BAP1 links metabolic regulation of ferroptosis to tumour suppression

• Published in: Nature cell biology Vol. 20; no. 10; pp. 1181 - 1192
• Main Authors: Zhang, Yilei, Shi, Jiejun, Liu, Xiaoguang, Feng, Li, Gong, Zihua, Koppula, Pranavi, Sirohi, Kapil, Li, Xu, Wei, Yongkun, Lee, Hyemin, Zhuang, Li, Chen, Gang, Xiao, Zhen-Dong, Hung, Mien-Chie, Chen, Junjie, Huang, Peng, Li, Wei, Gan, Boyi
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.10.2018; Nature Publishing Group
• Subjects: 13/1; 13/106; 13/107; 13/31; 13/51; 13/95; 14/5; 14/63; 38/22; 45/77; 631/67; 631/67/1244; 631/67/2327; 631/80/82; 64/60; 82/58; Amino Acid Transport System y+ - genetics; Amino Acid Transport System y+ - metabolism; Animals; Apoptosis; Biochemistry; Biological activity; Biomedical and Life Sciences; BRCA1 protein; Cancer; Cancer cells; Cancer genetics; Cancer Research; Cell Biology; Cell death; Cell Death - genetics; Cell Line, Tumor; Cells, Cultured; Chromatin; Cysteine; Cystine; Development and progression; Developmental Biology; Energy Metabolism - genetics; Enzymes; Epigenetic inheritance; Ferroptosis; Gene expression; Gene Expression Regulation, Neoplastic; Genetic aspects; Genomic analysis; HEK293 Cells; Histones - metabolism; Humans; Life Sciences; Lipid Peroxidation; Lipids; Medical schools; Metabolism; Mice; Neoplasms - genetics; Neoplasms - metabolism; Neoplasms - pathology; Occupancy; Peroxidation; Proteins; Regulatory mechanisms (biology); Stem Cells; Tumor Suppressor Proteins - genetics; Tumor Suppressor Proteins - metabolism; Tumors; Ubiquitin; Ubiquitin Thiolesterase - genetics; Ubiquitin Thiolesterase - metabolism; Ubiquitination
• ISSN: 1465-7392; 1476-4679
• DOI: 10.1038/s41556-018-0178-0

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. Zhang et al. show that BAP1 suppresses SLC7A11 expression and cystine uptake, thereby promoting ferroptosis and inhibiting tumour growth.