BAP1 links metabolic regulation of ferroptosis to tumour suppression

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.

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Fig. 1: Genome-wide analyses link BAP1 to metabolism-related biological processes.
Fig. 2: Cancer genomic analyses link SLC7A11 to BAP1-mediated tumour suppression in human cancers.
Fig. 3: BAP1 suppresses SLC7A11 expression and reduces H2Aub occupancy on the SLC7A11 promoter.
Fig. 4: BAP1 suppresses SLC7A11-mediated cystine uptake and promotes ferroptosis.
Fig. 5: BAP1 promotes ferroptosis through SLC7A11.
Fig. 6: BAP1 inhibits tumour development partly through SLC7A11 and ferroptosis.
Fig. 7: Cancer-associated BAP1 mutations are defective in regulating SLC7A11 and ferroptosis.

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Acknowledgements

The authors thank X. Shi for helpful discussion and suggestions and A. Ninetto from the Department of Scientific Publications at The University of Texas MD Anderson Cancer Center for manuscript editing. This research was supported by the Andrew Sabin Family Fellow Award, the Sister Institution Network Fund, an Institutional Research Grant from The University of Texas MD Anderson Cancer Center, Anna Fuller Fund (to B.G.) and grants from the National Institutes of Health (R01CA181196 to B.G.; R01HG007538 and R01CA193466 to W.L.; R01CA172724 to P.H.). B.G. is an Ellison Medical Foundation New Scholar and an Andrew Sabin Family Fellow. Y.Z. and P.K. are Scholars at the Center for Cancer Epigenetics at The University of Texas MD Anderson Cancer Center. P.K. is supported by a CPRIT Research Training Grant (RP170067). This research was also supported by a National Institutes of Health Cancer Center Support Grant P30CA016672 to The University of Texas MD Anderson Cancer Center.

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Contributions

Y.Z. performed most of the experiments shown in Figs. 3–7 with assistance from X. Liu, P.K., K.S., H.L., L.Z. and Z.X. J.S. conducted all the computational analyses shown in Figs. 1 and 2. F.L. and G.C. helped with cystine uptake experiments. W.Y. helped with the 4HNE IHC analysis. Z.G. conducted tandem affinity purification to identify BAP1-associated proteins. X.Li analysed BAP1-associated proteins. B.G. and W.L. supervised the study. Y.Z. and B.G. designed the experiments and wrote the manuscript. J.C., M.H. and P.H. helped with discussion and interpretation of results. All authors commented on the manuscript.

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Correspondence to Wei Li or Boyi Gan.

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Supplementary Information

Supplementary Information

Supplementary Figures 1–7 and Supplementary Table legends

Reporting Summary

Supplementary Table 1

The list of 354 upregulated and 187 downregulated genes with decreased H2Aub levels on restoration of BAP1 expression in UMRC6 cells, and the gene ontology analysis of these genes.

Supplementary Table 2

Cancer genomic analysis of BAP1 target genes in kidney clear cell carcinoma.

Supplementary Table 3

List of cancer-associated BAP1 mutants.

Supplementary Table 4

Sequence of oligonucleotides used in this study.

Supplementary Table 5

Statistics source data.

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Zhang, Y., Shi, J., Liu, X. et al. BAP1 links metabolic regulation of ferroptosis to tumour suppression. Nat Cell Biol 20, 1181–1192 (2018). https://doi.org/10.1038/s41556-018-0178-0

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