RESUMEN
BACKGROUND: The effect of histone deacetylase inhibitors (HDACIs) and DNA methyltransferase inhibitors (DNMTIs) on proliferation of endometrial cancer (EC) cells in vitro and in vivo was investigated. METHODS: Changes in methylation of the CDH1 promoter in HDACI- and DNMTI-treated HEC-1-B and RL-952 EC cells were detected. Nude mice with xenografted implants of human EC HEC-1-B cells were treated with valproic acid (VPA) and decitabine (DAC) and evaluated for tumor growth, CDH1 and Bcl-2 mRNA levels. RESULTS: DAC, VPA and suberoylanilide hydroxamic acid (SAHA) inhibited proliferation, induced cell cycle arrest and enhanced the apoptotic index in both cell lines, DAC, VPA and SAHA upregulated E-cadherin mRNA and protein levels and downregulated Bcl-2 mRNA levels in vitro. DAC and VPA inhibited tumor growth, upregulated CDH1 mRNA and downregulated Bcl-2 mRNA levels in vivo. CONCLUSIONS: A combination of HDACIs and DNMTIs suppresses the growth of EC, which is likely mediated by upregulation of E-cadherin and downregulation of Bcl-2.
Asunto(s)
Cadherinas/metabolismo , Carcinoma/tratamiento farmacológico , ADN (Citosina-5-)-Metiltransferasas/antagonistas & inhibidores , Neoplasias Endometriales/tratamiento farmacológico , Inhibidores Enzimáticos/farmacología , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Inhibidores de Histona Desacetilasas/farmacología , Animales , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Apoptosis/efectos de los fármacos , Azacitidina/análogos & derivados , Azacitidina/farmacología , Azacitidina/uso terapéutico , Cadherinas/genética , Puntos de Control del Ciclo Celular/efectos de los fármacos , Línea Celular Tumoral , ADN (Citosina-5-)-Metiltransferasas/metabolismo , Metilación de ADN , Decitabina , Inhibidores Enzimáticos/uso terapéutico , Femenino , Inhibidores de Histona Desacetilasas/uso terapéutico , Humanos , Ratones , Ratones Desnudos , Regiones Promotoras Genéticas , Proteínas Proto-Oncogénicas c-bcl-2/genética , Proteínas Proto-Oncogénicas c-bcl-2/metabolismo , Trasplante Heterólogo , Ácido Valproico/farmacología , Ácido Valproico/uso terapéuticoRESUMEN
The primary aim of this study is to evaluate the clinical significance of E-cadherin protein expression and the methylation status in CDH1 promoter in endometrial cancer. The expression of E-cadherin and methylation in its promoter region was analyzed, retrospectively, in 152 clinical tissue samples from patients with endometrial lesions. We found that the hypermethylation of CDH1 promoter, which caused low expression of E-cadherin in endometrial cancer, was associated with not only clinicopathological progress of endometrial cancer but also with the overall 5-year clinical survival rate. The findings provide the potential therapeutic and prognostic target molecule for patients with endomethrial cancer.