BAP1 links metabolic regulation of ferroptosis to tumour suppression.
Nat Cell Biol
; 20(10): 1181-1192, 2018 10.
Article
en En
| MEDLINE
| ID: mdl-30202049
ABSTRACT
The roles and regulatory mechanisms of ferroptosis (a non-apoptotic form of cell death) in cancer remain unclear. The tumour suppressor BRCA1-associated protein 1 (BAP1) encodes a nuclear deubiquitinating enzyme to reduce histone 2A ubiquitination (H2Aub) on chromatin. Here, integrated transcriptomic, epigenomic and cancer genomic analyses link BAP1 to metabolism-related biological processes, and identify cystine transporter SLC7A11 as a key BAP1 target gene in human cancers. Functional studies reveal that BAP1 decreases H2Aub occupancy on the SLC7A11 promoter and represses SLC7A11 expression in a deubiquitinating-dependent manner, and that BAP1 inhibits cystine uptake by repressing SLC7A11 expression, leading to elevated lipid peroxidation and ferroptosis. Furthermore, we show that BAP1 inhibits tumour development partly through SLC7A11 and ferroptosis, and that cancer-associated BAP1 mutants lose their abilities to repress SLC7A11 and to promote ferroptosis. Together, our results uncover a previously unappreciated epigenetic mechanism coupling ferroptosis to tumour suppression.
Texto completo:
1
Colección:
01-internacional
Banco de datos:
MEDLINE
Asunto principal:
Regulación Neoplásica de la Expresión Génica
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Proteínas Supresoras de Tumor
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Ubiquitina Tiolesterasa
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Metabolismo Energético
Límite:
Animals
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Humans
Idioma:
En
Revista:
Nat Cell Biol
Año:
2018
Tipo del documento:
Article
País de afiliación:
Estados Unidos