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PKM2 fosforila la histona H3 y promueve la transcripción génica y la tumorigénesis
Weiwei Yang1, Yan Xia, David Hawke
1Brain Tumor Center and Department of Neuro-Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
Cell
|August 21, 2012
Resumen
La proteína del tumor PKM2 modifica directamente la histona H3, afectando la transcripción génica y el crecimiento del tumor cerebral. Esta actividad de la proteína quinasa es crucial para la regulación epigenética y ofrece objetivos terapéuticos potenciales.
Área de la Ciencia:
- Biología Molecular Biología Molecular
- Investigación del cáncer Investigación del cáncer.
- La epigenética es la epigenética.
Sus antecedentes:
- La piruvato quinasa M2 (PKM2) impulsa el efecto Warburg en los tumores.
- PKM2 también regula la transcripción génica a través de funciones no metabólicas.
- El mecanismo preciso de la regulación transcripcional de PKM2 no se entiende completamente.
Objetivo del estudio:
- Para aclarar el mecanismo no metabólico por el cual PKM2 regula la transcripción génica.
- Para investigar el papel de PKM2 en la modificación de la histona y su impacto en la tumorigénesis.
Principales métodos:
- Se ha investigado la unión de PKM2 a la histona H3.
- Se analizó la fosforilación de la histona H3 en T11 y la acetilación en K9.
- Evaluó la disociación de HDAC3 de los promotores del gen diana.
- Se evaluaron los efectos sobre la ciclina D1 y la expresión de c-Myc.
- Los niveles correlacionados de modificación histónica con la expresión de PKM2, el grado de glioma y el pronóstico.
Principales resultados:
- PKM2 se une directamente y fosforila la histona H3 en T11 tras la activación del receptor del FEG.
- Esta fosforilación facilita la disociación de HDAC3 de los promotores de CCND1 y MYC.
- Las modificaciones histónicas dependientes de PKM2 promueven la expresión de ciclina D1 y c-Myc inducida por el FEA.
- Estos cambios epigenéticos son vitales para la proliferación de células tumorales, la progresión del ciclo celular y la tumorigénesis cerebral.
- Los niveles de fosforilación de la histona H3 T11 se correlacionan con la PKM2 nuclear, el grado de glioma y el pronóstico del paciente.
Conclusiones:
- PKM2 funciona como una proteína quinasa en su papel no metabólico, modificando la histona H3.3.
- Las modificaciones histónicas mediadas por PKM2 son esenciales para la regulación genética epigenética y la tumorigénesis.
- La fosforilación de la histona H3 T11 sirve como un biomarcador potencial para la malignidad y el pronóstico del glioma.
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