ATF4 suppresses hepatocarcinogenesis by inducing SLC7A11 (xCT) to suppress stress-related ferroptosis
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ABSTRACT:
PROVIDER: PRJNA789791 | ENA |
REPOSITORIES: ENA
Dataset's files
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| SRR17258735_1.fastq.gz | Fastqsanger.gz | |||
| SRR17258735_2.fastq.gz | Fastqsanger.gz | |||
| SRR17258736_1.fastq.gz | Fastqsanger.gz | |||
| SRR17258736_2.fastq.gz | Fastqsanger.gz | |||
| SRR17258737_1.fastq.gz | Fastqsanger.gz |
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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: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:The Deubiquitylase USP52 Regulates Cell Proliferation and Ferroptosis through Stabilizing SLC7A11/xCT in Bladder Cancer
| PRJNA1095871 | ENA
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:Tumor cells increase glutamate release through the cystine/glutamate transporter xCT to balance oxidative homeostasis in tumor cells and promote tumor progression. Here, we demonstrated that although inhibition of xCT either by pharmacological inhibitor (sulfasalazine, SAS), approved by FDA for inflammatory diseases, or genetic knockdown induced ROS-related death in melanoma cells. Taken together, our results reveal that inhibition of xCT by SAS is a promising therapeutic strategy for melanoma.
2021-02-11 | GSE166566 | 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:XCT was originally identified due to the short circadian period observed in plants mutant for this gene. Proteins with homology to XCT are found across eukaryotes, but their molecular function is unknown. We have recently demonstrated that in Schizosaccharomyces pombe, the XCT ortholog Xap5 is a chromatin-associated protein that acts in a similar manner as the histone variant H2A.Z to suppress aberrant gene expression. Here, we demonstrate that although XCT and H2A.Z act in similar pathways to control plant development, XCT's role in the circadian clock is independent of H2A.Z.
2019-05-01 | GSE67813 | GEO
Project description:We demonstrate that stress differentially regulates glutamate homeostasis in the dorsal and ventral hippocampus and established a previously unknown role for the glial marker xCT in the homeostatic regulation of the ventral dentate gyrus (vDG) in stress resilience and antidepressant responses. We provide RNAseq roadmap for the stress-sensitive vDG and show that the transcription factor REST binds to xCT promoter in co-occupancy with the epigenetic marker H3K27acet, to negatively regulate xCT expression. Reduced xCT was also observed in a genetic mouse model of inherent susceptibility to depression. Pharmacologically modulating histone acetylation with next-generation therapeutics, such as acetyl-N-cysteine (NAC) or acetyl-L-carnitine (LAC), rapidly increased xCT reduction and activated a network that included mGlu2 receptors to prime an enhanced glutamate homeostasis that promoted stress resilience and antidepressant-like responses. Moreover, pharmacological xCT blockage counteracted NAC prophylactic effects. Anatomical (vDG) and cell-type specific (GFAP+) virus-overexpression mimicked the effects of pharmacological treatments in increasing stress resilience. These findings establish xCT as critical regulator of the glutamate system in a network with mGlu2 receptors. These studies also point to a role of histone acetylation as mediator of stress resilience.
2017-10-11 | GSE103435 | GEO
Project description:Selecting neuronal cell lines for resistance against oxidative stress might recapitulate some adaptive processes in neurodegenerative diseases where oxidative stress is involved like Parkinson's disease. We recently reported that in hippocampal HT22 cells selected for resistance against oxidative glutamate toxicity, the cystine/glutamate antiporter system x(c)(-), which imports cystine for synthesis of the antioxidant glutathione, and its specific subunit, xCT, are upregulated. (Lewerenz et al., J Neurochem 98(3):916-25). Here, we show that in these glutamate-resistant HT22 cells upregulation of xCT mediates glutamate resistance, and xCT expression is induced by upregulation of the transcription factor ATF4. The mechanism of ATF4 upregulation consists of a 13?bp deletion in the upstream open reading frame (uORF2) overlapping the ATF4 open reading frame. The resulting uORF2-ATF4 fusion protein is efficiently translated even at a low phosphorylation levels of the translation initiation factor eIF2?, a condition under which ATF4 translation is normally suppressed. A similar ATF4 mutation associated with prominent upregulation of xCT expression was identified in PC12 cells selected for resistance against amyloid ?-peptide. Our data indicate that ATF4 has a central role in regulating xCT expression and resistance against oxidative stress. ATF4 mutations might have broader significance as upregulation of xCT is found in tumor cells and associated with anticancer drug resistance.
| S-EPMC3321624 | biostudies-literature