Journal
NATURE CELL BIOLOGY
Volume 20, Issue 10, Pages 1181-+Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/s41556-018-0178-0
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Funding
- Andrew Sabin Family Fellow Award
- Sister Institution Network Fund
- University of Texas MD Anderson Cancer Center, Anna Fuller Fund
- National Institutes of Health [R01CA181196, R01HG007538, R01CA193466, R01CA172724]
- CPRIT Research Training Grant [RP170067]
- National Institutes of Health Cancer Center Support Grant [P30CA016672]
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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 metabolismrelated 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.
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