The ZMYND8-regulated mevalonate pathway endows YAP-high intestinal cancer with metabolic vulnerability.
Mol Cell
; 81(13): 2736-2751.e8, 2021 07 01.
Article
em En
| MEDLINE
| ID: mdl-33932349
ABSTRACT
Cholesterol metabolism is tightly associated with colorectal cancer (CRC). Nevertheless, the clinical benefit of statins, the inhibitor of cholesterol biogenesis mevalonate (MVA) pathway, is inconclusive, possibly because of a lack of patient stratification criteria. Here, we describe that YAP-mediated zinc finger MYND-type containing 8 (ZMYND8) expression sensitizes intestinal tumors to the inhibition of the MVA pathway. We show that the oncogenic activity of YAP relies largely on ZMYND8 to enhance intracellular de novo cholesterol biogenesis. Disruption of the ZMYND8-dependent MVA pathway greatly restricts the self-renewal capacity of Lgr5+ intestinal stem cells (ISCs) and intestinal tumorigenesis. Mechanistically, ZMYND8 and SREBP2 drive the enhancer-promoter interaction to facilitate the recruitment of Mediator complex, thus upregulating MVA pathway genes. Together, our results establish that the epigenetic reader ZMYND8 endows YAP-high intestinal cancer with metabolic vulnerability.
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Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Neoplasias Colorretais
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Proteínas Supressoras de Tumor
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Proteínas Adaptadoras de Transdução de Sinal
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Ácido Mevalônico
Limite:
Animals
Idioma:
En
Ano de publicação:
2021
Tipo de documento:
Article