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SMYD3 vincula la metilación de lisina de MAP3K2 con el cáncer impulsado por Ras

Pawel K Mazur¹, Nicolas Reynoird², Purvesh Khatri³

¹1] Department of Pediatrics, Stanford University School of Medicine, California 94305, USA [2] Department of Genetics, Stanford University School of Medicine, California 94305, USA [3].

|May 23, 2014

Resumen

La metilación de la lisina por SMYD3 (dominio SET y MYND que contiene proteína 3) promueve los cánceres impulsados por Ras al activar la señalización de la quinasa MAP. La inhibición de la actividad catalítica de SMYD3 detiene el desarrollo tumoral, ofreciendo una potencial estrategia terapéutica.

Área de la Ciencia:

La bioquímica es la bioquímica.
Biología Molecular Biología Molecular
Investigación del cáncer Investigación del cáncer.

Sus antecedentes:

La desregulación de la metilación de la lisina es un factor clave en el cáncer.
Los inhibidores de la histona lisina metiltransferasa (KMT) se están desarrollando como productos quimioterapéuticos.
El citoplasmático KMT SMYD3 está sobreexpresado en muchos tumores humanos, pero su papel en el cáncer no está claro.

Objetivo del estudio:

Para dilucidar el mecanismo molecular de SMYD3 en las vías del cáncer.
Para investigar el papel de SMYD3 en la tumorigénesis in vivo.
Para identificar los objetivos de SMYD3 y entender su regulación de la señalización del cáncer.

Principales métodos:

Se utilizaron modelos de ratón para el adenocarcinoma pancreático y pulmonar.
Empleó tecnología de matriz de proteínas para identificar objetivos SMYD3.
Investigó la metilación mediada por SMYD3 de MAP3K2 y su efecto en las vías de señalización.

Principales resultados:

SMYD3 metila MAP3K2, mejorando la señalización de la MAP quinasa y promoviendo los carcinomas impulsados por Ras.
La abrogación de la actividad catalítica de SMYD3 inhibió el desarrollo tumoral en modelos de ratón.
El agotamiento de SMYD3 sinergizó con un inhibidor de MEK para bloquear la tumorigénesis impulsada por Ras.
La metilación de MAP3K2 por SMYD3 bloquea su interacción con el complejo PP2A fosfatasa.

Conclusiones:

SMYD3 juega un papel fundamental en la regulación de la señalización Ras oncogénica a través de la metilación de la lisina.
Este estudio revela un nuevo papel para la metilación de la lisina en la integración de las cascadas de señalización de la quinasa citoplasmática.
SMYD3 es un objetivo terapéutico potencial para los cánceres impulsados por Ras.

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