BAP1 links metabolic regulation of ferroptosis to tumour suppression

Zhang, Yilei; Shi, Jiejun; Liu, Xiaoguang; Li, Feng; Gong, Zihua; Koppula, Pranavi; Sirohi, Kapil; Xu, Li; Wei, Yongkun; Lee, Hyemin; Li, Zhuang; Chen, Gang; Xiao, Zhilong; Hung, Mien‐Chie; Chen, Junjie; Huang, Peng; Li, Wei; Gan, Boyi

doi:10.1038/s41556-018-0178-0

Cited by 650 publications

(621 citation statements)

References 71 publications

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“…Upregulation of GLS2 promotes p53‐dependent ferroptosis . Moreover, tumor suppressors, p53 and BRCA1‐associated protein 1 (BAP1) have been reported to downregulate the SLC7A11 gene, thus inhibiting cysteine uptake and positively regulating ferroptosis in cancer cell lines . Even the acetylation‐defective mutant p53 (K117R, K161R, and K162R) that fails to induce cell cycle arrest, senescence or apoptosis, maintains the ability to reduce SLC7A11 and trigger ferroptosis .…”

Section: Basis Of Ferroptosismentioning

confidence: 99%

Recent Progress in Ferroptosis Inducers for Cancer Therapy

et al. 2019

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Ferroptosis is a newly discovered form of regulated cell death that is the nexus between metabolism, redox biology, and human health. Emerging evidence shows the potential of triggering ferroptosis for cancer therapy, particularly for eradicating aggressive malignancies that are resistant to traditional therapies. Recently, there has been a great deal of effort to design and develop anticancer drugs based on ferroptosis induction. Recent advances of ferroptosis‐inducing agents at the intersection of chemistry, materials science, and cancer biology are presented. The basis of ferroptosis is summarized first to highlight the feasibility and characteristics of triggering ferroptosis for cancer therapy. A literature review of ferroptosis inducers (including small molecules and nanomaterials) is then presented to delineate their design, action mechanisms, and anticancer applications. Finally, some considerations for research on ferroptosis inducers are spotlighted, followed by a discussion on the challenges and future development directions of this burgeoning field.

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Section: Basis Of Ferroptosismentioning

confidence: 99%

Recent Progress in Ferroptosis Inducers for Cancer Therapy

et al. 2019

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“…GSH levels were detected using a GSH-Glo Glutathione Assay Kit (Promega, #V6911) following the manufacturer's instructions and a previous report [66].…”

Section: Measurement Of the Intracellular Gsh Levelsmentioning

confidence: 99%

“…Cell death analysis with PI staining was performed according to a previous report [66]. Briefly, cells were seeded into a 6-well plate for different treatment.…”

Section: Measurement Of Cell Death With Propidium Iodide (Pi) Staininmentioning

confidence: 99%

Epigenetic regulation of ferroptosis by H2B monoubiquitination and p53

Wang

Zhang³

et al. 2019

EMBO Reports

143

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Monoubiquitination of histone H2B on lysine 120 (H2Bub1) is an epigenetic mark generally associated with transcriptional activation, yet the global functions of H2Bub1 remain poorly understood. Ferroptosis is a form of non‐apoptotic cell death characterized by the iron‐dependent overproduction of lipid hydroperoxides, which can be inhibited by the antioxidant activity of the solute carrier family member 11 (SLC7A11/xCT), a component of the cystine/glutamate antiporter. Whether nuclear events participate in the regulation of ferroptosis is largely unknown. Here, we show that the levels of H2Bub1 are decreased during erastin‐induced ferroptosis and that loss of H2Bub1 increases the cellular sensitivity to ferroptosis. H2Bub1 epigenetically activates the expression of SLC7A11. Additionally, we show that the tumor suppressor p53 negatively regulates H2Bub1 levels independently of p53's transcription factor activity by promoting the nuclear translocation of the deubiquitinase USP7. Moreover, our studies reveal that p53 decreases H2Bub1 occupancy on the SLC7A11 gene regulatory region and represses the expression of SLC7A11 during erastin treatment. These data not only suggest a noncanonical role of p53 in chromatin regulation but also link p53 to ferroptosis via an H2Bub1‐mediated epigenetic pathway. Overall, our work uncovers a previously unappreciated epigenetic mechanism for the regulation of ferroptosis.

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“…No cell lines used in this study are found in the ICLAC database of commonly misidentified cell lines, based on short tandem repeat profiling performed by the vendor. Cell lines with stable expression of Flag-BAP1 WT or mutant were generated as described in our previous publication [18]. Briefly, lentiviral transfections were performed using Lipofectamine 3000 (Life Technologies).…”

Section: Cell Culture Studiesmentioning

confidence: 99%

“…Seeking to understand BAP1-mediated tumor suppression, we recently identified SLC7A11 as a key BAP1 target to mediate BAP1's function in tumor suppression through genome wide analyses [18]. We showed that BAP1 reduces H2Aub occupancy on the SLC7A11 promoter and gene body, represses SLC7A11 expression and SLC7A11mediated cystine import, and sensitizes cancer cells to erastin-or cystine depletion-induced ferroptosis.…”

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confidence: 99%

Regulation of H2A ubiquitination and SLC7A11 expression by BAP1 and PRC1

2019

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SLC7A11 (or xCT) imports extracellular cystine into cells to promote glutathione synthesis, thus inhibiting ferroptosis. SLC7A11 expression is tightly controlled in normal cells and its dysregulation results in aberrant expression of SLC7A11 in human cancers. We recently discovered that tumor suppressor BAP1, a H2A deubiquitinase, represses SLC7A11 expression by reducing H2A ubiquitination (H2Aub) on the SLC7A11 promoter. BAP1 inactivation in cancer cells leads to SLC7A11 derepression, ferroptosis resistance, and tumor development. Here we show that BAP1 promotes ferroptosis induced by class I ferroptosis inducer (FIN) erastin but not by class II FIN RSL3, further supporting that BAP1 regulates ferroptosis through SLC7A11. In addition, we studied how BAP1 coordinates with other transcription factors to regulate SLC7A11 expression and show that BAP1mediated SLC7A11 repression does not require NRF2 and ATF4 transcription factors. Finally, we show that, while BAP1 decreases whereas PRC1 (a major H2Aub ubiquitin ligase) increases H2Aub binding on the SLC7A11 promoter, both BAP1 and PRC1 represses SLC7A11 expression, suggesting that a dynamic regulation of H2Aub is important for SLC7A11 repression. Together, our data provide additional insights on epigenetic regulation of SLC7A11 expression in cancer cells. ARTICLE HISTORY

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BAP1 links metabolic regulation of ferroptosis to tumour suppression

Cited by 650 publications

References 71 publications

Recent Progress in Ferroptosis Inducers for Cancer Therapy

Recent Progress in Ferroptosis Inducers for Cancer Therapy

Epigenetic regulation of ferroptosis by H2B monoubiquitination and p53

Regulation of H2A ubiquitination and SLC7A11 expression by BAP1 and PRC1

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