BAP1 links metabolic regulation of ferroptosis to tumor suppression
By Yilei Zhang, Jiejun Shi, Xiaoguang Liu, Li Feng, Zihua Gong, Pranavi Koppula, Kapil Sirohi, Xu Li, Yongkun Wei, Hyemin Lee and 7 more. Nature Cell Biology, 2018
826 citations recorded by the source corpus.
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.
Subfields: Molecular Biology, Pulmonary and Respiratory Medicine
View Paper: https://www.semanticscholar.org/paper/dabb045480b41a4bb3fa0fff78d9e1c721e55727
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In Molecular Biology
In Pulmonary and Respiratory Medicine
Citations in the corpus
- Ferroptosis in cancer: from molecular mechanisms to therapeutic strategies (2024, background): “156 Deletions and mutations of BAP1 result in the loss of its ability to repress SLC7A11, enabling cells to evade ferroptosis and promoting tumor formation.”
- Ferroptosis turns 10: Emerging mechanisms, physiological functions, and therapeutic applications. (2022, neutral): “Abbreviations: AA, arachidonic acid; ALOXs, lipoxygenases; BAP1, ubiquitin carboxyl-terminal hydrolase; CoA, coenzyme A; GPX4, glutathione peroxidase 4; IFNg, interferon gamma; MLL4, histone-lysine N-methyltransferase 2B; NFS1, cysteine desulfurase, mitochondrial; p53, p53 tumor suppressor protein; ”