IRF8 regulates intrinsic ferroptosis through repressing p53 expression to maintain tumor cell sensitivity to cytotoxic T lymphocytes
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ABSTRACT:
PROVIDER: PRJNA882793 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR21658589_1.fastq.gz | Fastqsanger.gz | |||
| SRR21658589_2.fastq.gz | Fastqsanger.gz | |||
| SRR21658590_1.fastq.gz | Fastqsanger.gz | |||
| SRR21658590_2.fastq.gz | Fastqsanger.gz | |||
| SRR21658591_1.fastq.gz | Fastqsanger.gz |
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Project description:Ferroptosis has emerged as a cytotoxic T lymphocyte (CTL)-induced tumor cell death pathway. The regulation of tumor cell sensitivity to ferroptosis is still incompletely understood. We report here that the interferon regulatory factor 8 (IRF8) functions as a regulator of tumor cell intrinsic ferroptosis. Genome-wide gene expression profiling identified ferroptosis pathway as an IRF8-regulated pathway in tumor cells. IRF8.KO tumor cells acquire resistance to intrinsic ferroptosis induction and IRF8-deficient tumor cells exhibit decreased ferroptosis in response to tumor-specific CTLs. Irf8 deletion increases p53 expression in tumor cells and knocking out p53 in IRF8.KO tumor cells restored tumor cell sensitivity to intrinsic ferroptosis induction. Furthermore, IRF8.KO tumor cells grew significantly faster than WT tumor cells in immune competent mice. To restore IRF8 expression in tumor cells, we designed and synthesized codon usage-optimized IRF8-encoding DNA to generate IRF8-encoding plasmid NTC9385R-mIRF8. Restoring IRF8 expression via a lipid nanoparticle-encapsulated NTC9385R-mIRF8 plasmid therapy suppressed established tumor growth in vivo. In human cancer patients, nivolumab responders have a significant higher IRF8 expression level in their tumor cells as compared to the non-responders. Our data determine that IRF8 represses p53 expression to maintain tumor cell sensitivity to intrinsic ferroptosis
2022-09-25 | GSE213856 | GEO
Project description:Ferroptosis has emerged as a cytotoxic T lymphocyte (CTL)-induced tumor cell death pathway. The regulation of tumor cell sensitivity to ferroptosis is incompletely understood. Here, we report that interferon regulatory factor 8 (IRF8) functions as a regulator of tumor cell intrinsic ferroptosis. Genome-wide gene expression profiling identified the ferroptosis pathway as an IRF8-regulated pathway in tumor cells. IRF8.KO tumor cells acquire resistance to intrinsic ferroptosis induction and IRF8-deficient tumor cells also exhibit decreased ferroptosis in response to tumor-specific CTLs. Irf8 deletion increased p53 expression in tumor cells and knocking out p53 in IRF8.KO tumor cells restored tumor cell sensitivity to intrinsic ferroptosis induction. Furthermore, IRF8.KO tumor cells grew significantly faster than WT tumor cells in immune-competent mice. To restore IRF8 expression in tumor cells, we designed and synthesized codon usage-optimized IRF8-encoding DNA to generate IRF8-encoding plasmid NTC9385R-mIRF8. Restoring IRF8 expression via a lipid nanoparticle-encapsulated NTC9385R-mIRF8 plasmid therapy suppressed established tumor growth in vivo. In human cancer patients, nivolumab responders have a significantly higher IRF8 expression level in their tumor cells as compared to the non-responders. Our data determine that IRF8 represses p53 expression to maintain tumor cell sensitivity to intrinsic ferroptosis.
| S-EPMC9856547 | biostudies-literature
Project description:Ferroptosis, a non-apoptotic programmed cell death triggered by excessive iron-dependent lipid peroxidation, plays a pivotal role in tumor progression. Significant progress has been made in elucidating the role of transcription factors in the regulation of ferroptosis. Nevertheless, the identification of the key transcription factor responsible for inducing ferroptosis remains elusive. In this study, we discovered that ATOH8 is upregulated in prostate cancer cells treated with the ferroptosis inducer. Overexpression of ATOH8 increased the vulnerability of prostate cancer to ferroptosis, while ATOH8 deletion promotes ferroptosis evasion. Mechanistically, ATOH8 suppresses the transcription of SCD, reducing the synthesis of monounsaturated fatty acids that confer resistance to ferroptosis. Additionally, ATOH8 works in conjunction with the E protein E47 to form a transcriptional repression complex that inhibits SCD transcription. Furthermore, we discovered that EZH2 epigenetically suppresses the expression of ATOH8 through DNA methylation and H3K27 methylation. Interestingly, EZH2 was found to be downregulated in ferroptosis, resulting in an upregulation of ATOH8. Pharmacological inhibition of EZH2 combined with ferroptosis inducer significantly suppresses prostate cancer growth in vitro and in vivo. Together, our findings unveil that EZH2-mediated ATOH8 downregulation promotes ferroptosis evasion and suggest that pharmacological manipulation of EZH2 and ATOH8 is a promising therapeutic strategy for prostate cancer.
2025-01-30 | GSE282995 | GEO
Project description:Ferroptosis, a non-apoptotic programmed cell death triggered by excessive iron-dependent lipid peroxidation, plays a pivotal role in tumor progression. Significant progress has been made in elucidating the role of transcription factors in the regulation of ferroptosis. Nevertheless, the identification of the key transcription factor responsible for inducing ferroptosis remains elusive. In this study, we discovered that ATOH8 is upregulated in prostate cancer cells treated with the ferroptosis inducer. Overexpression of ATOH8 increased the vulnerability of prostate cancer to ferroptosis, while ATOH8 deletion promotes ferroptosis evasion. Mechanistically, ATOH8 suppresses the transcription of SCD, reducing the synthesis of monounsaturated fatty acids that confer resistance to ferroptosis. Additionally, ATOH8 works in conjunction with the E protein E47 to form a transcriptional repression complex that inhibits SCD transcription. Furthermore, we discovered that EZH2 epigenetically suppresses the expression of ATOH8 through DNA methylation and H3K27 methylation. Interestingly, EZH2 was found to be downregulated in ferroptosis, resulting in an upregulation of ATOH8. Pharmacological inhibition of EZH2 combined with ferroptosis inducer significantly suppresses prostate cancer growth in vitro and in vivo. Together, our findings unveil that EZH2-mediated ATOH8 downregulation promotes ferroptosis evasion and suggest that pharmacological manipulation of EZH2 and ATOH8 is a promising therapeutic strategy for prostate cancer.
2025-01-30 | GSE282996 | GEO
Project description:Tumor progression is associated with overstimulation of cytotoxic T lymphocytes (CTLs), resulting in a dysfunctional state of exhaustion. However, the identity of antigen-presenting cells that drive CTL exhaustion is poorly defined. Here we show that tumor-associated macrophages (TAMs) expressing the transcription factor interferon regulatory factor-8 (IRF8) promote CTL exhaustion in a murine model of breast cancer. While CTL priming in tumor-draining lymph nodes was enabled by IRF8-dependent type 1 dendritic cells, CTL exhaustion in tumor required TAM expression of IRF8 that supported the cancer cell antigen-presenting function of TAMs. Macrophage-specific ablation of IRF8 reversed exhaustion of cancer cell antigen-reactive CTLs, and suppressed tumor growth. Analysis of the immune-infiltrated human renal cell carcinoma tumors revealed abundant TAMs that expressed IRF8 and were enriched for an IRF8 gene expression signature. Furthermore, the TAM-IRF8 signature co-segregated with CTL exhaustion signatures across multiple cancer types. Thus, CTL exhaustion is promoted by TAMs via IRF8.
2022-09-06 | GSE212643 | GEO
Project description:To understand the differentiation program in monocyte/macrophage differentiation, we performed ChIP-seq for IRF8 and H3K4me1 together with gene expression profiling during IRF8-induced monocyte differentiation. Both promoter-proximal and -distal binding of IRF8 associated with induction of the genes especially those related to monocytes/macrophages and immunity. DNA motif analysis for cis-regulatory elements of indirect IRF8 target genes predicted KLF4, essential for Ly6C+ monocyte development, to be a downstream transcription factor regulating the indirect target gene expression. Introduction of KLF4 into an Irf8-/- myeloid progenitor cell line induced a subset of IRF8 target genes and partially induced monocyte/macrophage differentiation. Together, this study revealed the genome-wide behavior of IRF8 and the IRF8-KLF4 axis during monocyte differentiation. Gene expressions in monocyte-like cells differentiated by IRF8 or KLF4 were measured at day 4 after retroviral transductions to myeloid progenitor cell line, Tot2. Two independent experiments were performed.
2013-01-24 | E-GEOD-38810 | biostudies-arrayexpress
Project description:Lymphocyte activation and effector state differentiation critically depend on integration of multiple signals, including those from antigen, co-stimulatory ligand and cytokine receptors. Thus, discovery of molecular components and mechanisms underlying signal integration is vital for the understanding and control of adaptive immune responses. Stimulation of antigen receptors in lymphocytes leads to the activation of NFAT family transcription factors (TFs) as well as the inducible expression of the immune-selective IRFs, IRF4 and IRF8; the latter are differentially controlled by co-stimulatory ligand and cytokine receptor signaling. Despite their major overlapping functions in lymphocyte activation and differentiation, it has remained enigmatic if NFATs can perform signal integration with IRF4 and IRF8, via their cooperative assembly on composite genomic regulatory elements. Composite elements (CEs) provide a powerful means of signal integration by inducible TFs and despite their clear importance, CEs arguably remain the least explored elements within cis-regulomes. To test the above hypothesis, we deployed a generalizable computational strategy, which revealed a stereospecific NFAT-IRF composite element (NICE) motif that was enriched within active chromatin regions (H3K27Ac) of activated B and T lymphocytes. NICE containing DNA sequences promoted cooperative binding of NFATs with IRF4 or IRF8. Genomic analyses in activated B cells revealed co-dependent genes that undergo activation or repression and contain NICE motifs in their regulatory regions. Notably, NFATc2 and IRF8 form a positive feedforward loop and coordinately repress the Prdm1 gene by binding a NICE motif in a phylogenetically conserved region, thereby inhibiting extrafollicular plasma cell differentiation and promoting the germinal center fate of activated B cells. The NICE motif is also enriched in DNA sequences located in accessible chromatin of human lymphocytes, suggesting evolutionary conservation of its function. The cooperative assembly of NFAT family members with IRF4 and IRF8 on NICE motifs reveals a new genomic control mechanism that enables signal integration during lymphocyte activation and differentiation.
2018-10-06 | GSE104921 | GEO
Project description:Transcriptional profiling of IRF8-regulated genes in mouse CD11b-positive primary cells. CD11b-positive cells were isolated from spleens of age-matched wt and IRF8 KO mice, the compared for their gene expression profiles. The objective is to identify genes that are regulated by IRF8 in CD11b-positive primary cells. Two-condition experiments. Wt vs IRF8 KO cells. Biological replicates: 2 replicates for the comparison.
2011-10-19 | E-GEOD-31464 | biostudies-arrayexpress
Project description:ATOH8 confers the vulnerability of tumor cells to ferroptosis by repressing SCD expression [RNA-Seq]
| PRJNA1191429 | ENA
Project description:ATOH8 confers the vulnerability of tumor cells to ferroptosis by repressing SCD expression [ChIP-Seq]
| PRJNA1191431 | ENA