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2.
Medicine (Baltimore) ; 99(34): e21900, 2020 Aug 21.
Artigo em Inglês | MEDLINE | ID: mdl-32846854

RESUMO

BACKGROUND: Gene mutations with important prognostic roles have been identified in patients with myelodysplastic syndrome (MDS). Overall, it is not yet fully clear whether enhancer of zeste homolog 2 (EZH2) is affected and contributes to the disease in MDS patients. Thus, we performed a meta-analysis to investigate the effects of EZH2 mutations on the prognosis of patients with MDS. METHODS: We searched English-language databases (PubMed, Embase, and Cochrane Library) for studies published on the effects of EZH2 mutations in MDS patients. The study had to include at least 1 of the following indices as therapeutic evaluation data: overall survival (OS), transformation time to leukemia, and International Prognostic Scoring System risk. Revman, version 5.2 software was used for all statistical processing. We calculated the risk ratio and the 95% confidence interval (CI) of continuous variables, and determined the hazard ratio and 95% CI of time-to-event data. RESULTS: We included 5 studies with a total enrolment of 994 patients. There was a significant adverse effect on OS in the EZH2-mutation group compared to the unmutated group (hazard ratio = 2.47, 95% CI: 1.37-4.47, P < .00001), while the heterogeneity was relatively high (I = 68%). There was no significant correlation between EZH2 mutations and IPSS risk (low/int-1 vs int-2/high) (odds ratio: 0.69, 95% CI: 0.14-3.39, P = .65), with significant heterogeneity (I = 78%). The analysis did not show significant publication bias in the studies. CONCLUSION: This meta-analysis indicated an adverse effect of EZH2 mutations with regard to OS in patients with MDS. However, larger cohort trials are still needed to better understand the prognostic impacts of EZH2 mutations on MDS patients.


Assuntos
Proteína Potenciadora do Homólogo 2 de Zeste/genética , Síndromes Mielodisplásicas/genética , Síndromes Mielodisplásicas/mortalidade , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Estudos de Casos e Controles , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Mutação , Síndromes Mielodisplásicas/patologia , Razão de Chances , Prognóstico , Análise de Sobrevida , Adulto Jovem
3.
Zhongguo Shi Yan Xue Ye Xue Za Zhi ; 28(3): 855-860, 2020 Jun.
Artigo em Chinês | MEDLINE | ID: mdl-32552947

RESUMO

OBJECTIVE: To explore the expression and clinical significance of EZH2 in DLBCL patients accompanied by HBV infection. METHODS: The clinicopathological data of 59 patients with DLBCL accompanied by HBV infection in our hospital from February 2015 to October 2017 were analyzed retrospectively. The patients were divided into HBV negative and HBV positive groups by serological testing before surgery. The expression of EZH2 was detected by immumohistochemical staining, and the clinicopathological characteristics and survival were analyzed and compared between these two groups. RESULTS: There were 30 patients (50.8%) in the HBV negative group and 29 patients (49.2%)in the HBV positive group. The differences of age, LDH level and IPI score between two groups were statistically significant (P<0.05). The expression of EZH2 in HBV- positive group was significantly higher than that in the HBV- negative group (P<0.05), where the expression of EZH2 correlated with the expression of the BCL-6 (r=0.282, P<0.05), especially in the GCB-DLBCL (r=0.549, P<0.05). PFS was not significantly different between two groups of HBV (P>0.05), while the PFS in the R-CHOP regimen group was higher than that in the CHOP regimen group (P<0.05). COX multivariate analysis showed that both the chemotherapy regimen without R and the increased level of LDH were the risk factors affecting the prognosis of DLBCL patients (P<0.05). CONCLUSION: EZH2 highly expresses in HBV positive group, suggesting that the significance of EZH2 in DLBCL with HBV infection is worth further explore.


Assuntos
Proteína Potenciadora do Homólogo 2 de Zeste/genética , Vírus da Hepatite B , Hepatite B/complicações , Linfoma Difuso de Grandes Células B , Protocolos de Quimioterapia Combinada Antineoplásica , Ciclofosfamida , Doxorrubicina , Humanos , Linfoma Difuso de Grandes Células B/complicações , Linfoma Difuso de Grandes Células B/genética , Prognóstico , Estudos Retrospectivos , Rituximab , Vincristina
4.
Nat Rev Nephrol ; 16(8): 435-451, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32561872

RESUMO

The treatment landscape of metastatic renal cell carcinoma (RCC) has been revolutionized over the past two decades, bringing forth an era in which more than a dozen therapeutic agents are now available to treat patients. As a consequence, personalized care has become a critical part of developing effective treatment guidelines and improving patient outcomes. One of the most important emerging aspects of precision medicine in cancer is matching patients and treatments based on the genomic characteristics of an individual and their tumour. Despite the lack of a single genomic predictor of treatment response or prognostication feature in RCC, emerging research suggests that the identification of such markers remains promising. Mutations in VHL and alterations in its downstream pathways are the mainstay of RCC development and progression. However, the predictive value of VHL mutations has been questioned. Further research has examined mutations in genes involved in chromosome remodelling (for example, PBRM1, BAP1 and SETD2), DNA methylation and DNA damage repair, all of which have been associated with clinical outcomes. Here, we provide a comprehensive overview of genomic evidence in the context of RCC and its potential predictive and prognostic value.


Assuntos
Antineoplásicos/uso terapêutico , Carcinoma de Células Renais/genética , Genômica , Neoplasias Renais/genética , Inibidores da Angiogênese/uso terapêutico , Antineoplásicos Imunológicos/uso terapêutico , Carcinoma de Células Renais/tratamento farmacológico , Carcinoma de Células Renais/patologia , Metilação de DNA/genética , Reparo do DNA/genética , Proteínas de Ligação a DNA/genética , Proteína Potenciadora do Homólogo 2 de Zeste/genética , Histona-Lisina N-Metiltransferase/genética , Humanos , Neoplasias Renais/tratamento farmacológico , Neoplasias Renais/patologia , Terapia de Alvo Molecular , Neurofibromina 2/genética , PTEN Fosfo-Hidrolase/genética , Medicina de Precisão , Prognóstico , Inibidores de Proteínas Quinases/uso terapêutico , Proteínas Proto-Oncogênicas c-met/genética , Telomerase/genética , Fatores de Transcrição/genética , Transcriptoma , Proteína Supressora de Tumor p53/genética , Proteínas Supressoras de Tumor/genética , Ubiquitina Tiolesterase/genética , Proteína Supressora de Tumor Von Hippel-Lindau/genética
5.
Brain Tumor Pathol ; 37(3): 81-88, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32529280

RESUMO

The objective of this study is to clarify clinical significance of the H3F3A K27M mutation (H3K27M) and analyze the correlation between H3K27M, H3K27me3 status, and EZH2 expression and prognosis in spinal cord gliomas. Patients with spinal cord diffuse glioma regardless of World Health Organization (WHO) grade underwent genetic analysis for H3F3A, HIST1H3B, TERT promoter, IDH1/2, and BRAF. H3K27me3 status and EZH2 expression were analyzed through immunohistochemistry. Thereafter, the association between H3K27M, H3K27me3 status, and EZH2 expression and prognosis was retrospectively analyzed using the log-rank test. A total of 26 cases, 5 with WHO grade 4, 9 with grade 3, and 12 with grade 2 glioma, were analyzed. Although WHO grade 2 cases tended to present favorable overall survival, the difference was not statistically significant. H3K27M, which was detected in four grade 4 cases (80%) and three grade 3 cases (33%), was not associated with prognosis among grade 3 and 4 cases. Among WHO grade 2-4 cases, the combination of retained H3K27me3 and negative EZH2 expression was correlated with favorable overall survival (p = 0.03). The combination of H3K27me3 status and EZH2 expression was considered as a potential prognostic marker in WHO grade 2-4 diffuse spinal cord gliomas.


Assuntos
Proteína Potenciadora do Homólogo 2 de Zeste/genética , Proteína Potenciadora do Homólogo 2 de Zeste/metabolismo , Expressão Gênica , Glioma/genética , Histonas/metabolismo , Mutação de Sentido Incorreto , Neoplasias da Medula Espinal/genética , Glioma/terapia , Histonas/genética , Humanos , Metilação , Prognóstico , Estudos Retrospectivos , Neoplasias da Medula Espinal/terapia
6.
PLoS Genet ; 16(5): e1008796, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32428001

RESUMO

Sex differences in the incidence and progression of many liver diseases, including liver fibrosis and hepatocellular carcinoma, are associated with sex-biased hepatic expression of hundreds of genes. This sexual dimorphism is largely determined by the sex-specific pattern of pituitary growth hormone secretion, which controls a transcriptional regulatory network operative in the context of sex-biased and growth hormone-regulated chromatin states. Histone H3K27-trimethylation yields a major sex-biased repressive chromatin mark deposited at many strongly female-biased genes in male mouse liver, but not at male-biased genes in female liver, and is catalyzed by polycomb repressive complex-2 through its homologous catalytic subunits, Ezh1 and Ezh2. Here, we used Ezh1-knockout mice with a hepatocyte-specific knockout of Ezh2 to investigate the sex bias of liver H3K27-trimethylation and its functional role in regulating sex-differences in the liver. Combined hepatic Ezh1/Ezh2 deficiency led to a significant loss of sex-biased gene expression, particularly in male liver, where many female-biased genes were increased in expression while male-biased genes showed decreased expression. The associated loss of H3K27me3 marks, and increases in the active enhancer marks H3K27ac and H3K4me1, were also more pronounced in male liver. Further, Ezh1/Ezh2 deficiency in male liver, and to a lesser extent in female liver, led to up regulation of many genes linked to liver fibrosis and liver cancer, which may contribute to the observed liver pathologies and the increased sensitivity of these mice to hepatotoxin exposure. Thus, Ezh1/Ezh2-catalyzed H3K27-trimethyation regulates sex-dependent genetic programs in liver metabolism and liver fibrosis through its sex-dependent effects on the epigenome, and may thereby determine the sex-bias in liver disease susceptibility.


Assuntos
Proteína Potenciadora do Homólogo 2 de Zeste/genética , Cirrose Hepática/genética , Fígado/metabolismo , Complexo Repressor Polycomb 2/genética , Animais , Modelos Animais de Doenças , Proteína Potenciadora do Homólogo 2 de Zeste/metabolismo , Feminino , Perfilação da Expressão Gênica , Regulação da Expressão Gênica , Técnicas de Inativação de Genes , Histonas/metabolismo , Cirrose Hepática/metabolismo , Masculino , Metilação , Camundongos , Complexo Repressor Polycomb 2/metabolismo , Análise de Sequência de RNA , Caracteres Sexuais
7.
Mol Cell ; 78(3): 506-521.e6, 2020 05 07.
Artigo em Inglês | MEDLINE | ID: mdl-32386543

RESUMO

Higher-order chromatin structure and DNA methylation are implicated in multiple developmental processes, but their relationship to cell state is unknown. Here, we find that large (>7.3 kb) DNA methylation nadirs (termed "grand canyons") can form long loops connecting anchor loci that may be dozens of megabases (Mb) apart, as well as inter-chromosomal links. The interacting loci cover a total of ∼3.5 Mb of the human genome. The strongest interactions are associated with repressive marks made by the Polycomb complex and are diminished upon EZH2 inhibitor treatment. The data are suggestive of the formation of these loops by interactions between repressive elements in the loci, forming a genomic subcompartment, rather than by cohesion/CTCF-mediated extrusion. Interestingly, unlike previously characterized subcompartments, these interactions are present only in particular cell types, such as stem and progenitor cells. Our work reveals that H3K27me3-marked large DNA methylation grand canyons represent a set of very-long-range loops associated with cellular identity.


Assuntos
Cromatina/química , Cromatina/genética , Metilação de DNA , Células-Tronco Hematopoéticas/citologia , Células-Tronco Hematopoéticas/fisiologia , Fator de Ligação a CCCTC/genética , Fator de Ligação a CCCTC/metabolismo , Diferenciação Celular , Cromatina/metabolismo , Proteína Potenciadora do Homólogo 2 de Zeste/genética , Proteína Potenciadora do Homólogo 2 de Zeste/metabolismo , Epigênese Genética , Regulação da Expressão Gênica , Histonas/genética , Histonas/metabolismo , Proteínas de Homeodomínio/genética , Humanos , Hibridização in Situ Fluorescente , Lisina/genética , Lisina/metabolismo , Proteínas Nucleares/genética , Fatores de Transcrição SOXB1/genética , Proteína de Homoeobox de Baixa Estatura/genética , Fatores de Transcrição/genética
8.
Cancer Cell ; 37(5): 655-673.e11, 2020 05 11.
Artigo em Inglês | MEDLINE | ID: mdl-32396861

RESUMO

Follicular lymphomas (FLs) are slow-growing, indolent tumors containing extensive follicular dendritic cell (FDC) networks and recurrent EZH2 gain-of-function mutations. Paradoxically, FLs originate from highly proliferative germinal center (GC) B cells with proliferation strictly dependent on interactions with T follicular helper cells. Herein, we show that EZH2 mutations initiate FL by attenuating GC B cell requirement for T cell help and driving slow expansion of GC centrocytes that become enmeshed with and dependent on FDCs. By impairing T cell help, mutant EZH2 prevents induction of proliferative MYC programs. Thus, EZH2 mutation fosters malignant transformation by epigenetically reprograming B cells to form an aberrant immunological niche that reflects characteristic features of human FLs, explaining how indolent tumors arise from GC B cells.


Assuntos
Linfócitos B/imunologia , Transformação Celular Neoplásica/imunologia , Reprogramação Celular , Proteína Potenciadora do Homólogo 2 de Zeste/genética , Linfoma de Células B/imunologia , Linfoma Folicular/imunologia , Mutação , Animais , Linfócitos B/metabolismo , Linfócitos B/patologia , Transformação Celular Neoplásica/genética , Transformação Celular Neoplásica/patologia , Células Dendríticas/imunologia , Células Dendríticas/metabolismo , Células Dendríticas/patologia , Feminino , Centro Germinativo/imunologia , Centro Germinativo/metabolismo , Centro Germinativo/patologia , Humanos , Linfoma de Células B/genética , Linfoma de Células B/patologia , Linfoma Folicular/genética , Linfoma Folicular/patologia , Camundongos , Camundongos Endogâmicos C57BL
9.
Exp Hematol ; 85: 57-69, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32437908

RESUMO

Inhibition of the H3K79 histone methyltransferase DOT1L has exhibited encouraging preclinical and early clinical activity in KMT2A (MLL)-rearranged leukemia, supporting the development of combinatorial therapies. Here, we investigated two novel combinations: dual inhibition of the histone methyltransferases DOT1L and EZH2, and the combination with a protein synthesis inhibitor. EZH2 is the catalytic subunit in the polycomb repressive complex 2 (PRC2), and inhibition of EZH2 has been reported to have preclinical activity in KMT2A-r leukemia. When combined with DOT1L inhibition, however, we observed both synergistic and antagonistic effects. Interestingly, antagonistic effects were not due to PRC2-mediated de-repression of HOXA9. HOXA cluster genes are key canonical targets of both KMT2A and the PRC2 complex. The independence of the HOXA cluster from PRC2 repression in KMT2A-r leukemia thus affords important insights into leukemia biology. Further studies revealed that EZH2 inhibition counteracted the effect of DOT1L inhibition on ribosomal gene expression. We thus identified a previously unrecognized role of DOT1L in regulating protein production. Decreased translation was one of the earliest effects measurable after DOT1L inhibition and specific to KMT2A-rearranged cell lines. H3K79me2 chromatin immunoprecipitation sequencing patterns over ribosomal genes were similar to those of the canonical KMT2A-fusion target genes in primary AML patient samples. The effects of DOT1L inhibition on ribosomal gene expression prompted us to evaluate the combination of EPZ5676 with a protein translation inhibitor. EPZ5676 was synergistic with the protein translation inhibitor homoharringtonine (omacetaxine), supporting further preclinical/clinical development of this combination. In summary, we discovered a novel epigenetic regulation of a metabolic process-protein synthesis-that plays a role in leukemogenesis and affords a combinatorial therapeutic opportunity.


Assuntos
Epigênese Genética , Regulação Leucêmica da Expressão Gênica , Rearranjo Gênico , Leucemia Mieloide Aguda/metabolismo , Biossíntese de Proteínas , Linhagem Celular Tumoral , Proteína Potenciadora do Homólogo 2 de Zeste/antagonistas & inibidores , Proteína Potenciadora do Homólogo 2 de Zeste/genética , Proteína Potenciadora do Homólogo 2 de Zeste/metabolismo , Histona-Lisina N-Metiltransferase/antagonistas & inibidores , Histona-Lisina N-Metiltransferase/genética , Histona-Lisina N-Metiltransferase/metabolismo , Proteínas de Homeodomínio/genética , Proteínas de Homeodomínio/metabolismo , Humanos , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/patologia , Proteína de Leucina Linfoide-Mieloide/antagonistas & inibidores , Proteína de Leucina Linfoide-Mieloide/genética , Complexo Repressor Polycomb 2/genética , Complexo Repressor Polycomb 2/metabolismo
10.
Cancer Res ; 80(13): 2737-2750, 2020 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-32312833

RESUMO

Aberrant activation of histone methyltransferase EZH2 and ribosome synthesis strongly associate with cancer development and progression. We previously found that EZH2 regulates RNA polymerase III-transcribed 5S ribosomal RNA gene transcription. However, whether EZH2 regulates ribosome synthesis is still unknown. Here, we report that EZH2 promotes ribosome synthesis by targeting and silencing a long noncoding RNA PHACTR2-AS1. PHACTR2-AS1 directly bound ribosome DNA genes and recruited histone methyltransferase SUV39H1, which in turn triggered H3K9 methylation of these genes. Depletion of PHACTR2-AS1 resulted in hyperactivation of ribosome synthesis and instability of ribosomal DNA, which promoted cancer cell proliferation and metastasis. Administration of PHACTR2-AS1-30nt-RNA, which binds to SUV39H1, effectively inhibited breast cancer growth and lung metastasis in mice. PHACTR2-AS1 was downregulated in breast cancer patients, where lower PHACTR2-AS1 expression promoted breast cancer development and correlated with poor patient outcome. Taken together, we demonstrate that PHACTR2-AS1 maintains a H3K9 methylation-marked silent state of ribosomal DNA genes, comprising a regulatory axis that controls breast cancer growth and metastasis. SIGNIFICANCE: These findings reveal that EZH2 mediates ribosomal DNA stability via silencing of PHACTR2-AS1, representing a potential therapeutic target to control breast cancer growth and metastasis.


Assuntos
Biomarcadores Tumorais/metabolismo , Neoplasias da Mama/patologia , Proteína Potenciadora do Homólogo 2 de Zeste/metabolismo , Instabilidade Genômica , Neoplasias Pulmonares/secundário , RNA Longo não Codificante/genética , Ribossomos/metabolismo , Animais , Apoptose , Biomarcadores Tumorais/genética , Neoplasias da Mama/genética , Neoplasias da Mama/metabolismo , Proliferação de Células , Progressão da Doença , Proteína Potenciadora do Homólogo 2 de Zeste/genética , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Camundongos , Camundongos Endogâmicos NOD , Camundongos SCID , Proteínas dos Microfilamentos/antagonistas & inibidores , Proteínas do Tecido Nervoso/antagonistas & inibidores , Prognóstico , RNA Antissenso/genética , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de Xenoenxerto
11.
Cell ; 181(2): 211, 2020 04 16.
Artigo em Inglês | MEDLINE | ID: mdl-32302562

RESUMO

Tazemetostat is the first epigenetic therapy to gain FDA approval in a solid tumor. This lysine methyltransferase inhibitor targets EZH2, the enzymatic subunit of the PRC2 transcriptional silencing complex. Tumors with mutations in subunits of the SWI/SNF chromatin remodeling complex, inclusive of most epithelioid sarcomas, are sensitive to EZH2 inhibition.


Assuntos
Benzamidas/uso terapêutico , Epigênese Genética/genética , Piridonas/uso terapêutico , Sarcoma/tratamento farmacológico , Linhagem Celular Tumoral , Montagem e Desmontagem da Cromatina , DNA Helicases/metabolismo , Proteína Potenciadora do Homólogo 2 de Zeste/efeitos dos fármacos , Proteína Potenciadora do Homólogo 2 de Zeste/genética , Inibidores Enzimáticos/farmacologia , Epigenômica , Terapia Genética/métodos , Humanos , Proteínas Nucleares/metabolismo , Sarcoma/genética , Fatores de Transcrição/metabolismo
12.
Anticancer Res ; 40(4): 2133-2139, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32234906

RESUMO

BACKGROUND/AIM: Metaplastic breast carcinoma (MBC) is a rare malignancy, which is often triple-negative for the hormone receptors and human epidermal growth factor receptor 2, and thus, does not benefit from targeted therapy. In this study, we examined the expression of methylation and demethylation enzymes by immunostaining MBC and the adjacent normal tissues or triple-negative ductal carcinoma (TNDC), and identified alterations that may be used as therapeutic targets. MATERIALS AND METHODS: We retrospectively studied surgical specimens from 15 patients who underwent surgery for MBC at Kanagawa Cancer Center between 2005 and 2016, and similarly from 14 patients with TNDC. The frequencies of high methylation/demethylation enzyme expression were compared among them. RESULTS: The frequencies of high enhancer of zeste homolog 2 (EZH2) and multiple myeloma SET domain (MMSET) expression were significantly higher in both MBC and TNDC than in normal tissue. CONCLUSION: EZH2 and MMSET may be useful therapeutic targets in MBC.


Assuntos
Neoplasias da Mama/genética , Proteína Potenciadora do Homólogo 2 de Zeste/genética , Histona-Lisina N-Metiltransferase/genética , Metaplasia/genética , Proteínas Repressoras/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais/genética , Neoplasias da Mama/diagnóstico , Neoplasias da Mama/patologia , Intervalo Livre de Doença , Feminino , Humanos , Metaplasia/diagnóstico , Metaplasia/patologia , Pessoa de Meia-Idade , Recidiva Local de Neoplasia , Prognóstico , Receptor ErbB-2/genética , Receptores Estrogênicos/genética , Receptores de Progesterona/genética
13.
Am J Hum Genet ; 106(5): 596-610, 2020 05 07.
Artigo em Inglês | MEDLINE | ID: mdl-32243864

RESUMO

Weaver syndrome (WS), an overgrowth/intellectual disability syndrome (OGID), is caused by pathogenic variants in the histone methyltransferase EZH2, which encodes a core component of the Polycomb repressive complex-2 (PRC2). Using genome-wide DNA methylation (DNAm) data for 187 individuals with OGID and 969 control subjects, we show that pathogenic variants in EZH2 generate a highly specific and sensitive DNAm signature reflecting the phenotype of WS. This signature can be used to distinguish loss-of-function from gain-of-function missense variants and to detect somatic mosaicism. We also show that the signature can accurately classify sequence variants in EED and SUZ12, which encode two other core components of PRC2, and predict the presence of pathogenic variants in undiagnosed individuals with OGID. The discovery of a functionally relevant signature with utility for diagnostic classification of sequence variants in EZH2, EED, and SUZ12 supports the emerging paradigm shift for implementation of DNAm signatures into diagnostics and translational research.


Assuntos
Anormalidades Múltiplas/genética , Hipotireoidismo Congênito/genética , Anormalidades Craniofaciais/genética , Metilação de DNA , Proteína Potenciadora do Homólogo 2 de Zeste/genética , Deformidades Congênitas da Mão/genética , Deficiência Intelectual/genética , Mutação , Complexo Repressor Polycomb 2/genética , Adolescente , Adulto , Criança , Pré-Escolar , Estudos de Coortes , Feminino , Humanos , Lactente , Masculino , Mosaicismo , Mutação de Sentido Incorreto/genética , Reprodutibilidade dos Testes , Adulto Jovem
14.
Sci Adv ; 6(10): eaay4768, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-32181346

RESUMO

When self-renewing pluripotent cells receive a differentiation signal, ongoing cell duplication needs to be coordinated with entry into a differentiation program. Accordingly, transcriptional activation of lineage specifier genes and cell differentiation is confined to the G1 phase of the cell cycle by unknown mechanisms. We found that Polycomb repressive complex 2 (PRC2) subunits are differentially recruited to lineage specifier gene promoters across cell cycle in mouse embryonic stem cells (mESCs). Jarid2 and the catalytic subunit Ezh2 are markedly accumulated at target promoters during S and G2 phases, while the transcriptionally activating subunits EPOP and EloB are enriched during G1 phase. Fluctuations in the recruitment of PRC2 subunits promote changes in RNA synthesis and RNA polymerase II binding that are compromised in Jarid2 -/- mESCs. Overall, we show that differential recruitment of PRC2 subunits across cell cycle enables the establishment of a chromatin state that facilitates the induction of cell differentiation in G1 phase.


Assuntos
Ciclo Celular/genética , Cromatina/química , Proteína Potenciadora do Homólogo 2 de Zeste/genética , Regulação da Expressão Gênica no Desenvolvimento , Células-Tronco Embrionárias Murinas/metabolismo , Complexo Repressor Polycomb 2/genética , Animais , Diferenciação Celular , Linhagem Celular Transformada , Cromatina/metabolismo , Elonguina/genética , Elonguina/metabolismo , Proteína Potenciadora do Homólogo 2 de Zeste/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Células-Tronco Embrionárias Murinas/citologia , Complexo Repressor Polycomb 2/deficiência , Regiões Promotoras Genéticas , Ligação Proteica , Subunidades Proteicas/genética , Subunidades Proteicas/metabolismo , RNA Polimerase II/genética , RNA Polimerase II/metabolismo , Transdução de Sinais , Transcrição Genética
15.
Cancer Sci ; 111(5): 1582-1595, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32129914

RESUMO

Metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) is an oncogenic long noncoding RNA that has been found to promote carcinogenesis and metastasis in many tumors. However, the underlying role of MALAT1 in the progression and metastasis of hepatocellular carcinoma (HCC) remains unclear. In this study, aberrantly elevated levels of MALAT1 were detected in both HCC specimens and cell lines. We found that knockdown of MALAT1 caused retardation in proliferation, migration, and invasion both in vivo and in vitro. Mechanistic investigations showed that Snail family transcriptional repressor 1 (SNAI1) is a direct target of microRNA (miR)-22 and that MALAT1 modulates SNAI1 expression by acting as a competing endogenous RNA for miR-22. Inhibition of miR-22 restored SNAI1 expression suppressed by MALAT1 knockdown. Furthermore, MALAT1 facilitated the enrichment of enhancer of zeste homolog 2 (EZH2) at the promoter region of miR-22 and E-cadherin, which was repressed by MALAT1 knockdown. Cooperating with EZH2, MALAT1 positively regulated SNAI1 by repressing miR-22 and inhibiting E-cadherin expression, playing a vital role in epithelial to mesenchymal transition. In conclusion, our results reveal a mechanism by which MALAT1 promotes HCC progression and provides a potential target for HCC therapy.


Assuntos
Carcinoma Hepatocelular/patologia , Proteína Potenciadora do Homólogo 2 de Zeste/genética , Neoplasias Hepáticas/patologia , MicroRNAs/genética , RNA Longo não Codificante/genética , Fatores de Transcrição da Família Snail/genética , Animais , Antígenos CD/genética , Sítios de Ligação , Caderinas/genética , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/metabolismo , Linhagem Celular Tumoral , Movimento Celular , Proliferação de Células , Progressão da Doença , Proteína Potenciadora do Homólogo 2 de Zeste/metabolismo , Transição Epitelial-Mesenquimal/genética , Feminino , Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Técnicas de Silenciamento de Genes , Células Hep G2 , Humanos , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/metabolismo , Camundongos , Camundongos Nus , MicroRNAs/antagonistas & inibidores , MicroRNAs/metabolismo , Regiões Promotoras Genéticas , Fatores de Transcrição da Família Snail/metabolismo
16.
Cancer Res ; 80(11): 2273-2285, 2020 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-32098781

RESUMO

Lung metastasis is a major factor affecting long-term survival in patients with adenoid cystic carcinoma. Here, we showed that the long noncoding RNA (lncRNA) MRPL23 antisense RNA 1 (MRPL23-AS1) was highly expressed and correlated with lung metastasis and overall survival in patients with salivary adenoid cystic carcinoma (SACC). MRPL23-AS1 positively regulated epithelial-mesenchymal transition by forming an RNA-protein complex with enhancer of zeste homolog 2 (EZH2). MRPL23-AS1 increased the binding of EZH2 and H3K27me3 on the E-cadherin promoter region. Moreover, MRPL23-AS1 levels were higher in exosomes isolated from the blood plasma of patients with SACC, and exosomal MRPL23-AS1 affected pulmonary microvascular endothelial cells in an "exosomecrine" manner. MRPL23-AS1-enriched exosomes increased microvascular permeability and facilitated the metastasis of SACC in vivo. Collectively, these findings highlight a molecular mechanism of lung metastasis in SACC. MRPL23-AS1 may represent a biomarker and target for clinical intervention to control this intractable disease. SIGNIFICANCE: This study identifies a novel metastasis-promoting lncRNA MRPL23-AS1, which mediates the transcriptional silencing of E-cadherin through forming an RNA-protein complex with EZH2.


Assuntos
Carcinoma Adenoide Cístico/genética , Neoplasias Pulmonares/genética , RNA Antissenso/genética , RNA Longo não Codificante/genética , Proteínas de Ligação a RNA/genética , Proteínas Ribossômicas/genética , Neoplasias das Glândulas Salivares/genética , Animais , Antígenos CD/biossíntese , Antígenos CD/genética , Caderinas/biossíntese , Caderinas/genética , Carcinoma Adenoide Cístico/metabolismo , Carcinoma Adenoide Cístico/patologia , Proteína Potenciadora do Homólogo 2 de Zeste/genética , Proteína Potenciadora do Homólogo 2 de Zeste/metabolismo , Exoma , Humanos , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/secundário , Camundongos , Camundongos Endogâmicos NOD , Camundongos SCID , RNA Antissenso/metabolismo , Proteínas de Ligação a RNA/metabolismo , Proteínas Ribossômicas/metabolismo , Neoplasias das Glândulas Salivares/metabolismo , Neoplasias das Glândulas Salivares/patologia , Microambiente Tumoral , Regulação para Cima
17.
Sci Rep ; 10(1): 2706, 2020 02 17.
Artigo em Inglês | MEDLINE | ID: mdl-32066746

RESUMO

TET2 and EZH2 play important roles in the epigenetic regulation in many cancers. However, their specific roles in acute myeloid leukemia (AML) pathogenesis remain unknown. Here, the expression, methylation or mutation of EZH2 and TET2 was determined and further correlated with the levels of the chromosome instability (CIN) genes MAD2 and CDC20. We down-regulated EZH2 and TET2 in AML cell lines and assessed the effect on CIN using fluorescence in situ hybridization (FISH). Our results showed that TET2, EZH2, MAD2 and CDC20 were aberrantly expressed in AML patients. The expression level of MAD2 or CDC20 was positively correlated with that of TET2 or EZH2. Hypermethylation of the TET2 gene down-regulated its transcription. Down-regulation of EZH2 or TET2 expression inhibited apoptosis, affected MAD2 and CDC20 expression, and promoted CIN in AML cells. Decitabine treatment restored TET2 methylation and EZH2 transcription and ameliorated CIN in AML. Therefore, TET2 and EZH2 play a tumor-inhibiting role in AML that affects CIN via MAD2 and CDC20.


Assuntos
Proteínas Cdc20/genética , Instabilidade Cromossômica , Proteínas de Ligação a DNA/genética , Proteína Potenciadora do Homólogo 2 de Zeste/genética , Regulação Leucêmica da Expressão Gênica , Leucemia Mieloide Aguda/genética , Proteínas Mad2/genética , Proteínas Proto-Oncogênicas/genética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Antimetabólitos Antineoplásicos/uso terapêutico , Proteínas Cdc20/metabolismo , Linhagem Celular Tumoral , Cromossomos Humanos , Metilação de DNA , Proteínas de Ligação a DNA/antagonistas & inibidores , Proteínas de Ligação a DNA/metabolismo , Decitabina/uso terapêutico , Proteína Potenciadora do Homólogo 2 de Zeste/antagonistas & inibidores , Proteína Potenciadora do Homólogo 2 de Zeste/metabolismo , Epigênese Genética , Feminino , Humanos , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia Mieloide Aguda/metabolismo , Leucemia Mieloide Aguda/patologia , Proteínas Mad2/metabolismo , Masculino , Pessoa de Meia-Idade , Proteínas Proto-Oncogênicas/antagonistas & inibidores , Proteínas Proto-Oncogênicas/metabolismo , RNA Interferente Pequeno/genética , RNA Interferente Pequeno/metabolismo , Indução de Remissão , Transcrição Genética
18.
Mol Cell ; 78(1): 141-151.e5, 2020 04 02.
Artigo em Inglês | MEDLINE | ID: mdl-32027840

RESUMO

Polycomb repressive complex 2 (PRC2) places H3K27me3 at developmental genes and is causally implicated in keeping bivalent genes silent. It is unclear if that silence requires minimum H3K27me3 levels and how the mark transmits faithfully across mammalian somatic cell generations. Mouse intestinal cells lacking EZH2 methyltransferase reduce H3K27me3 proportionately at all PRC2 target sites, but ∼40% uniform residual levels keep target genes inactive. These genes, derepressed in PRC2-null villus cells, remain silent in intestinal stem cells (ISCs). Quantitative chromatin immunoprecipitation and computational modeling indicate that because unmodified histones dilute H3K27me3 by 50% each time DNA replicates, PRC2-deficient ISCs initially retain sufficient H3K27me3 to avoid gene derepression. EZH2 mutant human lymphoma cells also require multiple divisions before H3K27me3 dilution relieves gene silencing. In both cell types, promoters with high basal H3K4me2/3 activate in spite of some residual H3K27me3, compared to less-poised promoters. These findings have implications for PRC2 inhibition in cancer therapy.


Assuntos
Replicação do DNA , Proteína Potenciadora do Homólogo 2 de Zeste/fisiologia , Inativação Gênica , Código das Histonas , Regiões Promotoras Genéticas , Animais , Linhagem Celular Tumoral , Proteína Potenciadora do Homólogo 2 de Zeste/genética , Histonas/metabolismo , Humanos , Intestinos/citologia , Camundongos , Complexo Repressor Polycomb 2/metabolismo , Receptores Acoplados a Proteínas-G/metabolismo , Células-Tronco/metabolismo , Ativação Transcricional
19.
Int J Clin Oncol ; 25(3): 419-424, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-32020380

RESUMO

Ovarian clear cell carcinoma (OCCC) is a histological subtype of epithelial ovarian carcinoma prevalent in Asians. No clear therapeutic selection based on molecular profile has been implemented for this disease. Oncogenic PIK3CA mutation, which activates the PIK3CA/AKT/mTOR signaling pathway, is a promising druggable alteration in OCCC. Recent studies by our group and others have identified the ARID1A mutation as another alteration linked to therapeutic selection based on synthetic lethality: deleterious ARID1A mutations, resulting in ARID1A deficiency, make OCCC cells sensitive to drugs targeting poly (ADP-ribose) polymerase and EZH2, as well as to glutathione inhibitors. In addition, we recently obtained evidence that ARID1A-deficient OCCC could benefit from gemcitabine treatment. Precision medicine based on gene alteration profiling might improve the prognosis of OCCC patients.


Assuntos
Adenocarcinoma de Células Claras/tratamento farmacológico , Adenocarcinoma de Células Claras/genética , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias Ovarianas/genética , Medicina de Precisão/métodos , Adenocarcinoma de Células Claras/patologia , Antimetabólitos Antineoplásicos/farmacologia , Classe I de Fosfatidilinositol 3-Quinases/genética , Classe I de Fosfatidilinositol 3-Quinases/metabolismo , Proteínas de Ligação a DNA/genética , Desoxicitidina/análogos & derivados , Desoxicitidina/farmacologia , Proteína Potenciadora do Homólogo 2 de Zeste/genética , Proteína Potenciadora do Homólogo 2 de Zeste/metabolismo , Feminino , Dosagem de Genes , Glutationa/antagonistas & inibidores , Humanos , Terapia de Alvo Molecular/métodos , Mutação , Neoplasias Ovarianas/patologia , Fatores de Transcrição/genética
20.
Trends Immunol ; 41(3): 187-189, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-32061543

RESUMO

To keep autoreactive T cells under control in SLE patients, immunosuppressive regimens are used, which can increase susceptibility to bacterial and viral infections. Recently, Katsuyama et al., demonstrated that the CD38/NAD/Sirtuin1/EZH2 axis reduces cytolytic CD8+ T cell function and might be targeted to overcome incidence of infections.


Assuntos
Infecções , Lúpus Eritematoso Sistêmico , Linfócitos T CD8-Positivos , Proteína Potenciadora do Homólogo 2 de Zeste/genética , Humanos , NAD , Sirtuína 1
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