LncRNA SLC7A11-AS1 suppresses ferroptosis in hepatocellular carcinoma to promote tumorigenesis
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PROVIDER: PRJNA1024514 | ENA |
REPOSITORIES: ENA
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Project description:LncRNAs are playing essential roles in epigenetic regulation, mRNA translation, and protein modification. However, the function of SLC7A11-AS1, an antisense lncRNA derived from the solute carrier family 7 member 11 (SLC7A11) gene, remains incompletely known. In this study, we utilized shRNA technology to knock down SLC7A11-AS1 in HepG2 cells, aiming to investigate the role of SLC7A11-AS1 in hepatocellular carcinoma. RNA-seq results revealed that there were 2536 differentially expressed genes upon SLC7A11-AS1 knockdown.
2024-07-17 | GSE244762 | 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: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: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:Circular RNAs (circRNAs) have been implicated in the tumorigenesis of non-small cell lung cancer (NSCLC). Ferroptosis is considered a mechanism to suppress tumorigenesis. Herein, we identified a novel downregulated circRNA, circPOLA2 (hsa_circ_0004291), in NSCLC tissues and found that it was correlated with advanced clinical stage in patients. Nuclear-cytoplasmic fractionation assays and FISH assays confirmed that circPOLA2 was predominantly localized in the cytoplasm. Overexpression of circPOLA2 promoted lipid peroxidation and ferroptosis in NSCLC cells, thereby inhibiting cell proliferation and migration, while knockdown of circPOLA2 exerted the opposite effects. Mechanistically, circPOLA2 interacted with Merlin, a critical regulator of the Hippo pathway, and restricted Merlin phosphorylation at S518, leading to the activation of the Hippo pathway. In addition, circPOLA2 enhanced ferroptosis in NSCLC cells by activating the Hippo pathway. Together, circPOLA2 sensitizes cells to ferroptosis and suppresses tumorigenesis in NSCLC by facilitating Merlin-mediated activation of the Hippo signaling pathway.
2024-08-20 | GSE254362 | GEO
Project description:ATF4 suppresses hepatocarcinogenesis by inducing SLC7A11 (xCT) to suppress stress-related ferroptosis
| PRJNA789791 | ENA
Project description:Ferroptosis is a type of programmed cell death caused by disruption of redox homeostasis, and is closely linked to amino acid metabolism. Yin Yang 2 (YY2) and its homolog Yin Yang 1 (YY1) are members of the YY family with high homology, especially in their zinc-finger domains. Furthermore, they share consensus DNA binding motif. In contrast with the oncogenic YY1, increasing evidences have demonstrated the tumor suppressive effect of YY2; however, at present, little is known about its biological and pathological functions. Here we found that YY2 induces tumor cells ferroptosis and subsequently, suppresses tumorigenesis, by inhibiting SLC7A11 transcription, leading to the decreased glutathione biosynthesis. Furthermore, we reveal that YY2 and YY1 bind competitively to SLC7A11 promoter and antagonistically regulate tumor cells ferroptosis, thus suggesting the molecular mechanism underlying their opposite regulation on tumorigenesis. Moreover, we showed that mutations of YY2 zinc-finger domains in clinical cancer patients abrogated YY2/SLC7A11 axis and tumor cells ferroptosis. Together, these results provide a new insight regarding the regulatory mechanism of ferroptosis, and a mechanistic explanation regarding the tumor suppressive effect of YY2. Furthermore, our findings demonstrate that homeostasis between YY1 and YY2 is crucial for maintaining redox homeostasis in tumor cells.
2022-05-11 | GSE184138 | 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
Project description:Compared to the well-established roles of apoptosis in tumor suppression, the roles and regulatory mechanisms of ferroptosis, a non-apoptotic form of cell death, in tumor biology remain much less understood. BRCA1-associated protein 1 (BAP1) encodes a nuclear de-ubiquitinating (DUB) enzyme to reduce histone 2A ubiquitination (H2Aub) on chromatin, and is a tumor suppressor in several human cancers. Here, integrated transcriptomic, epigenomic, and cancer genomic analyses link BAP1 to metabolism-related biological processes, including oxidative stress response, and identify cystine transporter SLC7A11 as a BAP1-repressed target gene with high relevance to BAP1-mediated tumor suppression in human cancers. Functional studies reveal that BAP1, in a DUB-dependent manner, decreases H2Aub occupancy on the SLC7A11 promoter and represses SLC7A11 expression, and that BAP1 inhibits cystine uptake and promotes ferroptosis through repressing SLC7A11 expression. Finally, we show that BAP1 inhibits tumor development partly through SLC7A11, and that cancer-associated BAP1 mutants lose their abilities to repress SLC7A11 and to promote ferroptosis. Together, the results of our study show that BAP1 executes its tumor suppression function at least partly through its regulation of SLC7A11 and ferroptosis, and uncover a previously unappreciated mechanism coupling ferroptosis to tumor suppression.
2018-07-05 | GSE101987 | GEO