The Hippo Pathway Effector TAZ Regulates Ferroptosis in Renal Cell Carcinoma

Yang, Wen‐Hsuan; Ding, Chien‐Kuang Cornelia; Sun, Tianai; Rupprecht, Gabrielle; Lin, Chao-Chieh; Hsu, David S.; Chi, Jen-Tsan

doi:10.1016/j.celrep.2019.07.107

Cited by 335 publications

(243 citation statements)

References 52 publications

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“…S3E). These results are consistent with a recent study that demonstrated that the NOX4 induced by TAZ treatment leads to ferroptotic cell death [48].…”

Section: Nox4 As An Insufficient Marker For Erastin Sensitivitysupporting

confidence: 94%

Systematic identification of a nuclear receptor-enriched predictive signature for erastin-induced ferroptosis

Kwon

Kong

Choi

et al. 2020

Preprint

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Erastin, which has been initially identified as a synthetic lethal compound against cancer expressing an RAS oncogene, inhibits cystine/glutamate antiporters and causes ferroptic cell death in various cell types, including therapy-resistant mesenchymal cancer cells. However, despite recent emerging evidence for the mechanisms underlying ferroptosis, molecular biomarkers associated with erastin-dependent ferroptosis have not yet been identified. In the present study, we employed isogenic lung cancer cell models with therapyresistant mesenchymal properties to show that a redox imbalance leads to glutathione depletion and ferroptotic cell death. Subsequent gene expression analysis of pan-cancer cell lines revealed that the activity of transcription factors, including nuclear factor erythroid 2related factor 2 (NRF2) and aryl hydrocarbon receptor (AhR), serve as important markers of erastin resistance. Based on the integrated expression of genes in the nuclear receptor metapathway (NRM), we constructed an NRM model and validated its robustness using an independent pharmacogenomics dataset. The NRM model was further evaluated by employing it in the sensitivity testing of nine cancer cell lines for which erastin sensitivitieshad not yet been undetermined. Our pharmacogenomics approach has the potential to pave the way for the efficient classification of patients for therapeutic intervention using erastin or erastin analogs.

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“…S3E). These results are consistent with a recent study that demonstrated that the NOX4 induced by TAZ treatment leads to ferroptotic cell death [48].…”

Section: Nox4 As An Insufficient Marker For Erastin Sensitivitysupporting

confidence: 94%

Systematic identification of a nuclear receptor-enriched predictive signature for erastin-induced ferroptosis

Kwon

Kong

Choi

et al. 2020

Preprint

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“…Ferroptosis is a distinct form of iron-dependent cell death 5 that is triggered by oxidative stresses and characterized by the accumulation of lipid peroxidation products 14 . Even with the recent discovery of many genetic determinants [15][16][17][18]23,24 of ferroptosis by regulating lipid metabolism, iron availability, reactive oxygen species (ROS) and anti-oxidant capacity, much still remains unknown about the molecular mechanisms regulating ferroptosis. Our discovery of MESH1 as an NADPH phosphatase reveals an important role of the MESH1-mediated NADPH depletion and impairment of the glutathione regeneration in the execution of ferroptosis.…”

Section: Discussionmentioning

confidence: 99%

“…After establishing hMESH1 as a significant contributor to the cellular NADPH phosphatase activity and elucidating its molecular recognition of NADPH, we investigated whether the NADPH phosphatase activity of MESH1 plays a role in ferroptosis, a regulated form of cell death driven by the lethal accumulation of lipid hydroperoxides 14 . Various genetic determinants of ferroptosis have been identified [15][16][17][18] . Importantly, ferroptosis can be triggered by erastin, an inhibitor of the cystine importer xCT 5 , or by cystine deprivation, and is alleviated by high concentrations of NADPH 19 .…”

Section: Mesh1 Regulates Cellular Nadph Levels and Ferroptosismentioning

confidence: 99%

MESH1 is a cytosolic NADPH phosphatase that regulates ferroptosis

et al. 2020

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S tringent response is the main strategy used by bacteria to cope with fluctuating nutrient supplies and metabolic and oxidative stresses 1,2 . This process rapidly redirects energy from cell proliferation toward stress survival by reduction of biosynthesis, conservation of ATP and blockage of GTP production 3 . The stringent response is triggered by the accumulation of the bacterial 'alarmone' (p)ppGpp (guanosine tetra-or penta-phosphate, shortened as ppGpp below) through the regulation of ppGpp synthetases and hydrolases in the RelA and SpoT homologue family 2 .Recent studies suggest that the stringent response may also function in metazoans, as metazoan genomes encode a homologue of bacterial SpoT-MESH1 (Metazoan SpoT Homologue 1, encoded by HDDC3)-that can hydrolyse ppGpp in vitro and functionally complement SpoT in Escherichia coli 4 . Furthermore, Mesh1 deletion in Drosophila displays impaired starvation resistance and extensive transcriptional reprogramming 4 . Despite these supporting lines of evidence, neither ppGpp nor its synthetase has been discovered in metazoans, thus obscuring the genuine function and the relevant substrate(s) of MESH1 in mammalian cells. Here, we have identified NADPH as an efficient substrate of MESH1. MESH1 is a cytosolic NADPH phosphatase that is induced under stress conditions, leading to the NADPH depletion and ferroptosis-a novel form of iron-dependent regulated cell death characterized by lipid peroxidation 5 . Accordingly, MESH1 removal preserves the NADPH level in stressed cells and promotes their ferroptotic survival.Critical to the bacterial stringent response is the rapid relocation of resources from proliferation toward stress survival through the respective accumulation and degradation of (p)ppGpp by RelA and SpoT homologues. While mammalian genomes encode MESH1, a homologue of the bacterial (p)ppGpp hydrolase SpoT, neither (p)ppGpp nor its synthetase has been identified in mammalian cells. Here, we show that human MESH1 is an efficient cytosolic NADPH phosphatase that facilitates ferroptosis. Visualization of the MESH1-NADPH crystal structure revealed a bona fide affinity for the NADPH substrate. Ferroptosisinducing erastin or cystine deprivation elevates MESH1, whose overexpression depletes NADPH and sensitizes cells to ferroptosis, whereas MESH1 depletion promotes ferroptosis survival by sustaining the levels of NADPH and GSH and by reducing lipid peroxidation. The ferroptotic protection by MESH1 depletion is ablated by suppression of the cytosolic NAD(H) kinase, NADK, but not its mitochondrial counterpart NADK2. Collectively, these data shed light on the importance of cytosolic NADPH levels and their regulation under ferroptosis-inducing conditions in mammalian cells.

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“…Even many studies have identified genetic determinants of ferroptosis in other cancer types, it will still be important to validate and identify the specific determinants in OVCA. For example, the Hippo pathway has been shown to regulate ferroptosis in multiple tumor cell types [63,[77][78][79][80]. However, different Hippo effectors are employed in different cancer cells.…”

Section: Therapeutic Implication and Future Directionmentioning

confidence: 99%

Ferroptosis of epithelial ovarian cancer: genetic determinants and therapeutic potential

Lin

Chi

2020

Oncotarget

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Epithelial ovarian cancer (OVCA) is the most lethal gynecologic cancer. Current treatment for OVCA involves surgical debulking of the tumors followed by combination chemotherapies. While most patients achieve complete remission, many OVCA will recur and develop chemo-resistance. Whereas recurrent OVCA may be treated by angiogenesis inhibitors, PARP inhibitors, or immunotherapies, the clinical outcomes of recurrence OVCA are still unsatisfactory. One new promising anti-tumor strategy is ferroptosis, a novel form of regulated cell death featured by lipid peroxidation. In this review, we have summarized several recent studies on the ferroptosis of OVCA. Also, we summarize our current understanding of various genetic determinants of ferroptosis and their underlying mechanisms in OVCA. Furthermore, ferroptosis can be combined with other standard cancer therapeutics, which has shown synergistic effects. Therefore, such a combination of therapeutics could lead to new therapeutic strategies to improve the response rate and overcome resistance. By understanding the genetic determinants and underlying mechanisms, ferroptosis may have significant therapeutic potential to improve the clinical outcome of women with OVCA.

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The Hippo Pathway Effector TAZ Regulates Ferroptosis in Renal Cell Carcinoma

Cited by 335 publications

References 52 publications

Systematic identification of a nuclear receptor-enriched predictive signature for erastin-induced ferroptosis

Systematic identification of a nuclear receptor-enriched predictive signature for erastin-induced ferroptosis

MESH1 is a cytosolic NADPH phosphatase that regulates ferroptosis

Ferroptosis of epithelial ovarian cancer: genetic determinants and therapeutic potential

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