RESUMEN
The silencing of large chromosomal regions by epigenetic mechanisms has been reported to occur frequently in cancer. Epigenetic marks, such as histone methylation and acetylation, are altered at these loci. However, the mechanisms of formation of such aberrant gene clusters remain largely unknown. Here, we show that, in cancer cells, the epigenetic remodeling of chromatin into hypoacetylated domains covered with histone H3K27 trimethylation is paralleled by changes in higher-order chromatin structures. Using fluorescence in situ hybridization, we demonstrate that regional epigenetic silencing corresponds to the establishment of compact chromatin domains. We show that gene repression is tightly correlated to the state of chromatin compaction and not to the levels of H3K27me3-its removal through the knockdown of EZH2 does not induce significant gene expression nor chromatin decompaction. Moreover, transcription can occur with intact high-H3K27me3 levels; treatment with histone deacetylase inhibitors can relieve chromatin compaction and gene repression, without altering H3K27me3 levels. Our findings imply that compaction and subsequent repression of large chromatin domains are not direct consequences of PRC2 deregulation in cancer cells. By challenging the role of EZH2 in aberrant gene silencing in cancer, these findings have therapeutical implications, notably for the choice of epigenetic drugs for tumors with multiple regional epigenetic alterations.
Asunto(s)
Cromatina/genética , Metilación de ADN/genética , Complejo Represivo Polycomb 2/genética , Neoplasias de la Vejiga Urinaria/genética , Línea Celular Tumoral , Inmunoprecipitación de Cromatina , Proteína Potenciadora del Homólogo Zeste 2 , Epigénesis Genética/genética , Regulación Neoplásica de la Expresión Génica , Silenciador del Gen , N-Metiltransferasa de Histona-Lisina/biosíntesis , N-Metiltransferasa de Histona-Lisina/genética , Histonas/genética , Histonas/metabolismo , Humanos , Hibridación Fluorescente in Situ , Complejo Represivo Polycomb 2/antagonistas & inhibidores , Complejo Represivo Polycomb 2/biosíntesis , Neoplasias de la Vejiga Urinaria/patologíaRESUMEN
OBJECTIVE: Bladder spasms are a common cause of pain after surgical procedures that call for postoperative catheter drainage. Several therapeutic methods have been used to lessen these spasms but none have received widespread success. PATIENTS AND METHODS: Twenty-six children were included in a prospective randomized trial to evaluate the safety and efficacy of daily intravesical instillation of ropivacaine as prophylactic treatment for bladder spasms following ureteroneocystostomy. RESULTS: Although six patients experienced mild transient pain during instillation, there was no systemic toxicity attributable to the ropivacaine. The average number of spasms per day fell by half in the instillation group (p<0.01). CONCLUSION: Intravesical instillation of ropivacaine is a feasible alternative prophylactic treatment for postoperative bladder spasms.