The Deubiquitylase USP52 Regulates Cell Proliferation and Ferroptosis through Stabilizing SLC7A11/xCT in Bladder Cancer
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PROVIDER: PRJNA1095871 | ENA |
REPOSITORIES: ENA
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Project description:Ferroptosis, a recently coined non-apoptotic form of cell death, is triggered by lethal accumulation of iron-dependent lipid peroxidation. SLC7A11/xCT, acts as a central hub in ferroptosis, is closely related to the development of multiple human diseases. However, the specific functions and potential regulatory mechanisms of ferroptosis, especially xCT protein, in bladder cancer (BLCA) remain poorly understood. Herein, through an unbiased siRNA screen targeting 96 deubiquitinases (DUBs), we identified USP52/PAN2 as a top regulator essential for xCT protein translational activity and ferroptosis process. Functionally, loss of USP52 inhibits glutathione (GSH) synthesis through xCT degradation, leading to elevated lipid peroxidation and ferroptosis, thereby suppresses BLCA progression. Mechanistically, USP52 physically interacts with xCT through its WD40 domain, biochemically hydrolyzes the K48-conjugated ubiquitin chains of xCT at K4 and K12, thereby promotes its protein stability. Importantly, USP52 expression demonstrates a positive correlation with xCT expression in clinical BLCA samples, and high USP52 expression is linked to a worse progression and prognosis. Additionally, USP52 depletion and IKE synergistically restrained the progression of BLCA by triggering ferroptosis in vivo. Collectively, our findings reveal a molecular mechanism of USP52-xCT axis in ferroptosis, and uncover a previously unappreciated role of USP52 in BLCA tumorigenesis.
2024-12-09 | GSE263111 | GEO
Project description:ATF4 suppresses hepatocarcinogenesis by inducing SLC7A11 (xCT) to suppress stress-related ferroptosis
| PRJNA789791 | ENA
Project description:Acinar cell dedifferentiation is one of the most notable features of acute and chronic pancreatitis. It can also be the initial step that facilitates pancreatic cancer development. In the present study, we further decipher the precise mechanism and regulation using murine experimental models. Our RNAseq analysis indicates that, early acinar cell dedifferentiation is accompanied by multiple pathways related to cell survival that are highly enriched, and where SLC7A11 (xCT) is transiently upregulated. xCT is the specific subunit of the cystine/glutamate antiporter system xC-. Acinar cells with depleted or reduced xCT function show an increase in ferroptosis relating to lipid peroxidation. Lower glutathione levels and more lipid ROS accumulation could be rescued by the antioxidant N-acetylcysteine or the ferroptosis inhibitor Ferrostatin-1. In caerulein-induced acute pancreatitis in mice, xCT also prevents lipid peroxidation in acinar cells. In conclusion, during stress, acinar cell fate seems to be poised for avoiding several forms of cell death. xCT specifically prevents acinar cell ferroptosis by fueling the glutathione pool and maintaining ROS balance. The data suggest that xCT offers a druggable tipping point to steer the acinar cell fate in stress conditions.
2023-08-07 | GSE240106 | GEO
Project description:Background: Mucosal melanoma (MM) is epidemiologically, biologically, and molecularly distinct from cutaneous melanoma. Current treatment strategies have failed to significantly improve the prognosis for MM patients. This study aims to identify therapeutic targets and develop combination strategies by investigating the mechanisms underlying the tumorigenesis and progression of MM. Methods: We analyzed the copy number amplification of EZH2 in 547 melanoma patients and investigated its correlation with clinical prognosis. Utilizing cell lines, organoids, and patient-derived xenograft models, we assessed the impact of EZH2 on cell proliferation and sensitivity to ferroptosis. Further, we explored the mechanisms of ferroptosis resistance associated with EZH2 by conducting RNA sequencing and chromatin immunoprecipitation sequencing. Results: EZH2 copy number amplification was closely associated with malignant phenotype and poor prognosis in MM patients. EZH2 was essential for MM cell proliferation in vitro and in vivo. Moreover, genetic perturbation of EZH2 rendered MM cells sensitized to ferroptosis. Combination treatment of EZH2 inhibitor with ferroptosis inducer significantly inhibited the growth of MM. Mechanistically, EZH2 inhibited the expression of KLF14, which binds to the promoter of SLC7A11 to repress its transcription. Loss of EZH2 therefore reduced the expression of SLC7A11, leading to reduced intracellular SLC7A11-dependent glutathione synthesis to promote ferroptosis. Conclusion: Our findings not only establish EZH2 as a biomarker for MM prognosis, but also highlight the EZH2-KLF14-SLC7A11 axis as a potential target for MM treatment.
2024-06-20 | GSE269789 | GEO
Project description:Background: Mucosal melanoma (MM) is epidemiologically, biologically, and molecularly distinct from cutaneous melanoma. Current treatment strategies have failed to significantly improve the prognosis for MM patients. This study aims to identify therapeutic targets and develop combination strategies by investigating the mechanisms underlying the tumorigenesis and progression of MM. Methods: We analyzed the copy number amplification of EZH2 in 547 melanoma patients and investigated its correlation with clinical prognosis. Utilizing cell lines, organoids, and patient-derived xenograft models, we assessed the impact of EZH2 on cell proliferation and sensitivity to ferroptosis. Further, we explored the mechanisms of ferroptosis resistance associated with EZH2 by conducting RNA sequencing and chromatin immunoprecipitation sequencing. Results: EZH2 copy number amplification was closely associated with malignant phenotype and poor prognosis in MM patients. EZH2 was essential for MM cell proliferation in vitro and in vivo. Moreover, genetic perturbation of EZH2 rendered MM cells sensitized to ferroptosis. Combination treatment of EZH2 inhibitor with ferroptosis inducer significantly inhibited the growth of MM. Mechanistically, EZH2 inhibited the expression of KLF14, which binds to the promoter of SLC7A11 to repress its transcription. Loss of EZH2 therefore reduced the expression of SLC7A11, leading to reduced intracellular SLC7A11-dependent glutathione synthesis to promote ferroptosis. Conclusion: Our findings not only establish EZH2 as a biomarker for MM prognosis, but also highlight the EZH2-KLF14-SLC7A11 axis as a potential target for MM treatment.
2024-06-20 | GSE269788 | GEO
Project description:Palbociclib is a CDK4/6 inhibitor approved for the treatment of breast cancer by suppressing cell proliferation. However, monotherapy with palbociclib was discouraging in prostate cancer, calling for a mechanism-based effective therapy. In this study, we reported in prostate cancer that palbociclib is a potent sensitizer of ferroptosis, which is worked out by downregulating the expression of TRIB3, a gene highly expressed in prostate cancer. Specifically, TRIB3 knockdown augmented the response of prostate cancer cells to ferroptosis inducers, whereas, TRIB3 overexpression rescued prostate cancer cells from palbociclib-induced ferroptosis. Mechanistically, TRIB3 inhibition by palbociclib resulted in downregulation of SOX2, which subsequently led to compromised expression of SLC7A11, a cystine/glutamate antiporter that counteracts ferroptosis. Functionally, a combined treatment of palbociclib with ferroptosis inducer significantly suppressed prostate cancer growth in a xenograft tumor model. Together, these results uncover an essential role of TRIB3/SOX2/SLC7A11 axis in palbociclib-induced ferroptosis, suggesting palbociclib a promising targeted therapy in combine with ferroptosis induction for the treatment of prostate cancer.
2024-10-31 | GSE273622 | GEO
Project description:Aims: Myocardial ischemia–reperfusion (I/R) injury severely facilitates cardiomyocyte death and endangers human health. RNA N6-methyladenosine (m6A) methylation modification plays a critical role in cardiovascular diseases. M6A reader YTHDF2 could identify m6a-modified RNA and promote target RNA degradation. Hence, we hypothesized that YTHDF2 impacts I/R injury by regulating RNA stability, in turn revealing the potential regulatory mechanism. Results: Both the mRNA and protein levels of YTHDF2 were upregulated in I/R mice and hypoxia-reoxygenation (H/R)-induced cardiomyocytes. Silencing endogenous YTHDF2 abrogated cardiac dysfunction and lowered infarct size in I/R mice, and forced expression of YTHDF2 aggravated the above-mentioned adverse pathological process. Consistently, the protective effect of silencing YTHDF2 reappeared in cardiomyocytes induced by H/R and erastin. Furthermore, RNA-seq and RIP revealed that YTHDF2 could recognize the m6A modification sites of ferroptosis-related gene SLC7A11 mRNA to promote its degradation both in vivo and in vitro. Inhibition of SLC7A11 also aggravated cardiac function, infarct size and the release of LDH in I/R mice after silencing YTHDF2. The advantageous effect of si-YTHDF2 in H/R injury was reversed by cotransfection with si-SLC7A11, which substantially exacerbated ferroptosis and the production of ROS. Innovation and Conclusion: All of the obtained data demonstrate that the cardioprotective effects of silencing YTHDF2 are accomplished by enhancing SLC7A11 stability and expression and reducing the level of ferroptosis, furnishing novel potential therapeutic targets for treating ischemic cardiac diseases.
2024-08-20 | GSE236721 | GEO
Project description:Acute kidney injury (AKI) is a common and life-threatening condition associated with cell death, where ferroptosis plays a critical role. Chemerin, primarily produced in white adipose tissue, has multiple biological functions in renal pathophysiology. However, to date, whether and how chemerin regulates the progression of AKI remain unclear. Here, we found that chemerin expression was reduced in both AKI model mice and cells. Similarly, serum chemerin levels were also decreased in AKI patients. The administration of recombinant chemerin improves renal function in ischemia-reperfusion (I/R) model mice. Chemerin significantly attenuates ferroptosis in kidneys. In TCMK-1 cells, chemerin knockdown further aggravates ferroptosis. Mechanistically, chemerin activates AMP-activated protein kinase (AMPK), which induces the phosphorylation of nuclear factor erythroid 2-related factor 2 (NRF2) in renal tubular cells. Subsequently, NRF2 translocates into the nucleus, where it stimulates the expression of cystine/glutamate antiporter solute carrier (SLC7A11). As a result, cystine uptake and glutathione (GSH) biosynthesis in renal tubular cells were increased, which confers cells with higher capacity against ferroptosis. Overall, our findings indicate that chemerin plays a protective role in AKI by repressing ferroptosis in renal tubular cells, which is likely due to the activation in the AMPK/NRF2/SLC7A11 axis.
2024-12-01 | GSE283126 | GEO
Project description:Ulcerative colitis (UC), a form of inflammatory bowel disease, is characterized by a Q7 recurrent and persistent nonspecific inflammatory response. Polydatin (PD), a natural stilbenoid polyphenol with potent properties, exhibits unexpected beneficial effects beyond its well-documented anti-inflammatory and antioxidant activities. In this study, we presented evidence that PD confers protection against dextran sodium sulfate (DSS)-induced ulcerative colitis. Our findings demonstrated that PD mitigated the DSS-induced increases in proinflammatory cytokines (IL-6, TNF-α, and IL-1β), alleviated colon length shortening, reduced morphological damage to the intestinal mucosa, and preserved tight junction proteins (TJ) occludin and Zonula occludens-1 (ZO-1) in both Caco-2 cells and murine models of colitis. Results from bulk RNA sequencing and differential gene analysis suggested a potential role for ferroptosis in the protective mechanisms of PD against UC. Further investigations revealed that PD modulated the expression levels of several ferroptosis-related proteins and transcription factors within the DSS-induced colitis model. Notably, treatment with PD enhanced nuclear translocation of Nrf2, which inhibits ferroptosis while ameliorating oxidative stress through upregulation of Slc7a11 and Gpx4 expression. Additionally, erastin—a known inducer of ferroptosis—reversed the protective effects conferred by PD in the DSS-induced colitis model by downregulating Slc7a11 expression. These findings underscore that PD protects against DSS-induced ulcerative colitis via the Nrf2/ Slc7a11/Gpx4 signaling axis, highlighting its potential as a novel therapeutic agent for UC.
2025-01-07 | GSE285956 | GEO
Project description:Background: Autologous fat grafting is hampered by unpredictable graft survival, which is potentially regulated by ferroptosis. Glutathione (GSH), a powerful antioxidant used in tissue preservation, has ferroptosis-regulating activity; however, its effects on fat grafts are unclear. This study investigated the effects and mechanisms of GSH in fat graft survival. Methods: Human lipoaspirates were transplanted subcutaneously into the backs of normal saline-treated (control) or GSH-treated nude mice. Graft survival was evaluated by magnetic resonance imaging and histology. RNA sequencing was performed to identify differentially expressed genes and enriched pathways. GSH activity was evaluated in vitro using an oxygen and glucose deprivation (OGD) model of adipose-derived stem cells. Results: Compared with control group, GSH induced better outcomes, including superior graft retention, appearance, and histological structures. RNA sequencing suggested enhanced negative regulation of ferroptosis in the GSH-treated grafts, which showed reduced lipid peroxides, better mitochondrial ultrastructure, and SLC7A11/GPX4 axis activation. In vitro, OGD-induced ferroptosis was ameliorated by GSH, which restored cell proliferation, reduced oxidative stress, and upregulated ferroptosis defense factors. Conclusions: Our study confirms that ferroptosis participates in regulating fat graft survival and that GSH exerts a protective effect by inhibiting ferroptosis. GSH-assisted lipotransfer is a promising therapeutic strategy for future clinical application.
2023-05-08 | GSE231511 | GEO