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BAP1 links metabolic regulation of ferroptosis to tumour suppression.

Nature cell biology (2018-09-12)
Yilei Zhang, Jiejun Shi, Xiaoguang Liu, Li Feng, Zihua Gong, Pranavi Koppula, Kapil Sirohi, Xu Li, Yongkun Wei, Hyemin Lee, Li Zhuang, Gang Chen, Zhen-Dong Xiao, Mien-Chie Hung, Junjie Chen, Peng Huang, Wei Li, Boyi Gan
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.

MATERIALS
Product Number
Brand
Product Description

Sigma-Aldrich
Anti-ubiquityl-Histone H2A Antibody, clone E6C5, clone E6C5, Upstate®, from mouse
Sigma-Aldrich
Anti-Histone H2A Antibody, from rabbit, purified by affinity chromatography
Sigma-Aldrich
Monoclonal Anti-Vinculin antibody produced in mouse, clone VIN-11-5, ascites fluid
Sigma-Aldrich
tert-Butyl hydroperoxide solution, 70 wt. % in H2O
Sigma-Aldrich
Ferrostatin-1, ≥95% (HPLC)
Sigma-Aldrich
Liproxstatin-1, >98% (HPLC)