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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  1. 1.

    Pavlova, N. N. & Thompson, C. B. The emerging hallmarks of cancer metabolism. Cell Metab. 23, 27–47 (2016).

  2. 2.

    DeBerardinis, R. J. & Chandel, N. S. Fundamentals of cancer metabolism. Sci. Adv. 2, e1600200 (2016).

  3. 3.

    Green, D. R., Galluzzi, L. & Kroemer, G. Cell biology. Metabolic control of cell death. Science 345, 1250256 (2014).

  4. 4.

    Boroughs, L. K. & DeBerardinis, R. J. Metabolic pathways promoting cancer cell survival and growth. Nat. Cell. Biol. 17, 351–359 (2015).

  5. 5.

    Jones, R. G. & Thompson, C. B. Tumor suppressors and cell metabolism: a recipe for cancer growth. Genes Dev. 23, 537–548 (2009).

  6. 6.

    Hanahan, D. & Weinberg, R. A. Hallmarks of cancer: the next generation. Cell 144, 646–674 (2011).

  7. 7.

    Dixon, S. J. et al. Ferroptosis: an iron-dependent form of nonapoptotic cell death. Cell 149, 1060–1072 (2012).

  8. 8.

    Xie, Y. et al. Ferroptosis: process and function. Cell Death Differ. 23, 369–379 (2016).

  9. 9.

    Cao, J. Y. & Dixon, S. J. Mechanisms of ferroptosis. Cell Mol. Life Sci. 73, 2195–2209 (2016).

  10. 10.

    Yang, W. S. & Stockwell, B. R. Ferroptosis: death by lipid peroxidation. Trends Cell Biol. 26, 165–176 (2016).

  11. 11.

    Stockwell, B. R. et al. Ferroptosis: a regulated cell death nexus linking metabolism, redox biology, and disease. Cell 171, 273–285 (2017).

  12. 12.

    Lim, J. C. & Donaldson, P. J. Focus on molecules: the cystine/glutamate exchanger (System x(c)(-)). Exp. Eye Res. 92, 162–163 (2011).

  13. 13.

    Conrad, M. & Sato, H. The oxidative stress-inducible cystine/glutamate antiporter, System x(c)(-): cystine supplier and beyond. Amino Acids 42, 231–246 (2012).

  14. 14.

    Koppula, P., Zhang, Y., Zhuang, L. & Gan, B. Amino acid transporter SLC7A11/xCT at the crossroads of regulating redox homeostasis and nutrient dependency of cancer. Cancer Commun. 38, 12 (2018).

  15. 15.

    Yang, W. S. et al. Regulation of ferroptotic cancer cell death by GPX4. Cell 156, 317–331 (2014).

  16. 16.

    Friedmann Angeli, J. P. et al. Inactivation of the ferroptosis regulator Gpx4 triggers acute renal failure in mice. Nat. Cell. Biol. 16, 1180–1191 (2014).

  17. 17.

    Igney, F. H. & Krammer, P. H. Death and anti-death: tumour resistance to apoptosis. Nat. Rev. Cancer 2, 277–288 (2002).

  18. 18.

    Green, D. R. & Evan, G. I. A matter of life and death. Cancer Cell 1, 19–30 (2002).

  19. 19.

    Carbone, M. et al. BAP1 and cancer. Nat. Rev. Cancer 13, 153–159 (2013).

  20. 20.

    Dey, A. et al. Loss of the tumor suppressor BAP1 causes myeloid transformation. Science 337, 1541–1546 (2012).

  21. 21.

    Ji, Z. et al. The forkhead transcription factor FOXK2 acts as a chromatin targeting factor for the BAP1-containing histone deubiquitinase complex. Nucleic Acids Res. 42, 6232–6242 (2014).

  22. 22.

    Baymaz, H. I. et al. MBD5 and MBD6 interact with the human PR–DUB complex through their methyl-CpG-binding domain. Proteomics 14, 2179–2189 (2014).

  23. 23.

    Yu, H. et al. The ubiquitin carboxyl hydrolase BAP1 forms a ternary complex with YY1 and HCF-1 and is a critical regulator of gene expression. Mol. Cell. Biol. 30, 5071–5085 (2010).

  24. 24.

    Misaghi, S. et al. Association of C-terminal ubiquitin hydrolase BRCA1-associated protein 1 with cell cycle regulator host cell factor 1. Mol. Cell. Biol. 29, 2181–2192 (2009).

  25. 25.

    Machida, Y. J., Machida, Y., Vashisht, A. A., Wohlschlegel, J. A. & Dutta, A. The deubiquitinating enzyme BAP1 regulates cell growth via interaction with HCF-1. J. Biol. Chem. 284, 34179–34188 (2009).

  26. 26.

    Scheuermann, J. C. et al. Histone H2A deubiquitinase activity of the polycomb repressive complex PR-DUB. Nature 465, 243–247 (2010).

  27. 27.

    Kallin, E. M. et al. Genome-wide uH2A localization analysis highlights Bmi1-dependent deposition of the mark at repressed genes. PLoS Genet. 5, e1000506 (2009).

  28. 28.

    Weake, V. M. & Workman, J. L. Histone ubiquitination: triggering gene activity. Mol. Cell 29, 653–663 (2008).

  29. 29.

    Wang, H. et al. Role of histone H2A ubiquitination in polycomb silencing. Nature 431, 873–878 (2004).

  30. 30.

    Harbour, J. W. et al. Frequent mutation of BAP1 in metastasizing uveal melanomas. Science 330, 1410–1413 (2010).

  31. 31.

    Pena-Llopis, S. et al. BAP1 loss defines a new class of renal cell carcinoma. Nat. Genet. 44, 751–759 (2012).

  32. 32.

    Jiao, Y. et al. Exome sequencing identifies frequent inactivating mutations in BAP1, ARID1A and PBRM1 in intrahepatic cholangiocarcinomas. Nat. Genet. 45, 1470–1473 (2013).

  33. 33.

    Bott, M. et al. The nuclear deubiquitinase BAP1 is commonly inactivated by somatic mutations and 3p21.1 losses in malignant pleural mesothelioma. Nat. Genet. 43, 668–672 (2011).

  34. 34.

    Dai, F. et al. BAP1 inhibits the ER stress gene regulatory network and modulates metabolic stress response. Proc. Natl Acad. Sci. USA 114, 3192–3197 (2017).

  35. 35.

    Cancer Genome Atlas Research Network Comprehensive molecular characterization of clear cell renal cell carcinoma. Nature 499, 43–49 (2013).

  36. 36.

    Robertson, A. G. et al. Integrative analysis identifies four molecular and clinical subsets in uveal melanoma. Cancer Cell 32, 204–220 (2017).

  37. 37.

    Fishbein, L. et al. Comprehensive molecular characterization of pheochromocytoma and paraganglioma. Cancer Cell 31, 181–193 (2017).

  38. 38.

    Cancer Genome Atlas Research Network Comprehensive molecular characterization of papillary renal-cell carcinoma. N. Engl. J. Med. 374, 135–145 (2016).

  39. 39.

    Cancer Genome Atlas Research Network Comprehensive molecular portraits of human breast tumours. Nature 490, 61–70 (2012).

  40. 40.

    Jiang, L. et al. Ferroptosis as a p53-mediated activity during tumour suppression. Nature 520, 57–62 (2015).

  41. 41.

    Wang, S. J., Ou, Y., Jiang, L. & Gu, W. Ferroptosis: a missing puzzle piece in the p53 blueprint? Mol. Cell. Oncol. 3, e1046581 (2016).

  42. 42.

    Vissers, J. H., Nicassio, F., van Lohuizen, M., Di Fiore, P. P. & Citterio, E. The many faces of ubiquitinated histone H2A: insights from the DUBs. Cell Divis. 3, 8 (2008).

  43. 43.

    Li, B., Carey, M. & Workman, J. L. The role of chromatin during transcription. Cell 128, 707–719 (2007).

  44. 44.

    Hauri, S. et al. A high-density map for navigating the human polycomb complexome. Cell Rep. 17, 583–595 (2016).

  45. 45.

    Gao, M., Monian, P., Quadri, N., Ramasamy, R. & Jiang, X. Glutaminolysis and transferrin regulate ferroptosis. Mol. Cell 59, 298–308 (2015).

  46. 46.

    Young, O., Crotty, T., O’Connell, R., O’Sullivan, J. & Curran, A. J. Levels of oxidative damage and lipid peroxidation in thyroid neoplasia. Head Neck 32, 750–756 (2010).

  47. 47.

    Gao, J. et al. Integrative analysis of complex cancer genomics and clinical profiles using the cBioPortal. Sci. Signal 6, pl1 (2013).

  48. 48.

    Cerami, E. et al. The cBio cancer genomics portal: an open platform for exploring multidimensional cancer genomics data. Cancer Discov. 2, 401–404 (2012).

  49. 49.

    Zhang, W. et al. Stromal control of cystine metabolism promotes cancer cell survival in chronic lymphocytic leukaemia. Nat. Cell. Biol. 14, 276–286 (2012).

  50. 50.

    Bononi, A. et al. BAP1 regulates IP3R3-mediated Ca2+ flux to mitochondria suppressing cell transformation. Nature 546, 549–553 (2017).

  51. 51.

    Okino, Y., Machida, Y., Frankland-Searby, S. & Machida, Y. J. BRCA1-associated protein 1 (BAP1) deubiquitinase antagonizes the ubiquitin-mediated activation of FoxK2 target genes. J. Biol. Chem. 290, 1580–1591 (2015).

  52. 52.

    Schuettengruber, B. & Cavalli, G. The DUBle life of polycomb complexes. Dev. Cell 18, 878–880 (2010).

  53. 53.

    Henry, K. W. et al. Transcriptional activation via sequential histone H2B ubiquitylation and deubiquitylation, mediated by SAGA-associated Ubp8. Genes Dev. 17, 2648–2663 (2003).

  54. 54.

    Liu, X. et al. LncRNA NBR2 engages a metabolic checkpoint by regulating AMPK under energy stress. Nat. Cell. Biol. 18, 431–442 (2016).

  55. 55.

    Koppula, P., Zhang, Y., Shi, J., Li, W. & Gan, B. The glutamate/cystine antiporter SLC7A11/xCT enhances cancer cell dependency on glucose by exporting glutamate. J. Biol. Chem. 292, 14240–14249 (2017).

  56. 56.

    Liu, X. & Gan, B. lncRNA NBR2 modulates cancer cell sensitivity to phenformin through GLUT1. Cell Cycle 15, 3471–3481 (2016).

  57. 57.

    Lin, A. et al. The FoxO-BNIP3 axis exerts a unique regulation of mTORC1 and cell survival under energy stress. Oncogene 33, 3183–3194 (2014).

  58. 58.

    Lee, H. et al. BAF180 regulates cellular senescence and hematopoietic stem cell homeostasis through p21. Oncotarget 7, 19134–19146 (2016).

  59. 59.

    Lin, A. et al. FoxO transcription factors promote AKT Ser473 phosphorylation and renal tumor growth in response to pharmacological inhibition of the PI3K-AKT pathway. Cancer Res. 74, 1682–1693 (2014).

  60. 60.

    Gan, B. et al. Lkb1 regulates quiescence and metabolic homeostasis of haematopoietic stem cells. Nature 468, 701–704 (2010).

  61. 61.

    Gan, B. et al. mTORC1-dependent and -independent regulation of stem cell renewal, differentiation, and mobilization. Proc. Natl Acad. Sci. USA 105, 19384–19389 (2008).

  62. 62.

    Gan, B., Yoo, Y. & Guan, J. L. Association of focal adhesion kinase with tuberous sclerosis complex 2 in the regulation of s6 kinase activation and cell growth. J. Biol. Chem. 281, 37321–37329 (2006).

  63. 63.

    Gan, B., Melkoumian, Z. K., Wu, X., Guan, K. L. & Guan, J. L. Identification of FIP200 interaction with the TSC1–TSC2 complex and its role in regulation of cell size control. J. Cell Biol. 170, 379–389 (2005).

  64. 64.

    Li, X. et al. Proteomic analysis of the human tankyrase protein interaction network reveals its role in pexophagy. Cell Rep. 20, 737–749 (2017).

  65. 65.

    Gan, B. et al. FoxOs enforce a progression checkpoint to constrain mTORC1-activated renal tumorigenesis. Cancer Cell 18, 472–484 (2010).

  66. 66.

    Gan, B. et al. Role of FIP200 in cardiac and liver development and its regulation of TNFalpha and TSC-mTOR signaling pathways. J. Cell Biol. 175, 121–133 (2006).

  67. 67.

    Zhang, Y. et al. Model-based analysis of ChIP–seq (MACS). Genome Biol. 9, R137 (2008).

  68. 68.

    Wang, L., Feng, Z., Wang, X., Wang, X. & Zhang, X. DEGseq: an R package for identifying differentially expressed genes from RNA-seq data. Bioinformatics 26, 136–138 (2010).

  69. 69.

    Ramirez, F., Dundar, F., Diehl, S., Gruning, B. A. & Manke, T. deepTools: a flexible platform for exploring deep-sequencing data. Nucleic Acids Res. 42, W187–W191 (2014).

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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.

Author information

Author notes

    • Xu Li

    Present address: Institute of Biology, Westlake University, Hangzhou, Zhejiang Province, China

    • Zhen-Dong Xiao

    Present address: Guangdong Key Laboratory of Liver Disease Research, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China

  1. These authors contributed equally: Yilei Zhang, Jiejun Shi.


  1. Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

    • Yilei Zhang
    • , Xiaoguang Liu
    • , Zihua Gong
    • , Pranavi Koppula
    • , Kapil Sirohi
    • , Xu Li
    • , Hyemin Lee
    • , Li Zhuang
    • , Zhen-Dong Xiao
    • , Junjie Chen
    •  & Boyi Gan
  2. Division of Biostatistics, Dan L. Duncan Cancer Center and Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, USA

    • Jiejun Shi
    •  & Wei Li
  3. Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

    • Li Feng
    • , Gang Chen
    •  & Peng Huang
  4. Department of Cancer Biology, Cleveland Clinic Lerner Research Institute, Cleveland, OH, USA

    • Zihua Gong
  5. The University of Texas MD Anderson UT Health Graduate School of Biomedical Sciences, Houston, TX, USA

    • Pranavi Koppula
    • , Mien-Chie Hung
    • , Junjie Chen
    • , Peng Huang
    •  & Boyi Gan
  6. Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

    • Yongkun Wei
    • , Mien-Chie Hung
    •  & Boyi Gan
  7. Graduate Institute of Biomedical Sciences and Center for Molecular Medicine, China Medical University, Taichung, Taiwan

    • Mien-Chie Hung


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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.

Competing interests

The authors declare no competing interests.

Corresponding authors

Correspondence to Wei Li or Boyi Gan.

Supplementary Information

  1. Supplementary Information

    Supplementary Figures 1–7 and Supplementary Table legends

  2. Reporting Summary

  3. 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.

  4. Supplementary Table 2

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

  5. Supplementary Table 3

    List of cancer-associated BAP1 mutants.

  6. Supplementary Table 4

    Sequence of oligonucleotides used in this study.

  7. Supplementary Table 5

    Statistics source data.

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