MED12 and BRD4 cooperate to sustain cancer growth upon loss of mediator kinase.
Mol Cell
; 82(1): 123-139.e7, 2022 01 06.
Article
en En
| MEDLINE
| ID: mdl-34910943
ABSTRACT
Mediator kinases (CDK8/19) are transcriptional regulators broadly implicated in cancer. Despite their central role in fine-tuning gene-expression programs, we find complete loss of CDK8/19 is tolerated in colorectal cancer (CRC) cells. Using orthogonal functional genomic and pharmacological screens, we identify BET protein inhibition as a distinct vulnerability in CDK8/19-depleted cells. Combined CDK8/19 and BET inhibition led to synergistic growth retardation in human and mouse models of CRC. Strikingly, depletion of CDK8/19 in these cells led to global repression of RNA polymerase II (Pol II) promoter occupancy and transcription. Concurrently, loss of Mediator kinase led to a profound increase in MED12 and BRD4 co-occupancy at enhancer elements and increased dependence on BET proteins for the transcriptional output of cell-essential genes. In total, this work demonstrates a synthetic lethal interaction between Mediator kinase and BET proteins and exposes a therapeutic vulnerability that can be targeted using combination therapies.
Palabras clave
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Factores de Transcripción
/
Proteínas Nucleares
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Neoplasias Colorrectales
/
Quinasas Ciclina-Dependientes
/
Proteínas de Ciclo Celular
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Proliferación Celular
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Complejo Mediador
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Quinasa 8 Dependiente de Ciclina
Tipo de estudio:
Prognostic_studies
Límite:
Aged80
Idioma:
En
Revista:
Mol Cell
Asunto de la revista:
BIOLOGIA MOLECULAR
Año:
2022
Tipo del documento:
Article
País de afiliación:
Australia