BAP1 links metabolic regulation of ferroptosis to tumour suppression

Nat Cell Biol. 2018 Oct;20(10):1181-1192. doi: 10.1038/s41556-018-0178-0. Epub 2018 Sep 10.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Transport System y+ / genetics
  • Amino Acid Transport System y+ / metabolism
  • Animals
  • Cell Death / genetics
  • Cell Line, Tumor
  • Cells, Cultured
  • Energy Metabolism / genetics*
  • Gene Expression Regulation, Neoplastic*
  • HEK293 Cells
  • Histones / metabolism
  • Humans
  • Lipid Peroxidation
  • Mice
  • Neoplasms / genetics
  • Neoplasms / metabolism
  • Neoplasms / pathology
  • Tumor Suppressor Proteins / genetics*
  • Tumor Suppressor Proteins / metabolism
  • Ubiquitin Thiolesterase / genetics*
  • Ubiquitin Thiolesterase / metabolism
  • Ubiquitination


  • Amino Acid Transport System y+
  • BAP1 protein, human
  • Histones
  • SLC7A11 protein, human
  • Tumor Suppressor Proteins
  • Ubiquitin Thiolesterase