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DNMT1 y DNMT3b cooperan para silenciar los genes en las células cancerosas humanas
Ina Rhee1, Kurtis E Bachman, Ben Ho Park
1The Howard Hughes Medical Institute, Johns Hopkins University School of Medicine, Baltimore, Maryland 21231, USA.
Nature
|April 5, 2002
Resumen
Las células cancerosas humanas dependen de dos enzimas clave, la ADN metiltransferasa 1 (DNMT1) y DNMT3B, para la metilación del ADN y el silenciamiento de genes. Interrumpir ambos reduce significativamente la metilación, lo que afecta el crecimiento de las células cancerosas.
Área de la Ciencia:
- La epigenética es la epigenética.
- Biología del cáncer Biología del cáncer.
- Genética molecular La genética molecular.
Sus antecedentes:
- La inactivación del gen supresor tumoral es crucial en el desarrollo del cáncer, a menudo a través del silenciamiento epigenético a través de la hipermetilación.
- Los mecanismos de la metilación del ADN específico del locus y global en las células humanas no se comprenden completamente.
- Mientras que Dnmt1 es primario en ratones, las células cancerosas humanas que carecen de DNMT1 retienen una metilación sustancial.
Objetivo del estudio:
- Investigar las funciones de DNMT1 y DNMT3B en el mantenimiento de la metilación del ADN y el silenciamiento de genes en células cancerosas humanas.
- Determinar el impacto de la interrupción combinada de DNMT1 y DNMT3B en la metilación genómica y la proliferación de células cancerosas.
Principales métodos:
- Disrupción del gen humano DNMT3B en una línea celular de cáncer colorrectal.
- Disrupción genética tanto de DNMT1 como de DNMT3B.
- Evaluación de los niveles globales de metilación del ADN, secuencias repetidas, impresión de IGF2, silenciamiento de p16INK4a y crecimiento celular.
Principales resultados:
- La interrupción de DNMT3B solo tuvo un efecto mínimo en la metilación global del ADN (<3%).
- La interrupción simultánea de DNMT1 y DNMT3B casi eliminó la actividad de la metiltransferasa y redujo la metilación genómica en >95%.
- Esto condujo a la desmetilación de las secuencias repetidas, la pérdida de la impresión de IGF2, la reactivación de p16INK4a y la supresión del crecimiento de las células cancerosas.
Conclusiones:
- Dos ADN metiltransferasas, DNMT1 y DNMT3B, mantienen cooperativamente la metilación del ADN y el silenciamiento de genes en las células cancerosas humanas.
- La metilación del ADN es esencial para la proliferación óptima de las células neoplásicas.
- Dirigirse a estas enzimas podría ofrecer estrategias terapéuticas para el tratamiento del cáncer.
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