0 (Histocompatibility Antigens)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171016
[Lr] Data última revisão:
171016
[Sb] Subgrupo de revista:AIM; IM
[Da] Data de entrada para processamento:170928
[St] Status:MEDLINE
[do] DOI:10.1097/MD.0000000000008145


  7 / 10627 MEDLINE  
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[PMID]:28902875
[Au] Autor:Meng Z; Klinngam W; Edman MC; Hamm-Alvarez SF
[Ad] Endereço:Department of Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Southern California, Los Angeles, California, United States of America.
[Ti] Título:Interferon-γ treatment in vitro elicits some of the changes in cathepsin S and antigen presentation characteristic of lacrimal glands and corneas from the NOD mouse model of Sjögren's Syndrome.
[So] Source:PLoS One;12(9):e0184781, 2017.
[Is] ISSN:1932-6203
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Inflammation and impaired secretion by lacrimal and salivary glands are hallmarks of the autoimmune disease, Sjögren's Syndrome. These changes in the lacrimal gland promote dryness and inflammation of the ocular surface, causing pain, irritation and corneal damage. The changes that initiate and sustain autoimmune inflammation in the lacrimal gland are not well-established. Here we demonstrate that interferon-γ (IFN-γ) is significantly elevated in lacrimal gland and tears of the male NOD mouse, a model of autoimmune dacryoadenitis which exhibits many ocular characteristics of Sjögren's Syndrome, by 12 weeks of age early in lacrimal gland inflammation. Working either with primary cultured lacrimal gland acinar cells from BALB/c mice and/or rabbits, in vitro IFN-γ treatment for 48 hr decreased expression of Rab3D concurrent with increased expression of cathepsin S. Although total cellular cathepsin S activity was not commensurately increased, IFN-γ treated lacrimal gland acinar cells showed a significant increase in carbachol-stimulated secretion of cathepsin S similar to the lacrimal gland in disease. In vitro IFN-γ treatment did not increase the expression of most components of major histocompatibility complex (MHC) class II-mediated antigen presentation although antigen presentation was slightly but significantly stimulated in primary cultured lacrimal gland acinar cells. However, exposure of cultured human corneal epithelial cells to IFN-γ more robustly increased expression and activity of cathepsin S in parallel with increased expression and function of MHC class II-mediated antigen presentation. We propose that early elevations in IFN-γ contribute to specific features of ocular disease pathology in Sjögren's Syndrome.
[Mh] Termos MeSH primário: Apresentação do Antígeno/efeitos dos fármacos
Catepsinas/metabolismo
Córnea/efeitos dos fármacos
Interferon gama/farmacologia
Aparelho Lacrimal/efeitos dos fármacos
[Mh] Termos MeSH secundário: Animais
Células Cultivadas
Córnea/metabolismo
Córnea/patologia
Antígenos de Histocompatibilidade/metabolismo
Antígenos de Histocompatibilidade/fisiologia
Seres Humanos
Interferon gama/metabolismo
Interferon gama/fisiologia
Aparelho Lacrimal/metabolismo
Aparelho Lacrimal/patologia
Complexo Principal de Histocompatibilidade/imunologia
Masculino
Camundongos
Camundongos Endogâmicos BALB C
Camundongos Endogâmicos NOD
Coelhos
Síndrome de Sjogren/imunologia
Síndrome de Sjogren/metabolismo
Síndrome de Sjogren/patologia
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Histocompatibility Antigens); 82115-62-6 (Interferon-gamma); EC 3.4.- (Cathepsins); EC 3.4.22.27 (cathepsin S)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171024
[Lr] Data última revisão:
171024
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170914
[St] Status:MEDLINE
[do] DOI:10.1371/journal.pone.0184781


  8 / 10627 MEDLINE  
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[PMID]:28803780
[Au] Autor:Ferry L; Fournier A; Tsusaka T; Adelmant G; Shimazu T; Matano S; Kirsh O; Amouroux R; Dohmae N; Suzuki T; Filion GJ; Deng W; de Dieuleveult M; Fritsch L; Kudithipudi S; Jeltsch A; Leonhardt H; Hajkova P; Marto JA; Arita K; Shinkai Y; Defossez PA
[Ad] Endereço:Epigenetics and Cell Fate, University Paris Diderot, Sorbonne Paris Cité, UMR 7216 CNRS, 75013 Paris, France.
[Ti] Título:Methylation of DNA Ligase 1 by G9a/GLP Recruits UHRF1 to Replicating DNA and Regulates DNA Methylation.
[So] Source:Mol Cell;67(4):550-565.e5, 2017 Aug 17.
[Is] ISSN:1097-4164
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:DNA methylation is an essential epigenetic mark in mammals that has to be re-established after each round of DNA replication. The protein UHRF1 is essential for this process; it has been proposed that the protein targets newly replicated DNA by cooperatively binding hemi-methylated DNA and H3K9me2/3, but this model leaves a number of questions unanswered. Here, we present evidence for a direct recruitment of UHRF1 by the replication machinery via DNA ligase 1 (LIG1). A histone H3K9-like mimic within LIG1 is methylated by G9a and GLP and, compared with H3K9me2/3, more avidly binds UHRF1. Interaction with methylated LIG1 promotes the recruitment of UHRF1 to DNA replication sites and is required for DNA methylation maintenance. These results further elucidate the function of UHRF1, identify a non-histone target of G9a and GLP, and provide an example of a histone mimic that coordinates DNA replication and DNA methylation maintenance.
[Mh] Termos MeSH primário: Proteínas Estimuladoras de Ligação a CCAAT/metabolismo
DNA Ligase Dependente de ATP/metabolismo
Metilação de DNA
Replicação do DNA
DNA/biossíntese
Epigênese Genética
Antígenos de Histocompatibilidade/metabolismo
Histona-Lisina N-Metiltransferase/metabolismo
Processamento de Proteína Pós-Traducional
[Mh] Termos MeSH secundário: Animais
Proteínas Estimuladoras de Ligação a CCAAT/química
Proteínas Estimuladoras de Ligação a CCAAT/genética
DNA/genética
DNA Ligase Dependente de ATP/química
DNA Ligase Dependente de ATP/genética
Células-Tronco Embrionárias/enzimologia
Células HEK293
Células HeLa
Antígenos de Histocompatibilidade/química
Antígenos de Histocompatibilidade/genética
Histona-Lisina N-Metiltransferase/química
Histona-Lisina N-Metiltransferase/genética
Histonas/metabolismo
Seres Humanos
Lisina
Metilação
Camundongos
Modelos Moleculares
Mimetismo Molecular
Mutação
Ligação Proteica
Conformação Proteica
Relação Estrutura-Atividade
Transfecção
Domínio Tudor
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (CCAAT-Enhancer-Binding Proteins); 0 (Histocompatibility Antigens); 0 (Histones); 0 (LIG1 protein, human); 0 (Lig1 protein, mouse); 0 (UHRF1 protein, human); 9007-49-2 (DNA); EC 2.1.1.43 (EHMT2 protein, human); EC 2.1.1.43 (Histone-Lysine N-Methyltransferase); EC 6.5.1.1 (DNA Ligase ATP); K3Z4F929H6 (Lysine)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:170925
[Lr] Data última revisão:
170925
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170815
[St] Status:MEDLINE


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[PMID]:28787001
[Au] Autor:Cheng CC; Chang J; Huang SC; Lin HC; Ho AS; Lim KH; Chang CC; Huang L; Chang YC; Chang YF; Wu CW
[Ad] Endereço:Division of Hematology and Oncology, Department of Internal Medicine, MacKay Memorial Hospital, Taipei, Taiwan.
[Ti] Título:YM155 as an inhibitor of cancer stemness simultaneously inhibits autophosphorylation of epidermal growth factor receptor and G9a-mediated stemness in lung cancer cells.
[So] Source:PLoS One;12(8):e0182149, 2017.
[Is] ISSN:1932-6203
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Cancer stem cell survival is the leading factor for tumor recurrence after tumor-suppressive treatments. Therefore, specific and efficient inhibitors of cancer stemness must be discovered for reducing tumor recurrence. YM155 has been indicated to significantly reduce stemness-derived tumorsphere formation. However, the pharmaceutical mechanism of YM155 against cancer stemness is unclear. This study investigated the potential mechanism of YM155 against cancer stemness in lung cancer. Tumorspheres derived from epidermal growth factor receptor (EGFR)-mutant HCC827 and EGFR wild-type A549 cells expressing higher cancer stemness markers (CD133, Oct4, and Nanog) were used as cancer stemness models. We observed that EGFR autophosphorylation (Y1068) was higher in HCC827- and A549-derived tumorspheres than in parental cells; this autophosphorylation induced tumorsphere formation by activating G9a-mediated stemness. Notably, YM155 inhibited tumorsphere formation by blocking the autophosphorylation of EGFR and the EGFR-G9a-mediated stemness pathway. The chemical and genetic inhibition of EGFR and G9a revealed the significant role of the EGFR-G9a pathway in maintaining the cancer stemness property. In conclusion, this study not only revealed that EGFR could trigger tumorsphere formation by elevating G9a-mediated stemness but also demonstrated that YM155 could inhibit this formation by simultaneously blocking EGFR autophosphorylation and G9a activity, thus acting as a potent agent against lung cancer stemness.
[Mh] Termos MeSH primário: Antineoplásicos/farmacologia
Antígenos de Histocompatibilidade/metabolismo
Histona-Lisina N-Metiltransferase/metabolismo
Imidazóis/farmacologia
Neoplasias Pulmonares/tratamento farmacológico
Neoplasias Pulmonares/metabolismo
Naftoquinonas/farmacologia
Receptor do Fator de Crescimento Epidérmico/metabolismo
[Mh] Termos MeSH secundário: Linhagem Celular Tumoral
Avaliação Pré-Clínica de Medicamentos
Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos
Regulação Neoplásica da Expressão Gênica/fisiologia
Histona-Lisina N-Metiltransferase/antagonistas & inibidores
Seres Humanos
Neoplasias Pulmonares/genética
Neoplasias Pulmonares/patologia
Metilação/efeitos dos fármacos
Fator 3 de Transcrição de Octâmero/metabolismo
Fosforilação/efeitos dos fármacos
Fosforilação/fisiologia
Quinazolinas/farmacologia
RNA Mensageiro/metabolismo
Receptor do Fator de Crescimento Epidérmico/genética
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Antineoplastic Agents); 0 (Histocompatibility Antigens); 0 (Imidazoles); 0 (Naphthoquinones); 0 (Octamer Transcription Factor-3); 0 (POU5F1 protein, human); 0 (Quinazolines); 0 (RNA, Messenger); 0 (UNC0642); 0 (YM 155); 41UD74L59M (afatinib); EC 2.1.1.- (EHMT1 protein, human); EC 2.1.1.43 (EHMT2 protein, human); EC 2.1.1.43 (Histone-Lysine N-Methyltransferase); EC 2.7.10.1 (EGFR protein, human); EC 2.7.10.1 (Receptor, Epidermal Growth Factor)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171004
[Lr] Data última revisão:
171004
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170809
[St] Status:MEDLINE
[do] DOI:10.1371/journal.pone.0182149


  10 / 10627 MEDLINE  
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[PMID]:28739157
[Au] Autor:Liu Q; Cai X; Yang D; Chen Y; Wang Y; Shao L; Wang MW
[Ad] Endereço:School of Pharmacy, Fudan University, Shanghai 201203, China; The CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China; The National Center for Drug Screening, Shanghai 201203, China.
[Ti] Título:Cycloalkane analogues of sinefungin as EHMT1/2 inhibitors.
[So] Source:Bioorg Med Chem;25(17):4579-4594, 2017 Sep 01.
[Is] ISSN:1464-3391
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:A series of cycloalkyl substituted analogues of the natural product sinefungin lacking the amino-acid moiety was designed and synthesized. Two stereoisomers (6-R and 6-S) were separated and their bioactivities examined against EHMT1/2. Of which, compound 14d showed an inhibitory activity against EHMT1/2 (88.9%, IC =21.8µM for EHMT1 and 77.6%, IC =39.6µM for EHMT2, respectively) similar to that of sinefungin (100.0%, IC =28.4µM for EHMT1 and 79.5%, IC =30.1µM for EHMT2, respectively). Further studies against other methyltransferases such as PRMT1 showed no activity except that 12d displayed about 20% inhibition.
[Mh] Termos MeSH primário: Adenosina/análogos & derivados
Inibidores Enzimáticos/química
Histona-Lisina N-Metiltransferase/antagonistas & inibidores
[Mh] Termos MeSH secundário: Adenosina/química
Adenosina/metabolismo
Adenosina/toxicidade
Alcanos/química
Linhagem Celular Tumoral
Proliferação Celular/efeitos dos fármacos
Inibidores Enzimáticos/metabolismo
Inibidores Enzimáticos/toxicidade
Antígenos de Histocompatibilidade/metabolismo
Histona-Lisina N-Metiltransferase/metabolismo
Seres Humanos
Concentração Inibidora 50
Relação Estrutura-Atividade
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (9-(5',6',7'-deoxy-6'-amine-7'-cyclopropylheptafuranoside-1')adenine); 0 (Alkanes); 0 (Enzyme Inhibitors); 0 (Histocompatibility Antigens); EC 2.1.1.- (EHMT1 protein, human); EC 2.1.1.43 (EHMT2 protein, human); EC 2.1.1.43 (Histone-Lysine N-Methyltransferase); K72T3FS567 (Adenosine); W2U467CIIL (sinefungin)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:170926
[Lr] Data última revisão:
170926
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170726
[St] Status:MEDLINE



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