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Transcriptome profiling (RNA-seq) analysis of control and NaIO3-treated RPE cells

ABSTRACT: Purpose: The goal of this experiment is to investigate the relative contributions of various types of cell death in NaIO3-treated RPE cells Methods: RPE cell mRNA profiles were generated by deep sequencing, in triplicate, using Illumina HiSeq 4000. Results: According to the differential expressions of mRNA genes, among which 661 genes were upregulated and 637 genes were downregulated with significance after NaIO3 treatment . From the Gene Ontology (GO), and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis, it has been identified that ferroptosis ranked as the top pathway in comparison to other types of cell death (apoptosis, and necroptosis) upon NaIO3 treatment, which was additionally validated by the higher FPKM of main regulators in ferroptosis than that in apoptosis. Additionally, it was found that heme oxygenase-1 (HMOX1, also known as HO-1) as well as SLC7A11 (solute carrier family 7 member 11) mRNA were characterized as the most dramatically upregulated genes upon NaIO3 treatment against ARPE-19 cells Conclusions: Our study represented that ferroptosis serves as a predominant pathogenic factor involved in AMD pathological process.

ORGANISM(S): Homo sapiens

PROVIDER: GSE142591 | GEO | 2019/12/26

REPOSITORIES: GEO

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Transcriptome profiling (RNA-seq) analysis of NaIO3-induced RPE cells with or witout CaPB treatment

Project description:Purpose: The goal of this experiment is to investigate the role of CaPB in NaIO3-induced RPE cells Methods: RPE cell mRNA profiles were generated by deep sequencing, in triplicate, using Illumina HiSeq 4000. Results: According to the differential expressions of mRNA genes, among which 463 genes were upregulated and 397 genes were downregulated with significance in NaIO3-induced RPE cells after CaPB treatment . From the Gene Ontology (GO), and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis, it has been identified that ferroptosis ranked as the most downregulated pathway upon CaPB treatment. Conclusions: Our study represented that CaPB against NaIO3-treated RPE cell death via ferroptosis inhibition

2020-12-22 | GSE163591 | GEO

BAP1 links epigenetic regulation of ferroptosis to tumor suppression

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

Super-enhancer-driven MLX mediates redox balance maintanance via SLC7A11 in osteosarcoma

Project description:A systematic analysis of super-enhancers identified MLX as a potential oncogene in osteosarcoma. Knockdown of MLX impaired tumor aggressiveness in vitro and in vivo, suggesting oncogenic properties of MLX. Mechanistically, silencing of MLX downregulates SLC7A11, a key gene encoding glutamate/cystine antiporter, to attenuate the uptake of cystine and interrupt the redox balance, leading to ferroptotic cell death. Pharmacological inhibition of SLC7A11 triggered massive ferroptosis and caused impaired tumor growth, providing a promising approach for osteosarcoma treatment.

2023-08-08 | GSE220173 | GEO

Homeostasis imbalance of YY2 and YY1 promotes tumor growth by manipulating ferroptosis

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

lncRNA HOTAIRM1 Facilitates Nasopharyngeal Carcinoma Resistance to Irradiation and Ferroptosis by Increasing SLC7A11 Stability and Expression via METTL3-mediated m6A Methylation

Project description:Radiotherapy has become a main treatment for patients with nasopharyngeal carcinoma (NPC), who often develop residual or recurrent tumors due to radioresistance. The lncRNA HOTAIRM1 plays crucial roles in the formation and development of various cancers, but the interaction between HOTAIRM1 and radioresistant NPC remains unclear. In this study, we evaluated the potential of HOTAIRM1 as a biomarker of NPC radioresistance. Proliferation, apoptosis, DNA damage, and RNA-seq analyses were conducted to examine the mechanisms by which HOTAIRM1 contributes to NPC radioresistance, and in vivo experiments were performed using nude mice. Our findings indicated that HOTAIRM1 levels were upregulated in radioresistant NPC tissues and cell lines. High HOTAIRM1 expression was associated with increased NPC cell proliferation, decreased apoptosis, and decreased cellular DNA damage after radiotherapy. Mechanistically, HOTAIRM1 promoted NPC radioresistance by increasing SLC7A11 stability and expression through METTL3-mediated m6A demethylation. Additionally, high HOTAIRM1 expression decreased SLC7A11-associated ferroptosis. Our findings demonstrate that HOTAIRM1 promotes METTL3-mediated m6A methylation to increase SLC7A11 expression and stability, thereby inhibiting ferroptosis to trigger NPC radioresistance. This novel molecular mechanism underlying the role of HOTAIRM1 in the regulation of radioresistant NPC may aid in the identification of biomarkers and therapeutic targets for the treatment of radioresistant NPC.

2023-04-12 | GSE229333 | GEO

CD8+ T cells regulate tumor ferroptosis during cancer immunotherapy

Project description:CD8+ T cells activated by cancer immunotherapy execute tumor clearance mainly by inducing cell death through perforin-granzyme- and Fas/Fas ligand-pathways. Ferroptosis is a form of cell death that differs from apoptosis and results from iron-dependent lipid peroxide accumulation. Although it was mechanistically illuminated in vitro, emerging evidence has shown that ferroptosis may be implicated in a variety of pathological scenarios. However, the involvement of ferroptosis in T cell immunity and cancer immunotherapy is unknown. Here, we find that immunotherapy-activated CD8+ T cells enhance ferroptosis-specific lipid peroxidation in tumor cells, and in turn, increased ferroptosis contributes to the anti-tumor efficacy of immunotherapy. Mechanistically, IFNg released from CD8+ T cells downregulates expression of SLC3A2 and SLC7A11, two subunits of glutamate-cystine antiporter system xc-, restrains tumor cell cystine uptake, and as a consequence, promotes tumor cell lipid peroxidation and ferroptosis. In preclinical models, depletion of cyst(e)ine by cyst(e)inase in combination with checkpoint blockade synergistically enhances T cell-mediated anti-tumor immunity and induces tumor cell ferroptosis. Thus, T cell-promoted tumor ferroptosis is a novel anti-tumor mechanism. Targeting tumor ferroptosis pathway constitutes a therapeutic approach in combination with checkpoint blockade.

2019-03-16 | GSE128392 | GEO

Radiotherapy and IFNγ treatment effect on transcriptome in HT1080 cells

Project description:Immune checkpoint blockade is a powerful oncologic treatment modality for a wide variety of human malignancies. Randomized clinical trials are assessing how best to interdigitate this treatment modality with traditional therapies including radiotherapy. A challenge in oncology is to rationally and effectively integrate immunotherapy with traditional modalities including radiotherapy. Here, we demonstrate that radiotherapy induces tumor cell ferroptosis. Ferroptosis agonists augment and ferroptosis antagonists limit radiotherapy efficacy in tumor models. Immunotherapy sensitizes tumors to radiotherapy by promoting tumor cell ferroptosis. Mechanistically, IFN derived from immunotherapy-activated CD8+ T cells and radiotherapy-activated ATM independently, yet synergistically repress SLC7A11, a unit of the glutamate-cystine antiporter xc-, resulting in reduced cystine uptake, enhanced tumor lipid oxidation and ferroptosis, and improved tumor control. Thus, ferroptosis is an unappreciated mechanism and focus for the development of effective combinatorial cancer therapy.

2020-09-23 | GSE137946 | GEO

The vulnerability of actin cytoskeleton to disulfide stress dictates high SLC7A11-driven cell death upon glucose deprivation

Project description:Solute carrier family 7 member 11 (SLC7A11; also known as xCT) is a cystine transporter frequently overexpressed in cancers. Cancer cells with high expression of SLC7A11 (SLC7A11high) are resistant to ferroptosis but exquisitely sensitive to glucose deprivation-induced cell death, although the underlying mechanism of the latter cell death remains poorly understood. Here we show that We found that glucose deprivation induced a novel type of cell death in SLC7A11high cancer cells that was different from apoptosis or ferroptosis. And the bioorthogonal chemical proteomics analysis revealed that a large amount of actin cytoskeleton proteins were shown with significantly dysregulated disulfides induced by glucose starvation in SLC7A11high cancer cells. In mechanism, SLC7A11high mediated cystine uptake and subsequent reduction to cysteine forced disulfide stress on actin cytoskeleton upon glucose deprivation through draining intracellular reduced nicotinamide adenine dinucleotide phosphate (NADPH) pool, which was independent of generating reactive oxygen species (ROS). The disulfide stress on the actin cytoskeleton induced rapidly contracted actin filaments and detached from the plasma membrane, which incurred cell death. In the end, using whole-genome CRISPR/Cas9 knock-out screening we identified NCKAP1 as a downstream factor of SLC7A11 to promoting cell death upon glucose deprivation by inhibiting branched actin filaments.

| MSV000088066 | MassIVE

RNA-seq of human pancreatic cancer cell line PANC-1 treated with RSL-3, N6F11, Fin56 and Erastin against untreated controls

Project description:Ferroptotic cell death is dependent on unrestricted lipid peroxidation rather than activation of apoptotic effector caspases. A large number of ferroptosis activators have been reported recently. We used gene sequencing to analyze the effects of four ferroptosis activators (RSL3, N6F11, Fin56 and Erastin) on global gene expression in human PDAC1 cell line.

2023-10-18 | E-MTAB-12241 | biostudies-arrayexpress

Ferroptosis Induction in Multiple Myeloma Cells Triggers an Epigenomic Stress Response Associated with DNA Repair and Cellular Senescence

Project description:Acquired and primary therapy resistance remain a major hurdle in clinical treatment of multiple myeloma (MM). Despite the availability of broad spectrum anti-cancer drugs, most MM patients eventually relapse and become refractory to current treatments. Therefore, we explored whether therapy-resistant MM cells are sensitive to ferroptosis induction, an iron-catalyzed mode of cell death associated with increased lipid peroxidation. In this study, we exposed glucocorticoid-resistant MM1R and glucocorticoid-sensitive MM1S cells to ferroptosis inducers RSL3 and evaluated their transcriptional changes via RNA sequencing. Compared to untreated controls, ferroptotic RSL3-treated cells displayed a significant upregulation of genes involved in inflammation, kinase signaling, cellular stress, and cell death pathways. Pre-treatment with ferroptosis inhibitor Fer-1 partly reverted these RSL3-induced transcriptional changes and revealed that especially genes involved in metal binding, nuclear receptor signaling, chromatin remodeling, and gene transcription regulation are pivotal for ferroptosis induction. Overall, these findings suggest that ferroptosis effectively targets MM1 cells and that RSL3-mediated ferroptosis triggers similar oxidative stress and cell death pathways in both MM1R and MM1S cells, irrespective of their glucocorticoid-sensitivity status.

2021-11-08 | GSE182638 | GEO

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