RESUMEN
Colorectal cancer (CRC) is the third most common cancer worldwide, with more than 1.3 million new cases and 690 000 deaths each year. In China, the incidence of CRC has increased dramatically due to dietary and lifestyle changes, to become the fifth leading cause of cancer-related death. Here, we performed whole-exome sequencing in 50 rectal cancer cases among the Chinese population as part of the International Cancer Genome Consortium research project. Frequently mutated genes and enriched pathways were identified. Moreover, a previously unreported gene, PCDHB3, was found frequently mutated in 5.19% cases. Additionally, PCDHB3 expression was found decreased in 81.6% of CRC tissues and all eight CRC cell lines tested. Low expression and cytoplasmic localization of PCDHB3 predict poor prognosis in advanced CRC. Copy number decrease and/or CpG island hypermethylation contributes to the pervasive decreased expression of PCDHB3. PCDHB3 inhibits CRC cell proliferation, migration, and epithelial-mesenchymal transition. The tumor-suppressive effects of PCDHB3 are partially due to inhibition of NF-κB transcriptional activity through K63 deubiquitination of p50 at lysine 244/252, which increases the binding affinity of inactive p50 homodimer to κB DNA, resulting in competitive inhibition of the transcription of NF-κB target genes by p65 dimers. Our study identified PCDHB3 as a novel tumor suppressor in CRC via inhibition of the NF-κB pathway, and its expression and localization may serve as prognostic markers for advanced CRC. Copyright © 2018 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
Asunto(s)
Biomarcadores de Tumor/genética , Cadherinas/genética , Neoplasias Colorrectales/genética , Secuenciación del Exoma , Silenciador del Gen , Genes Supresores de Tumor , Mutación , Adulto , Anciano , Animales , Pueblo Asiatico/genética , Biomarcadores de Tumor/metabolismo , Cadherinas/metabolismo , Línea Celular Tumoral , Movimiento Celular , Proliferación Celular , China , Neoplasias Colorrectales/etnología , Neoplasias Colorrectales/metabolismo , Neoplasias Colorrectales/patología , Islas de CpG , Metilación de ADN , Regulación hacia Abajo , Femenino , Dosificación de Gen , Regulación Neoplásica de la Expresión Génica , Predisposición Genética a la Enfermedad , Humanos , Masculino , Ratones Endogámicos BALB C , Ratones Desnudos , Persona de Mediana Edad , FN-kappa B/genética , FN-kappa B/metabolismo , Fenotipo , ProtocadherinasRESUMEN
RNA polymerase III (Pol III) is responsible for the synthesis of 5S ribosomal RNA (rRNA) and transfer RNAs (tRNAs) essential for protein synthesis and cell growth. Pol III is tightly controlled by growth signals such as nutrients and deregulation of Pol III-dependent transcription can lead to oncogenic transformation. In response to extracellular stimuli, the target of rapamycin complex 1 (TORC1) regulates Pol III activity through Maf1, a key conserved Pol III repressor. Recent studies have unraveled intricate mechanisms by which Maf1 activity is controlled at multiple levels, including nuclear transport and phoshorylation at specific chromatin loci. These studies suggest an emerging mode of gene regulation by extracellular signals inside the nucleus.
Asunto(s)
Núcleo Celular/metabolismo , Proteínas Represoras/metabolismo , Transducción de Señal , Animales , Proliferación Celular , Humanos , ARN Polimerasa III/metabolismo , ARN Ribosómico 5S/genética , ARN Ribosómico 5S/metabolismoRESUMEN
Nutrient starvation or rapamycin treatment, through inhibition of target of rapamycin, causes condensation of ribosomal DNA (rDNA) array and nucleolar contraction in budding yeast. Here we report that under such conditions, condensin is rapidly relocated into the nucleolus and loaded to rDNA tandem repeats, which is required for rDNA condensation. Rpd3-dependent histone deacetylation is necessary and sufficient for condensin's relocalization and loading to rDNA array, suggesting that histone modification plays a regulatory role for condensin targeting. Rapamycin independently, yet coordinately, inhibits rDNA transcription and promotes condensin loading to rDNA array. Unexpectedly, we found that inhibition of rDNA transcription in the absence of condensin loading leads to rDNA instability. Our data suggest that enrichment of condensin prevents rDNA instability during nutrient starvation. Together, these observations unravel a novel role for condensin in the maintenance of regional genomic stability.