ATF4 suppresses hepatocarcinogenesis by inducing SLC7A11 (xCT) to suppress stress-related ferroptosis
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PROVIDER: PRJNA789791 | ENA |
REPOSITORIES: ENA
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Project description:The goal of this study is to provide the liver metabolic changes in the liver specific Atf4 knockout MUP-uPA (MUP-uPA/Atf4Δhep) mice and understand the function of ATF4 in the stressed liver
2023-12-09 | GSE191115 | GEO
Project description:Background & aimsHepatocellular carcinoma (HCC), a leading cause of cancer-related death, is associated with viral hepatitis, non-alcoholic steatohepatitis (NASH), and alcohol-related steatohepatitis, all of which trigger endoplasmic reticulum (ER) stress, hepatocyte death, inflammation, and compensatory proliferation. Using ER stress-prone MUP-uPA mice, we established that ER stress and hypernutrition cooperate to cause NASH and HCC, but the contribution of individual stress effectors, such as activating transcription factor 4 (ATF4), to HCC and their underlying mechanisms of action remained unknown.MethodsHepatocyte-specific ATF4-deficient MUP-uPA mice (MUP-uPA/Atf4Δhep) and control MUP-uPA/Atf4F/F mice were fed a high-fat diet to induce NASH-related HCC, and Atf4F/F and Atf4Δhep mice were injected with diethylnitrosamine to model carcinogen-induced HCC. Histological, biochemical, and RNA-sequencing analyses were performed to identify and define the role of ATF4-induced solute carrier family 7a member 11 (SLC7A11) expression in hepatocarcinogenesis. Reconstitution of SLC7A11 in ATF4-deficient primary hepatocytes and mouse livers was used to study its effects on ferroptosis and HCC development.ResultsHepatocyte ATF4 ablation inhibited hepatic steatosis, but increased susceptibility to ferroptosis, resulting in accelerated HCC development. Although ATF4 activates numerous genes, ferroptosis susceptibility and hepatocarcinogenesis were reversed by ectopic expression of a single ATF4 target, Slc7a11, coding for a subunit of the cystine/glutamate antiporter xCT, which is needed for glutathione synthesis. A ferroptosis inhibitor also reduced liver damage and inflammation. ATF4 and SLC7A11 amounts were positively correlated in human HCC and livers of patients with NASH.ConclusionsDespite ATF4 being upregulated in established HCC, it serves an important protective function in normal hepatocytes. By maintaining glutathione production, ATF4 inhibits ferroptosis-dependent inflammatory cell death, which is known to promote compensatory proliferation and hepatocarcinogenesis. Ferroptosis inhibitors or ATF4 activators may also blunt HCC onset.Impact and implicationsLiver cancer or hepatocellular carcinoma (HCC) is associated with multiple aetiologies. Most HCC aetiologies cause hepatocyte stress and death, as well as subsequent inflammation, and compensatory proliferation, thereby accelerating HCCdevelopment. The contribution of individual stress effectors to HCC and their underlying mechanisms of action were heretofore unknown. This study shows that the stress-responsive transcription factor ATF4 blunts liver damage and cancer development by suppressing iron-dependent cell death (ferroptosis). Although ATF4 ablation prevents hepatic steatosis, it also increases susceptibility to ferroptosis, due to decreased expression of the cystine/glutamate antiporter SLC7A11, whose expression in human HCC and NASH correlates with ATF4. These findings reinforce the notion that benign steatosis may be protective and does not increase cancer risk unless accompanied by stress-induced liver damage. These results have important implications for prevention of liver damage and cancer.
| S-EPMC11332364 | biostudies-literature
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:Understanding the mechanisms underlying evasive resistance in cancer is an unmet medical need to improve the efficacy of current therapies. In this study, a combination of shRNA-mediated synthetic lethality screening and transcriptomic analysis revealed the transcription factors YAP/TAZ as key drivers of Sorafenib resistance in hepatocellular carcinoma (HCC) by repressing Sorafenib-induced ferroptosis. Mechanistically, in a TEAD-dependent manner YAP/TAZ induce the expression of SLC7A11, a key transporter maintaining intracellular glutathione homeostasis, thus enabling HCC cells to overcome Sorafenib-induced ferroptosis. At the same time, YAP/TAZ sustain the protein stability, nuclear localization and transcriptional activity of ATF4 which in turn cooperates to induce SLC7A11 expression. Our study uncovered a critical role of YAP/TAZ in the repression of ferroptosis and thus in the establishment of Sorafenib resistance in HCC, highlighting YAP/TAZ-based rewiring strategies as potential approaches to overcome HCC therapy resistance.
2021-08-20 | GSE181771 | GEO
Project description:In response to a variety of upstream growth and oncogenic signals, the mechanistic target of rapamycin complex 1 (mTORC1) promotes anabolic metabolism, in part, through activation of downstream transcription factors. The transcription factor activating transcription factor 4 (ATF4) has been previously shown to function downstream of mTORC1 signaling to promote de novo purine synthesis and this activation of ATF4 can occur independently of the canonical activation of ATF4 through the integrated stress response (ISR). Here, we show that ATF4 activation through mTORC1 signaling drives a specific transcriptional program through ATF4 which is comprised of only a subset of genes involved in the broader cellular stress response. We find genes involved in amino acid uptake, biosynthesis, and charging by tRNA synthetases display transcriptional changes downstream of both mTORC1 and ATF4. We discovered that ATF4 activation contributes to the mTORC1-stimulated increase in protein synthesis, highlighting the importance of these transcriptional changes. Additionally, we observe regulation of the cystine transporter SLC7A11 by ATF4. We show that SLC7A11 is important for cell survival and is one mechanism by which cells with active mTORC1 signaling produce glutathione. Thus, ATF4 downstream of mTORC1 signaling regulates protein and glutathione synthesis.
2020-09-28 | GSE158605 | GEO
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:The tumor microenvironment (TME) is restricted in metabolic nutrients including the semi-essential amino acid arginine. While complete arginine deprivation causes T cell dysfunction, it remains unclear how arginine levels fluctuate in the TME to shape T cell fates. Here, we found that the 20μM low arginine condition, as present in multiple TMEs, confers upon activated T cells Treg-like immunosuppressive capacities. In vivo mouse tumor models and human scRNA-Seq datasets reveal positive correlations between low arginine condition and intratumoral Treg accumulation. Mechanistically, low-arginine activated T cells engage in metabolic and transcriptional reprogramming, using the ATF4-SLC7A11-GSH axis, to preserve their suppressive function. These findings improve our understanding of the role of arginine in human T cell biology with potential applications for immunotherapy strategies.
2024-02-25 | GSE256171 | 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: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