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1.
Nat Commun ; 11(1): 4374, 2020 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-32873787

RESUMO

Oncogene amplification, a major driver of cancer pathogenicity, is often mediated through focal amplification of genomic segments. Recent results implicate extrachromosomal DNA (ecDNA) as the primary driver of focal copy number amplification (fCNA) - enabling gene amplification, rapid tumor evolution, and the rewiring of regulatory circuitry. Resolving an fCNA's structure is a first step in deciphering the mechanisms of its genesis and the fCNA's subsequent biological consequences. We introduce a computational method, AmpliconReconstructor (AR), for integrating optical mapping (OM) of long DNA fragments (>150 kb) with next-generation sequencing (NGS) to resolve fCNAs at single-nucleotide resolution. AR uses an NGS-derived breakpoint graph alongside OM scaffolds to produce high-fidelity reconstructions. After validating its performance through multiple simulation strategies, AR reconstructed fCNAs in seven cancer cell lines to reveal the complex architecture of ecDNA, a breakage-fusion-bridge and other complex rearrangements. By reconstructing the rearrangement signatures associated with an fCNA's generative mechanism, AR enables a more thorough understanding of the origins of fCNAs.


Assuntos
Amplificação de Genes , Genômica/métodos , Neoplasias/genética , Oncogenes/genética , Linhagem Celular Tumoral , Mapeamento Cromossômico/métodos , Análise Citogenética , Genoma Humano/genética , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Humanos
2.
Anticancer Res ; 40(10): 5667-5671, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32988891

RESUMO

BACKGROUND: Renal cell carcinoma (RCC) is a common urological cancer, and its risk correlates with environmental factors such as obesity, smoking and hypertension. Microarray technology enables analysis of the expression pattern of the whole phosphatome, members of which are involved in many cellular pathways and may act as either tumour suppressors or oncogenes in cancers. MATERIALS AND METHODS: We analysed data for the expression level of 87 out of 107 known protein phosphatase genes included in the Hugo Gene Nomenclature Committee Website for 72 RCC tissues and paired healthy tissues obtained from the GEO Database. RESULTS: Our analysis revealed overexpression of DUSP1, DUSP4, PTP4A3, PTPRC and PTPRE genes at all examined stages of RCC. Moreover, we found overexpression of PTPN12 at stage 2, overexpression of CDKN3 at stages 3 and 4, and overexpression of DUSP10 and PTPN22 at stages 2, 3 and 4. Lower expression of DUSP9, PTPR9 and PTPRO was also observed at all stages. CONCLUSION: Significant changes in expression patterns of protein tyrosine phosphatase genes confirm the involvement of this group in crucial carcinogenesis pathways underlying RCC. Thus, we postulate that protein tyrosine phosphatases play an important role in RCC promotion and progression, and may be considered as potential therapeutic targets.


Assuntos
Carcinoma de Células Renais/genética , Proliferação de Células/genética , Oncogenes/genética , Proteínas Tirosina Fosfatases/genética , Carcinoma de Células Renais/patologia , Linhagem Celular Tumoral , Proteínas Inibidoras de Quinase Dependente de Ciclina/genética , Fosfatase 1 de Especificidade Dupla/genética , Fosfatases de Especificidade Dupla/genética , Feminino , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica/genética , Humanos , Antígenos Comuns de Leucócito/genética , Masculino , Fosfatases da Proteína Quinase Ativada por Mitógeno/genética , Proteínas de Neoplasias/genética , Estadiamento de Neoplasias , Proteínas Tirosina Fosfatases Classe 3 Semelhantes a Receptores/genética , Proteínas Tirosina Fosfatases Classe 4 Semelhantes a Receptores/genética , Fatores de Risco , Transdução de Sinais/genética , Fumar/efeitos adversos
3.
Nat Commun ; 11(1): 4551, 2020 09 11.
Artigo em Inglês | MEDLINE | ID: mdl-32917870

RESUMO

Circular RNAs (circRNAs) have recently gained substantial attention in the cancer research field where most, including the putative oncogene ciRS-7 (CDR1as), have been proposed to function as competitive endogenous RNAs (ceRNAs) by sponging specific microRNAs. Here, we report the first spatially resolved cellular expression patterns of ciRS-7 in colon cancer and show that ciRS-7 is completely absent in the cancer cells, but highly expressed in stromal cells within the tumor microenvironment. Additionally, our data suggest that this generally apply to classical oncogene-driven adenocarcinomas, but not to other cancers, including malignant melanoma. Moreover, we find that correlations between circRNA and mRNA expression, which are commonly interpreted as evidence of a ceRNA function, can be explained by different cancer-to-stromal cell ratios among the studied tumor specimens. Together, these results have wide implications for future circRNA studies and highlight the importance of spatially resolving expression patterns of circRNAs proposed to function as ceRNAs.


Assuntos
Neoplasias do Colo/genética , Regulação Neoplásica da Expressão Gênica , MicroRNAs/metabolismo , RNA Circular/metabolismo , RNA Longo não Codificante/metabolismo , Microambiente Tumoral/genética , Idoso , Neoplasias do Colo/patologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Oncogenes/genética , Estudos Prospectivos , RNA Circular/genética , RNA Longo não Codificante/genética , Análise Espacial
4.
Nat Commun ; 11(1): 4581, 2020 09 11.
Artigo em Inglês | MEDLINE | ID: mdl-32917893

RESUMO

Yes-associated protein 1 (YAP) is a transcriptional regulator with critical roles in mechanotransduction, organ size control, and regeneration. Here, using advanced tools for real-time visualization of native YAP and target gene transcription dynamics, we show that a cycle of fast exodus of nuclear YAP to the cytoplasm followed by fast reentry to the nucleus ("localization-resets") activates YAP target genes. These "resets" are induced by calcium signaling, modulation of actomyosin contractility, or mitosis. Using nascent-transcription reporter knock-ins of YAP target genes, we show a strict association between these resets and downstream transcription. Oncogenically-transformed cell lines lack localization-resets and instead show dramatically elevated rates of nucleocytoplasmic shuttling of YAP, suggesting an escape from compartmentalization-based control. The single-cell localization and transcription traces suggest that YAP activity is not a simple linear function of nuclear enrichment and point to a model of transcriptional activation based on nucleocytoplasmic exchange properties of YAP.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Fatores de Transcrição/metabolismo , Proteínas Adaptadoras de Transdução de Sinal/genética , Sistemas CRISPR-Cas , Cálcio/metabolismo , Linhagem Celular Tumoral , Núcleo Celular/metabolismo , Citoplasma/metabolismo , Regulação da Expressão Gênica , Técnicas de Introdução de Genes , Células HEK293 , Humanos , Mecanotransdução Celular/fisiologia , Oncogenes/genética , Fatores de Transcrição/genética
5.
Nat Commun ; 11(1): 3808, 2020 07 30.
Artigo em Inglês | MEDLINE | ID: mdl-32732999

RESUMO

Large-scale cancer genomic studies enable the systematic identification of mutations that lead to the genesis and progression of tumors, uncovering the underlying molecular mechanisms and potential therapies. While some such mutations are recurrently found in many tumors, many others exist solely within a few samples, precluding detection by conventional recurrence-based statistical approaches. Integrated analysis of somatic mutations and RNA expression data across 12 tumor types reveals that mutations of cancer genes are usually accompanied by substantial changes in expression. We use topological data analysis to leverage this observation and uncover 38 elusive candidate cancer-associated genes, including inactivating mutations of the metalloproteinase ADAMTS12 in lung adenocarcinoma. We show that ADAMTS12-/- mice have a five-fold increase in the susceptibility to develop lung tumors, confirming the role of ADAMTS12 as a tumor suppressor gene. Our results demonstrate that data integration through topological techniques can increase our ability to identify previously unreported cancer-related alterations.


Assuntos
Proteínas ADAMTS/genética , Adenocarcinoma de Pulmão/genética , Predisposição Genética para Doença/genética , Neoplasias Pulmonares/genética , Animais , Linhagem Celular Tumoral , Biologia Computacional/métodos , Análise de Dados , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Mutação/genética , Recidiva Local de Neoplasia/genética , Oncogenes/genética
6.
Nat Commun ; 11(1): 4330, 2020 08 28.
Artigo em Inglês | MEDLINE | ID: mdl-32859912

RESUMO

Sex differences have been observed in multiple facets of cancer epidemiology, treatment and biology, and in most cancers outside the sex organs. Efforts to link these clinical differences to specific molecular features have focused on somatic mutations within the coding regions of the genome. Here we report a pan-cancer analysis of sex differences in whole genomes of 1983 tumours of 28 subtypes as part of the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium. We both confirm the results of exome studies, and also uncover previously undescribed sex differences. These include sex-biases in coding and non-coding cancer drivers, mutation prevalence and strikingly, in mutational signatures related to underlying mutational processes. These results underline the pervasiveness of molecular sex differences and strengthen the call for increased consideration of sex in molecular cancer research.


Assuntos
Mutação , Neoplasias/genética , Oncogenes/genética , Caracteres Sexuais , Instabilidade Cromossômica , Exoma , Feminino , Genoma Humano , Instabilidade Genômica , Humanos , Modelos Logísticos , Masculino , Fases de Leitura Aberta , beta Catenina/genética
7.
Gene ; 758: 144960, 2020 Oct 20.
Artigo em Inglês | MEDLINE | ID: mdl-32687947

RESUMO

As a member of the ubiquitin-specific protease (USP) family, USP22 could remove ubiquitin moieties from its target proteins to control the function of the target proteins. Accumulating studies show that USP22 essentially participates in diverse types of cancer as an oncogene-like protein. However, the roles of USP22 in human pancreatic ductal adenocarcinoma (PDAC) and the underlying mechanism are unknown. Here we report that USP22 promotes the growth of PDAC cells by promoting the expression of dual-specificity tyrosine regulated kinase 1A (DYRK1A). Our results showed that the expression levels of USP22 were up-regulated in human PDAC tissues and cell lines (BxPC-3, AsPC-1, MIA-PaCa-2, PANC-1, and CAPAN-1). Lentivirus-mediated knockdown of USP22 repressed the rate of proliferation and capacity of colony formation of BxPC3 and CAPAN1 cancer cells and USP22 overexpression promoted the proliferation and capacity of the colony formation of BxPC3 and CAPAN1 cancer cells. The further mechanism study showed that USP22 elevated the expression of the mRNA and protein levels of DYRK1A in PDAC cancer cells. Inhibition of DYRK1A with EHT-5732 or lentivirus-mediated knockdown of DYRK1A blocked the function of USP22 overexpression in the regulation of the proliferation and colony formation of PDAC cells. Taken together, our findings demonstrated that USP22 overexpression in PDAC promoted the growth of the cancer cells partially through upregulating the expression of DYRK1A.


Assuntos
Carcinoma Ductal Pancreático/genética , Neoplasias Pancreáticas/genética , Proteínas Serina-Treonina Quinases/metabolismo , Proteínas Tirosina Quinases/metabolismo , Ubiquitina Tiolesterase/genética , Animais , Apoptose/genética , Linhagem Celular Tumoral , Proliferação de Células/genética , Regulação Neoplásica da Expressão Gênica , Humanos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Transplante de Neoplasias , Oncogenes/genética , Ductos Pancreáticos/patologia , RNA Mensageiro/genética , Transplante Heterólogo
8.
Nature ; 583(7818): 807-812, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32669708

RESUMO

The majority of targeted therapies for non-small-cell lung cancer (NSCLC) are directed against oncogenic drivers that are more prevalent in patients with light exposure to tobacco smoke1-3. As this group represents around 20% of all patients with lung cancer, the discovery of stratified medicine options for tobacco-associated NSCLC is a high priority. Umbrella trials seek to streamline the investigation of genotype-based treatments by screening tumours for multiple genomic alterations and triaging patients to one of several genotype-matched therapeutic agents. Here we report the current outcomes of 19 drug-biomarker cohorts from the ongoing National Lung Matrix Trial, the largest umbrella trial in NSCLC. We use next-generation sequencing to match patients to appropriate targeted therapies on the basis of their tumour genotype. The Bayesian trial design enables outcome data from open cohorts that are still recruiting to be reported alongside data from closed cohorts. Of the 5,467 patients that were screened, 2,007 were molecularly eligible for entry into the trial, and 302 entered the trial to receive genotype-matched therapy-including 14 that re-registered to the trial for a sequential trial drug. Despite pre-clinical data supporting the drug-biomarker combinations, current evidence shows that a limited number of combinations demonstrate clinically relevant benefits, which remain concentrated in patients with lung cancers that are associated with minimal exposure to tobacco smoke.


Assuntos
Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/terapia , Marcadores Genéticos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/terapia , Terapia de Alvo Molecular , Medicina de Precisão , Fumar/genética , Teorema de Bayes , Carcinoma Pulmonar de Células não Pequenas/etiologia , Protocolos Clínicos , Ensaios Clínicos como Assunto , Estudos de Coortes , Genótipo , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Neoplasias Pulmonares/etiologia , Oncogenes/genética , Seleção de Pacientes , Fumaça/efeitos adversos , Triagem
9.
Nature ; 582(7810): 95-99, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32494066

RESUMO

Sporadic reports have described cancer cases in which multiple driver mutations (MMs) occur in the same oncogene1,2. However, the overall landscape and relevance of MMs remain elusive. Here we carried out a pan-cancer analysis of 60,954 cancer samples, and identified 14 pan-cancer and 6 cancer-type-specific oncogenes in which MMs occur more frequently than expected: 9% of samples with at least one mutation in these genes harboured MMs. In various oncogenes, MMs are preferentially present in cis and show markedly different mutational patterns compared with single mutations in terms of type (missense mutations versus in-frame indels), position and amino-acid substitution, suggesting a cis-acting effect on mutational selection. MMs show an overrepresentation of functionally weak, infrequent mutations, which confer enhanced oncogenicity in combination. Cells with MMs in the PIK3CA and NOTCH1 genes exhibit stronger dependencies on the mutated genes themselves, enhanced downstream signalling activation and/or greater sensitivity to inhibitory drugs than those with single mutations. Together oncogenic MMs are a relatively common driver event, providing the underlying mechanism for clonal selection of suboptimal mutations that are individually rare but collectively account for a substantial proportion of oncogenic mutations.


Assuntos
Carcinogênese/genética , Mutação/genética , Neoplasias/genética , Oncogenes/genética , Animais , Viés , Linhagem da Célula , Classe I de Fosfatidilinositol 3-Quinases/genética , Repetições Palindrômicas Curtas Agrupadas e Regularmente Espaçadas/genética , Feminino , Humanos , Camundongos , Neoplasias/patologia , Seleção Genética
10.
Nat Commun ; 11(1): 2977, 2020 06 12.
Artigo em Inglês | MEDLINE | ID: mdl-32532995

RESUMO

Independent scientific achievements have led to the discovery of aberrant splicing patterns in oncogenesis, while more recent advances have uncovered novel gene fusions involving neurotrophic tyrosine receptor kinases (NTRKs) in gliomas. The exploration of NTRK splice variants in normal and neoplastic brain provides an intersection of these two rapidly evolving fields. Tropomyosin receptor kinase B (TrkB), encoded NTRK2, is known for critical roles in neuronal survival, differentiation, molecular properties associated with memory, and exhibits intricate splicing patterns and post-translational modifications. Here, we show a role for a truncated NTRK2 splice variant, TrkB.T1, in human glioma. TrkB.T1 enhances PDGF-driven gliomas in vivo, augments PDGF-induced Akt and STAT3 signaling in vitro, while next generation sequencing broadly implicates TrkB.T1 in the PI3K signaling cascades in a ligand-independent fashion. These TrkB.T1 findings highlight the importance of expanding upon whole gene and gene fusion analyses to include splice variants in basic and translational neuro-oncology research.


Assuntos
Neoplasias Encefálicas/genética , Glioma/genética , Glicoproteínas de Membrana/genética , Oncogenes/genética , Isoformas de RNA/genética , Processamento de RNA , Receptor trkB/genética , Animais , Encéfalo/metabolismo , Encéfalo/patologia , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/patologia , Carcinogênese/genética , Células Cultivadas , Perfilação da Expressão Gênica , Ontologia Genética , Glioma/metabolismo , Glioma/patologia , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Glicoproteínas de Membrana/metabolismo , Camundongos , Células NIH 3T3 , Células-Tronco Neurais/metabolismo , Proteínas de Fusão Oncogênica/genética , Proteínas de Fusão Oncogênica/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Isoformas de RNA/metabolismo , Receptor trkB/metabolismo , Transdução de Sinais/genética
11.
PLoS One ; 15(6): e0235343, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32584896

RESUMO

Triple Negative Breast Cancer (TNBC) is a heterogeneous disease lacking known molecular drivers and effective targeted therapies. Cytotoxic chemotherapy remains the mainstay of treatment for TNBCs, which have significantly poorer survival rates compared to other breast cancer subtypes. In addition to changes within the coding genome, aberrant enhancer activity is a well-established contributor to tumorigenesis. Here we use H3K27Ac chromatin immunoprecipitation followed by sequencing (ChIP-Seq) to map the active cis-regulatory landscape in TNBC. We identify distinct disease subtypes associated with specific enhancer activity, and over 2,500 unique superenhancers acquired by tumor cells but absent from normal breast tissue. To identify potential actionable disease drivers, we probed the dependency on genes that associate with tumor-specific enhancers by CRISPR screening. In this way we identify a number of tumor-specific dependencies, including a previously uncharacterized dependency on the TGFß pseudo-receptor BAMBI.


Assuntos
Elementos Facilitadores Genéticos/genética , Oncogenes/genética , Neoplasias de Mama Triplo Negativas/patologia , Linhagem Celular Tumoral , Imunoprecipitação da Cromatina , Feminino , Edição de Genes , Regulação Neoplásica da Expressão Gênica , Histonas/química , Histonas/genética , Histonas/metabolismo , Humanos , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismo , RNA Guia/metabolismo , Neoplasias de Mama Triplo Negativas/genética
12.
Nat Commun ; 11(1): 2649, 2020 05 27.
Artigo em Inglês | MEDLINE | ID: mdl-32461571

RESUMO

Pregnancy causes a series of cellular and molecular changes in mammary epithelial cells (MECs) of female adults. In addition, pregnancy can also modify the predisposition of rodent and human MECs to initiate oncogenesis. Here, we investigate how pregnancy reprograms enhancer chromatin in the mammary epithelium of mice and influences the transcriptional output of the oncogenic transcription factor cMYC. We find that pregnancy induces an expansion of the active cis-regulatory landscape of MECs, which influences the activation of pregnancy-related programs during re-exposure to pregnancy hormones in vivo and in vitro. Using inducible cMYC overexpression, we demonstrate that post-pregnancy MECs are resistant to the downstream molecular programs induced by cMYC, a response that blunts carcinoma initiation, but does not perturb the normal pregnancy-induced epigenomic landscape. cMYC overexpression drives post-pregnancy MECs into a senescence-like state, and perturbations of this state increase malignant phenotypic changes. Taken together, our findings provide further insight into the cell-autonomous signals in post-pregnancy MECs that underpin the regulation of gene expression, cellular activation, and resistance to malignant development.


Assuntos
Glândulas Mamárias Animais/metabolismo , Animais , Carcinogênese/genética , Transformação Celular Neoplásica/patologia , Epigênese Genética , Epigenoma , Células Epiteliais/metabolismo , Feminino , Regulação da Expressão Gênica , Glândulas Mamárias Animais/citologia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Oncogenes/genética , Gravidez , Complicações na Gravidez/etiologia , Complicações na Gravidez/genética , Transdução de Sinais , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo
13.
Am J Chin Med ; 48(3): 651-678, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32349518

RESUMO

Cinobufagin is a Na+/K+-ATPase (NKA) inhibitor with excellent anticancer effects to prolong the survival of patients. The purpose of the present study was to clarify the underlying mechanism of the anticancer effects of cinobufagin using overexpression or inhibition of aurora kinase A (AURKA) signaling. First, high expression of Na+/K+-ATPase alpha 1 subunit (ATP1A1) and AURAK resulted in increased malignant transformation in hepatocellular carcinoma (HCC) patients using the cancer genome atlas (TCGA) data and tissue samples. After treatment with cinobufagin, we successfully screened 202, 249, and 335 changing expression proteins in Huh-7 cells under normal, overexpression, and inhibition of AURKA using tandem mass tags (TMT)-labeled quantitative proteomics coupled to 2D liquid chromatography-tandem mass spectrometry (LC-MS/MS). Bioinformatics analysis revealed that these molecules were closely associated with chromosome segregation, DNA damage, and regulation of translation processes. We further confirmed that cinobufagin induced DNA damage and chromosome segregation disorders and suppresses translational processing in oncogenes by decreasing the expression of AURKA, mechanistic target of rapamycin kinase (mTOR), p-mTOR, p-extracellular regulated protein kinases (ERK), eukaryotic translation initiation factor 4E (eIF4E), and p-eIF4E, while increasing the expression of p-eukaryotic translation initiation factor 4E binding protein 1 (4E-BP1) (S65, T37, T46, T45) and increasing the interaction between eIF4 and 4E-BP1. Our results suggested that cinobufagin performed an antitumor effects in liver cancer cells by inhibiting the AURKA-mTOR-eIF4E axis.


Assuntos
Antineoplásicos Fitogênicos , Aurora Quinase A/metabolismo , Bufanolídeos/farmacologia , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/metabolismo , Proteínas de Ligação a DNA/metabolismo , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/metabolismo , Biossíntese de Proteínas/efeitos dos fármacos , Serina-Treonina Quinases TOR/metabolismo , Fatores de Transcrição/metabolismo , Segregação de Cromossomos/efeitos dos fármacos , Dano ao DNA/efeitos dos fármacos , Expressão Gênica/efeitos dos fármacos , Oncogenes/genética , ATPase Trocadora de Sódio-Potássio/metabolismo , Células Tumorais Cultivadas
14.
Nature ; 582(7810): 100-103, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32461694

RESUMO

Cancers develop as a result of driver mutations1,2 that lead to clonal outgrowth and the evolution of disease3,4. The discovery and functional characterization of individual driver mutations are central aims of cancer research, and have elucidated myriad phenotypes5 and therapeutic vulnerabilities6. However, the serial genetic evolution of mutant cancer genes7,8 and the allelic context in which they arise is poorly understood in both common and rare cancer genes and tumour types. Here we find that nearly one in four human tumours contains a composite mutation of a cancer-associated gene, defined as two or more nonsynonymous somatic mutations in the same gene and tumour. Composite mutations are enriched in specific genes, have an elevated rate of use of less-common hotspot mutations acquired in a chronology driven in part by oncogenic fitness, and arise in an allelic configuration that reflects context-specific selective pressures. cis-acting composite mutations are hypermorphic in some genes in which dosage effects predominate (such as TERT), whereas they lead to selection of function in other genes (such as TP53). Collectively, composite mutations are driver alterations that arise from context- and allele-specific selective pressures that are dependent in part on gene and mutation function, and which lead to complex-often neomorphic-functions of biological and therapeutic importance.


Assuntos
Carcinogênese/genética , Modelos Genéticos , Mutação , Neoplasias/genética , Oncogenes/genética , Alelos , Animais , Feminino , Genes p53/genética , Humanos , Camundongos , Seleção Genética , Telomerase/genética
15.
Nucleic Acids Res ; 48(12): 6775-6787, 2020 07 09.
Artigo em Inglês | MEDLINE | ID: mdl-32453417

RESUMO

Cell growth requires a high level of protein synthesis and oncogenic pathways stimulate cell proliferation and ribosome biogenesis. Less is known about how cells respond to dysfunctional mRNA translation and how this feeds back into growth regulatory pathways. The Epstein-Barr virus (EBV)-encoded EBNA1 causes mRNA translation stress in cis that activates PI3Kδ. This leads to the stabilization of MDM2, induces MDM2's binding to the E2F1 mRNA and promotes E2F1 translation. The MDM2 serine 166 regulates the interaction with the E2F1 mRNA and deletion of MDM2 C-terminal RING domain results in a constitutive E2F1 mRNA binding. Phosphorylation on serine 395 following DNA damage instead regulates p53 mRNA binding to its RING domain and prevents the E2F1 mRNA interaction. The p14Arf tumour suppressor binds MDM2 and in addition to preventing degradation of the p53 protein it also prevents the E2F1 mRNA interaction. The data illustrate how two MDM2 domains selectively bind specific mRNAs in response to cellular conditions to promote, or suppress, cell growth and how p14Arf coordinates MDM2's activity towards p53 and E2F1. The data also show how EBV via EBNA1-induced mRNA translation stress targets the E2F1 and the MDM2 - p53 pathway.


Assuntos
Fator de Transcrição E2F1/genética , Neoplasias/genética , Proteínas Proto-Oncogênicas c-mdm2/genética , Proteína Supressora de Tumor p53/genética , Carcinogênese/genética , Ciclo Celular/genética , Proliferação de Células/genética , Dano ao DNA/genética , Genes Supressores de Tumor , Herpesvirus Humano 4/genética , Humanos , Neoplasias/virologia , Oncogenes/genética , Fosforilação/genética , Domínios Proteicos/genética , Proteínas com Motivo de Reconhecimento de RNA/genética , RNA Mensageiro/genética , Proteína Supressora de Tumor p14ARF/genética
16.
Mol Cell ; 78(6): 1133-1151.e14, 2020 06 18.
Artigo em Inglês | MEDLINE | ID: mdl-32402252

RESUMO

Precise control of the RNA polymerase II (RNA Pol II) cycle, including pausing and pause release, maintains transcriptional homeostasis and organismal functions. Despite previous work to understand individual transcription steps, we reveal a mechanism that integrates RNA Pol II cycle transitions. Surprisingly, KAP1/TRIM28 uses a previously uncharacterized chromatin reader cassette to bind hypo-acetylated histone 4 tails at promoters, guaranteeing continuous progression of RNA Pol II entry to and exit from the pause state. Upon chromatin docking, KAP1 first associates with RNA Pol II and then recruits a pathway-specific transcription factor (SMAD2) in response to cognate ligands, enabling gene-selective CDK9-dependent pause release. This coupling mechanism is exploited by tumor cells to aberrantly sustain transcriptional programs commonly dysregulated in cancer patients. The discovery of a factor integrating transcription steps expands the functional repertoire by which chromatin readers operate and provides mechanistic understanding of transcription regulation, offering alternative therapeutic opportunities to target transcriptional dysregulation.


Assuntos
RNA Polimerase II/metabolismo , Proteína 28 com Motivo Tripartido/metabolismo , Acetilação , Linhagem Celular Tumoral , Cromatina/genética , Cromatina/metabolismo , Quinase 9 Dependente de Ciclina/metabolismo , Regulação da Expressão Gênica/genética , Histonas/metabolismo , Humanos , Oncogenes/genética , Regiões Promotoras Genéticas/genética , Processamento de Proteína Pós-Traducional/genética , RNA Polimerase II/genética , Proteína Smad2/metabolismo , Fatores de Transcrição/metabolismo , Transcrição Genética , Proteína 28 com Motivo Tripartido/genética
17.
DNA Cell Biol ; 39(5): 890-899, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32282228

RESUMO

Lung adenocarcinoma (LUAD) is the most common subtype of nonsmall cell lung cancer, and 5-year survival rate is only 15% in recent years. This study aimed to explore the FAM83A expression and its potential functions in LUAD. Data of LUAD were downloaded from The Cancer Genome Atlas database. Expression level of FAM83A was compared between LUAD samples and adjacent normal samples. The association between FAM83A expression and clinic-pathological parameters was analyzed, as well as copy number variation and methylation status. Kaplan-Meier curve was used to visualize the relationship of FAM83A expression with survival outcomes. Finally, gene set enrichment analysis was used to identify potential signaling pathways in LUAD specimens. FAM83A expression was significantly correlated with four clinical factors in LUAD specimens, age, gender, smoking, and overall survival status (all p < 0.05). High expression level of FAM83A was negatively correlated with methylation level. Moreover, patients in low expression groups exhibited a better prognosis than those in high expressed groups, which was independent of gender (p < 0.001). Histidine metabolism pathway was significantly upregulated in FAM83A-high expressed samples than FAM83A-low expressed samples according to functional enrichment analysis. High expression of FAM83A predicted a poor prognosis in LUAD patients. Our study demonstrated that FAM83A might be a potential biomarker and meaningful therapeutic target in LUAD.


Assuntos
Adenocarcinoma de Pulmão/diagnóstico , Adenocarcinoma de Pulmão/genética , Proteínas de Neoplasias/genética , Oncogenes/genética , Adenocarcinoma de Pulmão/metabolismo , Adenocarcinoma de Pulmão/patologia , Idoso , Carcinogênese/genética , Proliferação de Células/genética , Metilação de DNA/genética , Feminino , Regulação Neoplásica da Expressão Gênica , Histidina/metabolismo , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Prognóstico
18.
PLoS One ; 15(4): e0231470, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32320427

RESUMO

The prognosis for people with the high-grade brain tumor glioblastoma is very poor, due largely to low cell death in response to genotoxic therapy. The transcription factor BCL6, a protein that normally suppresses the DNA damage response during immune cell maturation, and a known driver of B-cell lymphoma, was shown to mediate the survival of glioblastoma cells. Expression was observed in glioblastoma tumor specimens and cell lines. When BCL6 expression or activity was reduced in these lines, increased apoptosis and a profound loss of proliferation was observed, consistent with gene expression signatures suggestive of anti-apoptotic and pro-survival signaling role for BCL6 in glioblastoma. Further, treatment with the standard therapies for glioblastoma-ionizing radiation and temozolomide-both induced BCL6 expression in vitro, and an in vivo orthotopic animal model of glioblastoma. Importantly, inhibition of BCL6 in combination with genotoxic therapies enhanced the therapeutic effect. Together these data demonstrate that BCL6 is an active transcription factor in glioblastoma, that it drives survival of cells, and that it increased with DNA damage, which increased the survival rate of therapy-treated cells. This makes BCL6 an excellent therapeutic target in glioblastoma-by increasing sensitivity to standard DNA damaging therapy, BCL6 inhibitors have real potential to improve the outcome for people with this disease.


Assuntos
Neoplasias Encefálicas/genética , Dano ao DNA/genética , Glioblastoma/genética , Oncogenes/genética , Proteínas Proto-Oncogênicas c-bcl-6/genética , Regulação para Cima/genética , Animais , Linhagem Celular Tumoral , Regulação Neoplásica da Expressão Gênica/genética , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Transdução de Sinais/genética , Ativação Transcricional/genética , Ensaios Antitumorais Modelo de Xenoenxerto/métodos
19.
Magy Onkol ; 64(1): 7-11, 2020 Mar 17.
Artigo em Húngaro | MEDLINE | ID: mdl-32181757

RESUMO

Cancer susceptibility but not specific cancer types can be inherited. This susceptibility(ies) is due to inherited germline mutations of key genes of the controllers of genome integrity, translational control, the cell cycle regulation or even the tumor vascularization. Cancer susceptibility can be manifested in various forms of specific syndromes, each associated with different alterations of genes. Most of these genes are tumor suppressors, and the mutations affect one or both alleles. Interestingly, inherited mutations of oncogenes resulting in cancer susceptibility are much rarer, typically affect only one allele, and the inheritance is dominant. However, cancer susceptibility is influenced not only by high penetrance gene defects but also by inherited low penetrance gene mutations, complicating the effective identification of affected individuals and their families.


Assuntos
Predisposição Genética para Doença , Mutação em Linhagem Germinativa/genética , Neoplasias/genética , Humanos , Oncogenes/genética
20.
Biochim Biophys Acta Rev Cancer ; 1873(2): 188353, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32112817

RESUMO

Glioma is the most common primary malignant tumor in the human brain. Although there are a variety of treatments, such as surgery, radiation and chemotherapy, glioma is still an incurable disease. Super-enhancers (SEs) are implicated in the control of tumor cell identity, and they promote oncogenic transcription, which supports tumor cells. Inhibition of the SE complex, which is required for the assembly and maintenance of SEs, may repress oncogenic transcription and impede tumor growth. In this review, we discuss the unique characteristics of SEs compared to typical enhancers, and we summarize the recent advances in the understanding of their properties and biological role in gene regulation. Additionally, we highlight that SE-driven lncRNAs, miRNAs and genes are involved in the malignant phenotype of glioma. Most importantly, the application of SE inhibitors in different cancer subtypes has introduced new directions in glioma treatment.


Assuntos
Antineoplásicos/farmacologia , Neoplasias Encefálicas/genética , Elementos Facilitadores Genéticos/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Glioma/genética , Antineoplásicos/uso terapêutico , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/patologia , Carcinogênese/efeitos dos fármacos , Carcinogênese/genética , Glioma/tratamento farmacológico , Glioma/patologia , Humanos , MicroRNAs/genética , Oncogenes/genética , RNA Longo não Codificante/genética , Transcrição Genética/efeitos dos fármacos
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