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A Murine Cell Line Based Model of Chronic CDK9 Inhibition to Study Widespread Non-Genetic Transcriptional Elongation Defects TEdeff in Cancers

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Published on: September 26, 2019

El eje PP2A-Integrator-CDK9 ajusta la transcripción y puede ser dirigido terapéuticamente en el cáncer

Stephin J Vervoort¹, Sarah A Welsh², Jennifer R Devlin¹

¹Peter MacCallum Cancer Centre, Melbourne 3000, VIC, Australia; The Sir Peter MacCallum Department of Oncology, University of Melbourne, Parkville 3010, VIC, Australia.

|May 18, 2021

Resumen

Un complejo de proteína fosfatasa 2A (PP2A) recientemente descubierto se opone a la actividad de la cinasa 9 dependiente de la ciclina (CDK9) en la regulación génica. Este hallazgo revela una nueva estrategia terapéutica mediante la combinación de la activación de PP2A con la inhibición de CDK9 para el tratamiento del cáncer.

Área de la Ciencia:

Biología molecular
Biología del cáncer
La bioquímica

Sus antecedentes:

La expresión génica está regulada por las cinasas dependientes de la ciclina (CDK) durante la transcripción.
CDK9 controla el punto de control de pausa de la transcripción de la ARN polimerasa II (RNAPII).

Objetivo del estudio:

Investigar los mecanismos reguladores que se oponen a la actividad de CDK9 en la transcripción de RNAPII.
Explorar el potencial terapéutico de dirigir el equilibrio entre la actividad de la quinasa y la fosfatasa en el cáncer.

Principales métodos:

Investigó el papel de la proteína fosfatasa 2A (PP2A) y la subunidad del complejo integrador INTS6 en la transcripción de RNAPII.
Se analizaron los efectos de la pérdida de INTS6 en los fosfosubstratos de CDK9 y en las respuestas transcripcionales oncogénicas.
Se evaluó la eficacia terapéutica de la activación combinada de PP2A y la inhibición de CDK9 en modelos de cáncer preclínicos.

Principales resultados:

Se descubrió que un complejo PP2A, reclutado por INTS6, antagoniza la transcripción mediada por CDK9.
La pérdida de INTS6 conduce a la resistencia a la inhibición de la CDK9, a un aumento de los fosfosubstratos de la CDK9 y a una amplificación de la transcripción oncogénica.
La activación farmacológica de PP2A combinada con la inhibición de CDK9 demostró beneficios terapéuticos in vivo tanto contra la leucemia como contra los tumores sólidos.

Conclusiones:

La expresión génica de ajuste fino requiere un equilibrio entre la actividad de la quinasa y la fosfatasa durante la transcripción.
La desregulación de este equilibrio en el cáncer presenta una vulnerabilidad terapéutica.
Dirigirse al eje PP2A-CDK9 ofrece una estrategia prometedora para el tratamiento del cáncer.

Palabras clave:

El CDK9 Pantalla de CRISPR-Cas9 El CTD El integrador El PP2A Activación del PP2A La ARN polimerasa II el cáncer pausa-liberación Fósfatasa y sus derivados Elongamiento transcripcional

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