RESUMEN

Ovarian cancer survival rates have stagnated in the last 20 years despite the development of novel chemotherapeutic agents. Modulators of gene expression, such as histone deacetylase (HDAC) inhibitors, are among the new agents being used in clinical trials. Predictors of sensitivity to chemotherapy have remained elusive. In this study, we show that the expression of the transcriptional corepressor C-terminal binding protein-2 (CtBP2) is elevated in human ovarian tumors. Downregulation of CtBP2 expression in ovarian cancer cell lines using short-hairpin RNA strategy suppressed the growth rate and migration of the resultant cancer cells. The knockdown cell lines also showed upregulation of HDAC activity and increased sensitivity to selected HDAC inhibitors. Conversely, forced expression of wild-type CtBP2 in the knockdown cell lines reversed HDAC activity and partially rescued cellular sensitivity to the HDAC inhibitors. We propose that CtBP2 is an ovarian cancer oncogene that regulates gene expression program by modulating HDAC activity. CtBP2 expression may be a surrogate indicator of cellular sensitivity to HDAC inhibitors.

Asunto(s)

Oxidorreductasas de Alcohol/metabolismo , Resistencia a Antineoplásicos/fisiología , Regulación Neoplásica de la Expresión Génica/fisiología , Histona Desacetilasas/metabolismo , Neoplasias Glandulares y Epiteliales/metabolismo , Proteínas del Tejido Nervioso/metabolismo , Neoplasias Ováricas/metabolismo , Oxidorreductasas de Alcohol/genética , Antineoplásicos/farmacología , Western Blotting , Carcinoma Epitelial de Ovario , Proteínas Co-Represoras , Femenino , Técnicas de Silenciamiento del Gen , Inhibidores de Histona Desacetilasas/farmacología , Histona Desacetilasas/genética , Humanos , Inmunohistoquímica , Neoplasias Glandulares y Epiteliales/genética , Proteínas del Tejido Nervioso/genética , Oncogenes , Neoplasias Ováricas/genética