SWI/SNF regulates a transcriptional program that induces senescence to prevent liver cancer.
Genes Dev
; 30(19): 2187-2198, 2016 Oct 01.
Article
en En
| MEDLINE
| ID: mdl-27737960
ABSTRACT
Oncogene-induced senescence (OIS) is a potent tumor suppressor mechanism. To identify senescence regulators relevant to cancer, we screened an shRNA library targeting genes deleted in hepatocellular carcinoma (HCC). Here, we describe how knockdown of the SWI/SNF component ARID1B prevents OIS and cooperates with RAS to induce liver tumors. ARID1B controls p16INK4a and p21CIP1a transcription but also regulates DNA damage, oxidative stress, and p53 induction, suggesting that SWI/SNF uses additional mechanisms to regulate senescence. To systematically identify SWI/SNF targets regulating senescence, we carried out a focused shRNA screen. We discovered several new senescence regulators, including ENTPD7, an enzyme that hydrolyses nucleotides. ENTPD7 affects oxidative stress, DNA damage, and senescence. Importantly, expression of ENTPD7 or inhibition of nucleotide synthesis in ARID1B-depleted cells results in re-establishment of senescence. Our results identify novel mechanisms by which epigenetic regulators can affect tumor progression and suggest that prosenescence therapies could be employed against SWI/SNF-mutated cancers.
Palabras clave
Texto completo:
1
Bases de datos:
MEDLINE
Asunto principal:
Factores de Transcripción
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Regulación Neoplásica de la Expresión Génica
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Senescencia Celular
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Carcinoma Hepatocelular
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Proteínas de Unión al ADN
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Neoplasias Hepáticas
Tipo de estudio:
Prognostic_studies
Límite:
Animals
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Female
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Humans
/
Male
Idioma:
En
Revista:
Genes Dev
Asunto de la revista:
BIOLOGIA MOLECULAR
Año:
2016
Tipo del documento:
Article
País de afiliación:
Reino Unido