RESUMEN
Objectives: Secondary peritonitis is caused by infection of the peritoneal cavity due to perforation of the alimentary tract. Mannheim's peritonitis index (MPI) is a prognostic scoring system that predicts outcomes in peritonitis. Increasing MPI scores correlate with poor outcomes and mortality. The objective of this study is to evaluate the effectiveness of MPI-based prognosis and its impact on Indian patients with secondary peritonitis. Material and Methods: For understanding the effectiveness of the MPI scoring system, a cross-sectional data analysis of published studies on secondary peritonitis from 10 geographical locations in India was performed. The 10-site study results were compared with unpublished in-house study data for individual MPI parameters to analyze any variations of MPI score-based predictions across a diverse Indian population. Patients were divided into risk groups on the basis of MPI scores: <21 mild, MPI= 21-29 moderate, MPI> 29 severe risk. Results: We observed a significant correlation between mortality with age and gender as reported worldwide. Site of perforations were prevalent in the upper alimentary tract with the majority being gastro-duodenal for the Indian population as opposed to distal parts in the western population. Higher lethality in India is often associated with evolution time, organ failure, and sepsis due to delayed presentation and poor management. Conclusion: MPI scoring is effective in predicting risk across geographically diverse Indian populations. The sensitivity and specificity of MPI scores are more reliable and a score >29 specifically recommends aggressive resuscitation & monitoring of patients, initiation of broad-spectrum antibiotics, and intensive care support to reduce mortality and morbidity.
RESUMEN
The presence of ERG gene fusion; from developing prostatic intraepithelial neoplasia (PIN) lesions to hormone resistant high grade prostate cancer (PCa) dictates disease progression, altered androgen metabolism, proliferation and metastasis1-3. ERG driven transcriptional landscape may provide pro-tumorigenic cues in overcoming various strains like hypoxia, nutrient deprivation, inflammation and oxidative stress. However, insights on the androgen independent regulation and function of ERG during stress are limited. Here, we identify PGC1α as a coactivator of ERG fusion under various metabolic stress. Deacetylase SIRT1 is necessary for PGC1α-ERG interaction and function. We reveal that ERG drives the expression of antioxidant genes; SOD1 and TXN, benefitting PCa growth. We observe increased expression of these antioxidant genes in patients with high ERG expression correlates with poor survival. Inhibition of PGC1α-ERG axis driven transcriptional program results in apoptosis and reduction in PCa xenografts. Here we report a function of ERG under metabolic stress which warrants further studies as a therapeutic target for ERG fusion positive PCa.
Asunto(s)
Antioxidantes , Coactivador 1-alfa del Receptor Activado por Proliferadores de Peroxisomas gamma , Neoplasias de la Próstata , Andrógenos , Antioxidantes/farmacología , Fusión Génica , Humanos , Masculino , Coactivador 1-alfa del Receptor Activado por Proliferadores de Peroxisomas gamma/genética , Coactivador 1-alfa del Receptor Activado por Proliferadores de Peroxisomas gamma/metabolismo , Neoplasias de la Próstata/patología , Estrés Fisiológico , Regulador Transcripcional ERG/genética , Regulador Transcripcional ERG/metabolismoRESUMEN
Pancreatic ductal adenocarcinoma (PDAC) is notoriously difficult to treat due to its aggressive, ever resilient nature. A major drawback lies in its tumor grade; a phenomenon observed across various carcinomas, where highly differentiated and undifferentiated tumor grades, termed as low and high grade respectively, are found in the same tumor. One eminent problem due to such heterogeneity is drug resistance in PDAC. This has been implicated to ABC transporter family of proteins that are upregulated in PDAC patients. However, the regulation of these transporters with respect to tumor grade in PDAC is not well understood. To combat these issues, a study was designed to identify novel genes that might regulate drug resistance phenotype and be used as targets. By integrating epigenome with transcriptome data, several genes were identified based around high grade PDAC. Further analysis indicated oncogenic PAX2 transcription factor as a novel regulator of drug resistance in high grade PDAC cell lines. It was observed that silencing of PAX2 resulted in increased susceptibility of high grade PDAC cells to various chemotherapeutic drugs. Mechanistically, the study showed that PAX2 protein can bind and alter transcriptionally; expression of many ABC transporter genes in high grade PDAC cell lines. Overall, the study indicated that PAX2 significantly upregulated ABC family of genes resulting in drug resistance and poor survival in PDAC.
Asunto(s)
Carcinoma Ductal Pancreático/genética , Resistencia a Antineoplásicos/genética , Epigenoma , Perfilación de la Expresión Génica , Factor de Transcripción PAX2/genética , Neoplasias Pancreáticas/genética , Transcriptoma , Biomarcadores de Tumor , Carcinoma Ductal Pancreático/metabolismo , Carcinoma Ductal Pancreático/mortalidad , Línea Celular Tumoral , Movimiento Celular , Proliferación Celular , Epigénesis Genética , Regulación Neoplásica de la Expresión Génica , Humanos , Clasificación del Tumor , Estadificación de Neoplasias , Factor de Transcripción PAX2/metabolismo , Neoplasias Pancreáticas/metabolismo , Neoplasias Pancreáticas/mortalidad , Neoplasias PancreáticasRESUMEN
Ewing sarcoma (EWS) is a soft tissue and bone tumor that occurs primarily in adolescents and young adults. In most cases of EWS, the chimeric transcription factor, EWS-FLI1 is the primary oncogenic driver. The epigenome of EWS cells reflects EWS-FLI1 binding and activation or repression of transcription. Here, we demonstrate that EWS-FLI1 positively regulates the expression of proteins required for serine-glycine biosynthesis and uptake of the alternative nutrient source glutamine. Specifically, we show that EWS-FLI1 activates expression of PHGDH, PSAT1, PSPH, and SHMT2. Using cell-based studies, we also establish that EWS cells are dependent on glutamine for cell survival and that EWS-FLI1 positively regulates expression of the glutamine transporter, SLC1A5 and two enzymes involved in the one-carbon cycle, MTHFD2 and MTHFD1L. Inhibition of serine-glycine biosynthesis in EWS cells impacts their redox state leading to an accumulation of reactive oxygen species, DNA damage, and apoptosis. Importantly, analysis of EWS primary tumor transcriptome data confirmed that the aforementioned genes we identified as regulated by EWS-FLI1 exhibit increased expression compared with normal tissues. Furthermore, retrospective analysis of an independent data set generated a significant stratification of the overall survival of EWS patients into low- and high-risk groups based on the expression of PHGDH, PSAT1, PSPH, SHMT2, SLC1A5, MTHFD2, and MTHFD1L. In summary, our study demonstrates that EWS-FLI1 reprograms the metabolism of EWS cells and that serine-glycine metabolism or glutamine uptake are potential targetable vulnerabilities in this tumor type.
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Glutamina/metabolismo , Glicina/biosíntesis , Proteínas de Fusión Oncogénica/metabolismo , Proteína Proto-Oncogénica c-fli-1/metabolismo , Proteína EWS de Unión a ARN/metabolismo , Serina/biosíntesis , Sistema de Transporte de Aminoácidos ASC/genética , Sistema de Transporte de Aminoácidos ASC/metabolismo , Aminohidrolasas/genética , Aminohidrolasas/metabolismo , Apoptosis/genética , Neoplasias Óseas/genética , Neoplasias Óseas/metabolismo , Neoplasias Óseas/patología , Línea Celular Tumoral , Supervivencia Celular/genética , Formiato-Tetrahidrofolato Ligasa/genética , Formiato-Tetrahidrofolato Ligasa/metabolismo , Regulación Neoplásica de la Expresión Génica , Células HCT116 , Células HEK293 , Humanos , Metilenotetrahidrofolato Deshidrogenasa (NADP)/genética , Metilenotetrahidrofolato Deshidrogenasa (NADP)/metabolismo , Antígenos de Histocompatibilidad Menor/genética , Antígenos de Histocompatibilidad Menor/metabolismo , Complejos Multienzimáticos/genética , Complejos Multienzimáticos/metabolismo , Enzimas Multifuncionales/genética , Enzimas Multifuncionales/metabolismo , Proteínas de Fusión Oncogénica/genética , Fosfoglicerato-Deshidrogenasa/genética , Fosfoglicerato-Deshidrogenasa/metabolismo , Proteína Proto-Oncogénica c-fli-1/genética , Proteína EWS de Unión a ARN/genética , Sarcoma de Ewing/genética , Sarcoma de Ewing/metabolismo , Sarcoma de Ewing/patologíaRESUMEN
Alveolar rhabdomyosarcoma is a life-threatening myogenic cancer of children and adolescent young adults, driven primarily by the chimeric transcription factor PAX3-FOXO1. The mechanisms by which PAX3-FOXO1 dysregulates chromatin are unknown. We find PAX3-FOXO1 reprograms the cis-regulatory landscape by inducing de novo super enhancers. PAX3-FOXO1 uses super enhancers to set up autoregulatory loops in collaboration with the master transcription factors MYOG, MYOD, and MYCN. This myogenic super enhancer circuitry is consistent across cell lines and primary tumors. Cells harboring the fusion gene are selectively sensitive to small-molecule inhibition of protein targets induced by, or bound to, PAX3-FOXO1-occupied super enhancers. Furthermore, PAX3-FOXO1 recruits and requires the BET bromodomain protein BRD4 to function at super enhancers, resulting in a complete dependence on BRD4 and a significant susceptibility to BRD inhibition. These results yield insights into the epigenetic functions of PAX3-FOXO1 and reveal a specific vulnerability that can be exploited for precision therapy.Significance: PAX3-FOXO1 drives pediatric fusion-positive rhabdomyosarcoma, and its chromatin-level functions are critical to understanding its oncogenic activity. We find that PAX3-FOXO1 establishes a myoblastic super enhancer landscape and creates a profound subtype-unique dependence on BET bromodomains, the inhibition of which ablates PAX3-FOXO1 function, providing a mechanistic rationale for exploring BET inhibitors for patients bearing PAX-fusion rhabdomyosarcoma. Cancer Discov; 7(8); 884-99. ©2017 AACR.This article is highlighted in the In This Issue feature, p. 783.
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Elementos de Facilitación Genéticos/genética , Proteínas Nucleares/genética , Proteínas de Fusión Oncogénica/genética , Factores de Transcripción Paired Box/genética , Rabdomiosarcoma Alveolar/tratamiento farmacológico , Factores de Transcripción/genética , Animales , Proteínas de Ciclo Celular , Línea Celular Tumoral , Cromatina/genética , Elementos de Facilitación Genéticos/efectos de los fármacos , Epigénesis Genética/efectos de los fármacos , Epigénesis Genética/genética , Femenino , Humanos , Masculino , Ratones , Proteína MioD/genética , Miogenina/genética , Proteína Proto-Oncogénica N-Myc/genética , Unión Proteica/genética , Dominios Proteicos/genética , Rabdomiosarcoma Alveolar/genética , Rabdomiosarcoma Alveolar/patología , Bibliotecas de Moléculas Pequeñas/administración & dosificación , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Ewing sarcoma cells depend on the EWS-FLI1 fusion transcription factor for cell survival. Using an assay of EWS-FLI1 activity and genome-wide RNAi screening, we have identified proteins required for the processing of the EWS-FLI1 pre-mRNA. We show that Ewing sarcoma cells harboring a genomic breakpoint that retains exon 8 of EWSR1 require the RNA-binding protein HNRNPH1 to express in-frame EWS-FLI1. We also demonstrate the sensitivity of EWS-FLI1 fusion transcripts to the loss of function of the U2 snRNP component, SF3B1. Disrupted splicing of the EWS-FLI1 transcript alters EWS-FLI1 protein expression and EWS-FLI1-driven expression. Our results show that the processing of the EWS-FLI1 fusion RNA is a potentially targetable vulnerability in Ewing sarcoma cells.
Asunto(s)
Proteínas de Fusión Oncogénica/metabolismo , Proteína Proto-Oncogénica c-fli-1/metabolismo , Proteína EWS de Unión a ARN/metabolismo , Secuencia de Bases , Sitios de Unión , Proteínas de Unión a Calmodulina/antagonistas & inhibidores , Proteínas de Unión a Calmodulina/genética , Proteínas de Unión a Calmodulina/metabolismo , Línea Celular Tumoral , Supervivencia Celular , Exones , Regulación Neoplásica de la Expresión Génica , Ribonucleoproteína Heterogénea-Nuclear Grupo F-H/antagonistas & inhibidores , Ribonucleoproteína Heterogénea-Nuclear Grupo F-H/genética , Ribonucleoproteína Heterogénea-Nuclear Grupo F-H/metabolismo , Humanos , Proteínas de Microfilamentos/antagonistas & inhibidores , Proteínas de Microfilamentos/genética , Proteínas de Microfilamentos/metabolismo , Proteínas de Fusión Oncogénica/antagonistas & inhibidores , Proteínas de Fusión Oncogénica/genética , Fosfoproteínas/antagonistas & inhibidores , Fosfoproteínas/genética , Fosfoproteínas/metabolismo , Proteína Proto-Oncogénica c-fli-1/antagonistas & inhibidores , Proteína Proto-Oncogénica c-fli-1/genética , Interferencia de ARN , Precursores del ARN/metabolismo , Empalme del ARN , Factores de Empalme de ARN , ARN Interferente Pequeño/metabolismo , Proteína EWS de Unión a ARN/antagonistas & inhibidores , Proteína EWS de Unión a ARN/genética , Proteínas de Unión al ARN/antagonistas & inhibidores , Proteínas de Unión al ARN/genética , Proteínas de Unión al ARN/metabolismo , Receptores Citoplasmáticos y Nucleares/antagonistas & inhibidores , Receptores Citoplasmáticos y Nucleares/genética , Receptores Citoplasmáticos y Nucleares/metabolismo , Ribonucleoproteína Nuclear Pequeña U2/antagonistas & inhibidores , Ribonucleoproteína Nuclear Pequeña U2/genética , Ribonucleoproteína Nuclear Pequeña U2/metabolismo , Sarcoma de Ewing/patología , Transactivadores , Factores de Transcripción/antagonistas & inhibidores , Factores de Transcripción/genética , Factores de Transcripción/metabolismoRESUMEN
Although the functional significance of the metastasic tumor antigen (MTA) family of chromatin remodeling proteins in the pathobiology of cancer is fairly well recognized, the physiological role of MTA proteins continues to be an understudied research area and is just beginning to be recognized. Similar to cancer cells, MTA1 also modulates the expression of target genes in normal cells either by acting as a corepressor or coactivator. In addition, physiological functions of MTA proteins are likely to be influenced by its differential expression, subcellular localization, and regulation by upstream modulators and extracellular signals. This review summarizes our current understanding of the physiological functions of the MTA proteins in model systems. In particular, we highlight recent advances of the role MTA proteins play in the brain, eye, circadian rhythm, mammary gland biology, spermatogenesis, liver, immunomodulation and inflammation, cellular radio-sensitivity, and hematopoiesis and differentiation. Based on the growth of knowledge regarding the exciting new facets of the MTA family of proteins in biology and medicine, we speculate that the next burst of findings in this field may reveal further molecular regulatory insights of non-redundant functions of MTA coregulators in the normal physiology as well as in pathological conditions outside cancer.
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Ensamble y Desensamble de Cromatina/genética , Histona Desacetilasas/genética , Complejo Desacetilasa y Remodelación del Nucleosoma Mi-2/genética , Neoplasias/genética , Proteínas Represoras/genética , Animales , Caenorhabditis elegans , Ensamble y Desensamble de Cromatina/fisiología , Modelos Animales de Enfermedad , Drosophila melanogaster , Histona Desacetilasas/biosíntesis , Humanos , Complejo Desacetilasa y Remodelación del Nucleosoma Mi-2/fisiología , Proteínas de Neoplasias/biosíntesis , Proteínas de Neoplasias/genética , Neoplasias/fisiopatología , Proteínas Represoras/biosíntesis , Transducción de Señal/genética , TransactivadoresRESUMEN
The MTA1 protein contributes to the process of cancer progression and metastasis through multiple genes and protein targets and interacting proteins with roles in transformation, anchorage-independent growth, invasion, survival, DNA repair, angiogenesis, hormone independence, metastasis, and therapeutic resistance. Because the roles and clinical significance of MTA proteins in human cancer are discussed by other contributors in this issue, this review will focus on our current understanding of the underlying principles of action behind the biological effects of MTA1. MTA proteins control a spectrum of cancer-promoting processes by modulating the expression of target genes and/or the activity of MTA-interacting proteins. In the case of MTA1, these functions are manifested through posttranslational modifications of MTA1 in response to upstream signals, MTA1 interaction with binding proteins, and the expression of target gene products. Studies delineating the molecular basis of dual functionality of MTA1 reveal that the functions of MTA1-chromatin-modifying complexes in the context of target gene regulation are dynamic in nature. The nature and targets of MTA1-chromatin-modifying complexes are also governed by the dynamic plasticity of the nucleosome landscape as well as kinetics of activation and inactivation of enzymes responsible for posttranslational modifications on the MTA1 protein. These broadly applicable functions also explain why MTA1 may be a "hub" gene in cancer. Because the deregulation of enzymes and their substrates with roles in MTA1 biology is not necessarily limited to cancer, we speculate that the lessons from MTA1 as a prototype dual master coregulator will be relevant for other human diseases. In this context, the concept of the dynamic nature of corepressor versus coactivator complexes and the MTA1 proteome as a function of time to signal is likely to be generally applicable to other multiprotein regulatory complexes in living systems.
Asunto(s)
Ensamble y Desensamble de Cromatina/genética , Histona Desacetilasas/genética , Complejo Desacetilasa y Remodelación del Nucleosoma Mi-2/genética , Neoplasias/genética , Proteínas Represoras/genética , Ensamble y Desensamble de Cromatina/fisiología , Regulación Neoplásica de la Expresión Génica , Histona Desacetilasas/biosíntesis , Humanos , Complejo Desacetilasa y Remodelación del Nucleosoma Mi-2/fisiología , Neoplasias/fisiopatología , Proteoma/genética , Proteínas Represoras/biosíntesis , Transducción de Señal/genética , TransactivadoresRESUMEN
Despite being one of the most well-studied transcription factors, the temporal regulation of p53-mediated transcription is not very well understood. Recent data suggest that target specificity of p53-mediated transactivation is achieved by posttranslational modifications of p53. K120 acetylation is a modification critical for recruitment of p53 to proapoptotic targets. Our data reveal that histone deacetylase 5 (HDAC5) binds to p53 and abrogates K120 acetylation, resulting in preferential recruitment of p53 to proarrest and antioxidant targets at early phases of stress. However, upon prolonged genotoxic stress, HDAC5 undergoes nuclear export. Concomitantly, p53 is acetylated at the K120 residue and selectively transactivates proapoptotic target genes, leading to onset of apoptosis. Furthermore, upon genotoxic stress in mice where HDAC5 expression is downregulated, the onset of apoptosis is accelerated in the highly vulnerable tissues. These findings suggest that HDAC5 is a key determinant of p53-mediated cell fate decisions in response to genotoxic stress.
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Acetilación/efectos de los fármacos , Apoptosis/genética , Daño del ADN/genética , Histona Desacetilasas/genética , Proteína p53 Supresora de Tumor/metabolismo , Transporte Activo de Núcleo Celular/genética , Adenoviridae/metabolismo , Adenoviridae/patogenicidad , Animales , Apoptosis/efectos de los fármacos , Etopósido/farmacología , Regulación de la Expresión Génica/efectos de los fármacos , Regulación de la Expresión Génica/genética , Células HCT116 , Histona Desacetilasas/metabolismo , Humanos , Lisina/metabolismo , Ratones , Unión Proteica , Especies Reactivas de Oxígeno/metabolismo , Activación Transcripcional/efectos de los fármacos , Activación Transcripcional/genética , Proteína p53 Supresora de Tumor/genéticaRESUMEN
Metabolic reprogramming is an integral part of tumorigenesis. Tumor suppressor p53 is a well studied transcription factor intimately linked with the control of cell cycle progression and apoptosis. Here, we discuss the emerging role of p53 in the transcriptional regulation of metabolism. This activity is a key component of p53 tumor suppression function.
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Transformación Celular Neoplásica/metabolismo , Regulación Neoplásica de la Expresión Génica , Proteína p53 Supresora de Tumor/metabolismo , Apoptosis , Ciclo Celular , Transformación Celular Neoplásica/genética , Humanos , Factores de Transcripción , Proteína p53 Supresora de Tumor/genéticaRESUMEN
Metabolic stress results in p53 activation, which can trigger cell-cycle arrest, ROS clearance, or apoptosis. However, what determines the p53-mediated cell fate decision upon metabolic stress is not very well understood. We show here that PGC-1α binds to p53 and modulates its transactivation function, resulting in preferential transactivation of proarrest and metabolic target genes. Thus glucose starvation results in p53-dependent cell-cycle arrest and ROS clearance, but abrogation of PGC-1α expression results in extensive apoptosis. Additionally, prolonged starvation results in PGC-1α degradation concomitant with induction of apoptosis. We have also identified RNF2, a Polycomb group (PcG) protein, as the cognate E3 ubiquitin ligase. Starvation of mice where PGC-1α expression is abrogated results in loss of p53-mediated ROS clearance, enhanced p53-dependent apoptosis, and consequent severe liver atrophy. These findings provide key insights into the role of PGC-1α in regulating p53-mediated cell fate decisions in response to metabolic stress.