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| Status |
Public on Feb 16, 2017 |
| Title |
CD95/Fas increases stemness in cancer cells by inducing a STAT1 dependent Type I interferon response [ChIP-seq] |
| Organism |
Homo sapiens |
| Experiment type |
Genome binding/occupancy profiling by high throughput sequencing
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| Summary |
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.
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| Overall design |
One samples per condition
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| Contributor(s) |
Peter ME, Qadir AS, Ceppi P |
| Citation(s) |
28273453 |
| |
| Submission date |
May 25, 2016 |
| Last update date |
Sep 08, 2022 |
| Contact name |
Marcus Peter |
| E-mail(s) |
m-peter@northwestern.edu
|
| Organization name |
Northwestern University Feinberg School of Medicine
|
| Street address |
303 East Superior Street, Lurie 6-123
|
| City |
Chicago |
| State/province |
IL |
| ZIP/Postal code |
60611 |
| Country |
USA |
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| Platforms (1) |
| GPL15456 |
Illumina HiScanSQ (Homo sapiens) |
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| Samples (2) |
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| This SubSeries is part of SuperSeries: |
| GSE81860 |
CD95/Fas increases stemness in cancer cells by inducing a STAT1 dependent Type I interferon response |
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| Relations |
| BioProject |
PRJNA322762 |
| SRA |
SRP075680 |
