CD95/Fas increases stemness in cancer cells by inducing a STAT1 dependent Type I interferon response
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA322761 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR3585090.fastq.gz | Fastqsanger.gz | |||
| SRR3585091.fastq.gz | Fastqsanger.gz | |||
| SRR3585092.fastq.gz | Fastqsanger.gz | |||
| SRR3585093.fastq.gz | Fastqsanger.gz | |||
| SRR3585089.fastq.gz | Fastqsanger.gz |
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Project description:CD95 was found to be important for both the formation of CSCs and their maintenance. Using a stable isotope labeling by amino acids in cell culture (SILAC) analysis we have now identified STAT1 as a critical gene that mediates the CSC-driving activity of CD95. We report that chronic stimulation of CD95 by either agonist antibodies, soluble CD95L or stably expressed membrane CD95L causes both serine and tyrosine phosphorylation of STAT1 and activation of STAT1 regulated genes. The genes most significantly induced were part of an interferon (IFN)-related DNA damage resistance signature (IRDS) recently identified in a radiation resistant squamous cell carcinoma cell line Nu61 when compared to parental SCC61 cells. The IRDS was found to strongly correlate with therapy resistance (chemotherapy and radiation) in multiple cancer cells as well as in 5 human primary cancers. We now report that CD95 stimulation of breast cancer cell lines or the SCC61 cells induces the upregulation of Type I IFNs that bind to both Type I receptors IFNAR1 and IFNR2 resulting in activation of JAK kinases, activation of STAT1 and induction of a number of STAT1-regulated genes. This process can be inhibited by active caspases. Consequently, we identified Type I IFNs as drivers of cancer stemness. Knockdown of STAT1 using either siRNAs or shRNAs, or deleting two independent sites in the STAT1 gene in MCF-7 cells using the CRIPSR/Cas9 gene editing system resulted in a loss of the ability of CD95 to increase stemness. This identifies STAT1 as a critical mediator of the CSCs-inducing activity of CD95.
2017-02-16 | GSE81853 | GEO
Project description:CD95 was found to be important for both the formation of CSCs and their maintenance. Using a stable isotope labeling by amino acids in cell culture (SILAC) analysis we have now identified STAT1 as a critical gene that mediates the CSC-driving activity of CD95. We report that chronic stimulation of CD95 by either agonist antibodies, soluble CD95L or stably expressed membrane CD95L causes both serine and tyrosine phosphorylation of STAT1 and activation of STAT1 regulated genes. The genes most significantly induced were part of an interferon (IFN)-related DNA damage resistance signature (IRDS) recently identified in a radiation resistant squamous cell carcinoma cell line Nu61 when compared to parental SCC61 cells. The IRDS was found to strongly correlate with therapy resistance (chemotherapy and radiation) in multiple cancer cells as well as in 5 human primary cancers. We now report that CD95 stimulation of breast cancer cell lines or the SCC61 cells induces the upregulation of Type I IFNs that bind to both Type I receptors IFNAR1 and IFNR2 resulting in activation of JAK kinases, activation of STAT1 and induction of a number of STAT1-regulated genes. This process can be inhibited by active caspases. Consequently, we identified Type I IFNs as drivers of cancer stemness. Knockdown of STAT1 using either siRNAs or shRNAs, or deleting two independent sites in the STAT1 gene in MCF-7 cells using the CRIPSR/Cas9 gene editing system resulted in a loss of the ability of CD95 to increase stemness. This identifies STAT1 as a critical mediator of the CSCs-inducing activity of CD95. androgen receptor (AR) activation independently of androgen. We have previously reported that AR can directly repress the expression of many target genes, one of which is NOV/CCN3. Here we show that NOV, primarily localized in the cytoplasm, physically interacts with AR at its Nterminus and sequesters AR and AR variants in the cytoplasm, thereby reducing AR chromatintargeting. This negative feedback loop, however, is disrupted in CRPC due to epigenetic silencing of NOV by the Polycomb group protein EZH2, rendering AR transcriptional activities and drug-resistant prostate cancer progression. Our findings thus suggest a working model wherein AR-repressed genes critically prevent CRPC through negative feedback loops inhibiting AR signaling.
2017-02-16 | GSE81859 | GEO
Project description:Chronic viral infections incapacitate adaptive immune responses by 'exhausting' virus-specific T cells, inducing their deletion and reducing productive T cell memory. Viral infection rapidly induces death receptor Fas (CD95) expression by dendritic cells (DCs) making them susceptible to elimination by the immune response. Lymphocytic Choriomeningitis Virus (LCMV) Clone 13, which normally establishes a chronic infection, is rapidly cleared in C57Black/J mice with conditional deletion of Fas in DCs. The immune response to LCMV is characterized by an extended survival of virus-specific effector T cells. Moreover, transfer of Fas-negative DCs from non-infected mice to already-infected animals results in either complete clearance of the virus or a significant reduction of viral titers. Thus, DC-specific Fas expression plays a role in regulation of anti-viral responses and suggests a strategy for stimulation of T cells in chronically infected animals and humans in order to achieve the clearance of persistent viruses. We compared gene expression between splenic DCs from B6.FasKI and B6.CD11c-Cre.FasKI mice. DCs were isolated on day 5 after LCMV infection with 3 mice in each group, for a total of 6 samples. Spleens were collagenase-DNAse digested and sorted by flow to isolate DCs.
2014-05-09 | E-GEOD-57443 | biostudies-arrayexpress
Project description:Stimulation of CD95/Fas drives and maintains cancer stem cells (CSCs). We now report that this involves activation of signal transducer and activator of transcription 1 (STAT1) and induction of STAT1-regulated genes and that this process is inhibited by active caspases. STAT1 is enriched in CSCs in cancer cell lines, patient-derived human breast cancer, and CD95high-expressing glioblastoma neurospheres. CD95 stimulation of cancer cells induced secretion of type I interferons (IFNs) that bind to type I IFN receptors, resulting in activation of Janus-activated kinases, activation of STAT1, and induction of a number of STAT1-regulated genes that are part of a gene signature recently linked to therapy resistance in five primary human cancers. Consequently, we identified type I IFNs as drivers of cancer stemness. Knockdown or knockout of STAT1 resulted in a strongly reduced ability of CD95L or type I IFN to increase cancer stemness. This identifies STAT1 as a key regulator of the CSC-inducing activity of CD95.
| S-EPMC5474321 | biostudies-literature
Project description:Chronic viral infections incapacitate adaptive immune responses by 'exhausting' virus-specific T cells, inducing their deletion and reducing productive T cell memory. Viral infection rapidly induces death receptor Fas (CD95) expression by dendritic cells (DCs) making them susceptible to elimination by the immune response. Lymphocytic Choriomeningitis Virus (LCMV) Clone 13, which normally establishes a chronic infection, is rapidly cleared in C57Black/J mice with conditional deletion of Fas in DCs. The immune response to LCMV is characterized by an extended survival of virus-specific effector T cells. Moreover, transfer of Fas-negative DCs from non-infected mice to already-infected animals results in either complete clearance of the virus or a significant reduction of viral titers. Thus, DC-specific Fas expression plays a role in regulation of anti-viral responses and suggests a strategy for stimulation of T cells in chronically infected animals and humans in order to achieve the clearance of persistent viruses.
2014-05-09 | GSE57443 | GEO
Project description:CD95/Fas ligand mRNA is toxic to cells
| PRJNA403815 | ENA
Project description:The death receptor Fas removes activated lymphocytes through apoptosis. Previous transcriptional profiling predicted that Fas positively regulates interleukin (IL)-17-producing T helper (Th17) cells. We here demonstrate that Fas promoted the generation and stability of Th17 cells and prevented their differentiation into Th1 cells. Mice with T cell- and Th17 cell-specific deletion of Fas were protected from induced autoimmunity and Th17 cell differentiation and stability was impaired. Fas deficient Th17 cells instead developed a Th1 cell-like transcriptional profile, which we predicted by a new algorithm to depend on STAT1. Experimentally, Fas indeed bound and sequestered STAT1 and Fas deficiency enhanced IL-6 induced STAT1 activation and nuclear translocation, whereas Fas-STAT1 double-deficiency reversed the transcriptional changes induced by Fas deficiency. Thus, our computational and experimental approach identified Fas as a regulator of the Th17-to-Th1 cell balance by controlling the availability of the opposing STAT1 and STAT3 proteins with direct impact on autoimmunity.
2018-03-10 | GSE111244 | GEO
Project description:This SuperSeries is composed of the SubSeries listed below.
2017-02-16 | GSE81860 | GEO
Project description:We examine the differential RNA expression after knocking out CD95/Fas gene in 4T1 cells
2020-07-19 | GSE154676 | GEO
Project description:CD95/Fas increases stemness in cancer cells by inducing a STAT1 dependent Type I interferon response [array]
| PRJNA322750 | ENA