Ferroptosis Induction in Multiple Myeloma Cells Triggers an Epigenomic Stress Response Associated with DNA Repair and Cellular Senescence
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ABSTRACT:
PROVIDER: PRJNA757240 | ENA |
REPOSITORIES: ENA
Dataset's files
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| SRR15593062.fastq.gz | Fastqsanger.gz | |||
| SRR15593063.fastq.gz | Fastqsanger.gz | |||
| SRR15593064.fastq.gz | Fastqsanger.gz | |||
| SRR15593065.fastq.gz | Fastqsanger.gz | |||
| SRR15593066.fastq.gz | Fastqsanger.gz |
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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
Project description:Ageing in space: microgravity triggers ferroptosis and accelerates senescence in osteoblastic cells
| PRJNA932730 | ENA
Project description:Disease relapse and therapy resistance remain key challenges in treating multiple myeloma. Underlying (epi-)mutational events can promote myelomagenesis and contribute to multi-drug and apoptosis resistance. Therefore, compounds inducing ferroptosis, a form of iron and lipid peroxidation-regulated cell death, are appealing alternative treatment strategies for multiple myeloma and other malignancies. Both ferroptosis and the epigenetic machinery are heavily influenced by oxidative stress and iron metabolism changes. Yet, only a limited number of epigenetic enzymes and modifications have been identified as ferroptosis regulators. In this study, we found that MM1 multiple myeloma cells are sensitive to ferroptosis induction and epigenetic reprogramming by RSL3, irrespective of their glucocorticoid-sensitivity status. LC-MS/MS analysis revealed the formation of non-heme iron-histone complexes and altered expression of histone modifications associated with DNA repair and cellular senescence. In line with this observation, EPIC BeadChip measurements of significant DNA methylation changes in ferroptotic myeloma cells demonstrated an enrichment of CpG probes located in genes associated with cell cycle progression and senescence, such as Nuclear Receptor Subfamily 4 Group A member 2 (NR4A2). Overall, our data show that ferroptotic cell death is associated with an epigenomic stress response that might advance the therapeutic applicability of ferroptotic compounds.
| S-EPMC8618106 | biostudies-literature
Project description:To investigate ferroptosis-dependent changes in DNA methylation, a genome wide DNA methylation profiling of ferroptotic (RSL3-treated) multiple myeloma cells (MM1S & MM1R) was performed using the 850K MethylationEPIC BeadChip Array. The ferroptotic DNA methylation signature was compared to myeloma cells pre-treated with the ferroptosis inhibitor ferrostatin-1 (FRSL3), which served as a negative control. In total, three biological replicates per treatment per cell line were included.
2021-11-08 | GSE184576 | GEO
Project description:The amino acid cysteine and its oxidized dimeric form cystine are commonly believed to be synonymous in metabolic functions. Cyst(e)ine depletion not only induces amino acid response, but also triggers ferroptosis, a non-apoptotic cell death. Here we report that, unlike general amino acid starvation, cyst(e)ine deprivation triggers ATF4 induction at the transcriptional level. Unexpectedly, it is the shortage of lysosomal cystine, but not the cytosolic cysteine, that elicits the adaptative ATF4 response. The lysosome-nucleus signaling pathway involves the aryl hydrocarbon receptor (AhR) that senses lysosomal cystine via the kynurenine pathway. A blockade of lysosomal cystine efflux attenuates ATF4 induction and sensitizes ferroptosis. To potentiate ferroptosis in cancer, we develop a synthetic mRNA reagent CysRx that converts cytosolic cysteine to lysosomal cystine. CysRx maximizes cancer cell ferroptosis and effectively suppresses tumor growth in vivo. Thus, intracellular nutrient reprogramming has the potential to induce selective ferroptosis in cancer without systematic perturbation.
2023-08-30 | GSE237928 | GEO
Project description:Ferroptosis is an iron-dependent programmed cell death associated with severe kidney diseases, linked to decreased glutathione peroxidase 4 (GPX4). However, the spatial distribution of renal GPX4-mediated ferroptosis and the molecular events causing GPX4 reduction during ischemia-reperfusion (I/R) remain largely unknown. Using spatial transcriptomics, we identify that GPX4 is situated at the interface of the inner cortex and outer medulla, a hyperactive ferroptosis site post-I/R injury. We show that OTU deubiquitinase 5 (OTUD5) is a GPX4-binding protein that confers ferroptosis resistance by stabilizing GPX4. During I/R, ferroptosis is induced by mTORC1-mediated autophagy, causing OTUD5 degradation and subsequent GPX4 decay. Functionally, OTUD5 deletion intensifies renal tubular cell ferroptosis and exacerbates acute kidney injury, while AAV-mediated OTUD5 delivery mitigates ferroptosis and promotes renal function recovery from I/R injury. In this work, our study highlights a new autophagy-dependent ferroptosis module: hypoxia/ischemia-induced OTUD5 autophagy triggers GPX4 degradation, offering a potential therapeutic avenue for I/R-related kidney diseases.
2023-11-29 | GSE244330 | GEO
Project description:Immune checkpoint blockade (ICB) triggers tumor ferroptosis. However, most patients are unresponsive to ICB. Tumors might evade ferroptosis in the tumor microenvironment (TME). Here, we discovered SLC13A3 is an itaconate transporter in tumor cells and endows tumor ferroptosis resistance, diminishing tumor immunity and ICB efficacy. Mechanistically, tumor cells uptake itaconate via SLC13A3 from tumor-associated macrophages (TAMs), thereby activating the NRF2-SLC7A11 pathway and escaping from immune-mediated ferroptosis. Structural modeling and molecular docking analysis identified a functional inhibitor for SLC13A3 (SLC13A3i). Deletion of ACOD1 (an essential enzyme for itaconate synthesis) in macrophages, genetic ablation of SLC13A3 in tumors, or treatment with SLC13A3i sensitized tumors to ferroptosis, curbed tumor progression, and bolstered ICB effectiveness. Thus, we identify the interplay between tumors and TAMs via the SLC13A3-itaconate-NRF2-SLC7A11 axis as a previously unknown immune ferroptosis resistant mechanism in the TME and SLC13A3 as a promising immunometabolic target and disease indication for treating SLC13A3+cancer.
2024-09-19 | GSE268205 | GEO
Project description:Immune checkpoint blockade (ICB) triggers tumor ferroptosis. However, most patients are unresponsive to ICB. Tumors might evade ferroptosis in the tumor microenvironment (TME). Here, we discovered SLC13A3 is an itaconate transporter in tumor cells and endows tumor ferroptosis resistance, diminishing tumor immunity and ICB efficacy. Mechanistically, tumor cells uptake itaconate via SLC13A3 from tumor-associated macrophages (TAMs), thereby activating the NRF2-SLC7A11 pathway and escaping from immune-mediated ferroptosis. Structural modeling and molecular docking analysis identified a functional inhibitor for SLC13A3 (SLC13A3i). Deletion of ACOD1 (an essential enzyme for itaconate synthesis) in macrophages, genetic ablation of SLC13A3 in tumors, or treatment with SLC13A3i sensitized tumors to ferroptosis, curbed tumor progression, and bolstered ICB effectiveness. Thus, we identify the interplay between tumors and TAMs via the SLC13A3-itaconate-NRF2-SLC7A11 axis as a previously unknown immune ferroptosis resistant mechanism in the TME and SLC13A3 as a promising immunometabolic target and disease indication for treating SLC13A3+cancer.
2024-09-19 | GSE268293 | GEO
Project description:Osteocytes are the main cells in mineralized bone tissue. Elevated osteocyte apoptosis has been observed in lytic bone lesions of patients with multiple myeloma. However, their precise contribution to bone metastasis remains unclear.Here, we investigated the pathogenic mechanisms driving melanoma-induced osteocyte death. Both in vivo models and in vitro assays were combined with untargeted RNA sequencing approaches to explore the pathways governing melanoma-induced osteocyte death. We could show that ferroptosis is the primary mechanism behind osteocyte death in the context of melanoma bone metastasis. HMOX1 was identified as a crucial regulatory factor in this process, directly involved in inducing ferroptosis and affecting osteocyte viability. We uncover a non-canonical pathway that involves excessive autophagy-mediated ferritin degradation, highlighting the complex relationship between autophagy and ferroptosis in melanoma-induced osteocyte death. In addition, HIF1α pathway was shown as an upstream regulator, providing a potential target for modulating HMOX1 expression and influencing autophagy-dependent ferroptosis. In conclusion, our study provides insight into the pathogenic mechanisms of osteocyte death induced by melanoma bone metastasis, with a specific focus on ferroptosis and its regulation. This would enhance our comprehension of melanoma-induced osteocyte death.
2024-11-24 | GSE276370 | 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