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CD95/Fas Increases Stemness in Cancer Cells by Inducing a STAT1-Dependent Type I Interferon Response.

ABSTRACT: 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.

SUBMITTER: Qadir AS

PROVIDER: S-EPMC5474321 | biostudies-literature | 2017 Mar

REPOSITORIES: biostudies-literature

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CD95/Fas Increases Stemness in Cancer Cells by Inducing a STAT1-Dependent Type I Interferon Response.

Qadir Abdul S AS Ceppi Paolo P Brockway Sonia S Law Calvin C Mu Liang L Khodarev Nikolai N NN Kim Jung J Zhao Jonathan C JC Putzbach William W Murmann Andrea E AE Chen Zhuo Z Chen Wenjing W Liu Xia X Salomon Arthur R AR Liu Huiping H Weichselbaum Ralph R RR Yu Jindan J Peter Marcus E ME

Cell reports 20170301 10

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 CD95<sup>high</sup>-expressing glioblastoma neurospheres. CD95 stimulation of cancer cells induced secretion of type I interferons (IFNs) th ...[more]

PMID: 28273453

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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. 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.

Project description:BackgroundIn humans, interferon-α treatment for chronic viral hepatitis is a well-recognized clinical model for inflammation-induced depression, but the molecular mechanisms underlying these effects are not clear. Following peripheral administration in rodents, interferon-α induces signal transducer and activator of transcription-1 (STAT1) within the hippocampus and disrupts hippocampal neurogenesis.MethodsWe used the human hippocampal progenitor cell line HPC0A07/03C to evaluate the effects of 2 concentrations of interferon-α, similar to those observed in human serum during its therapeutic use (500 pg/mL and 5000 pg/mL), on neurogenesis and apoptosis.ResultsBoth concentrations of interferon-α decreased hippocampal neurogenesis, with the high concentration also increasing apoptosis. Moreover, interferon-α increased the expression of interferon-stimulated gene 15 (ISG15), ubiquitin-specific peptidase 18 (USP18), and interleukin-6 (IL-6) via activation of STAT1. Like interferon-α, co-treatment with a combination of ISG15, USP18, and IL-6 was able to reduce neurogenesis and enhance apoptosis via further downstream activation of STAT1. Further experiments showed that ISG15 and USP18 mediated the interferon-α-induced reduction in neurogenesis (potentially through upregulation of the ISGylation-related proteins UBA7, UBE2L6, and HERC5), while IL-6 mediated the interferon-α-induced increase in apoptosis (potentially through downregulation of aquaporin 4). Using transcriptomic analyses, we showed that interferon-α regulated pathways involved in oxidative stress and immune response (e.g., Nuclear Factor (erythroid-derived 2)-like 2 [Nrf2] and interferon regulatory factor [IRF] signaling pathway), neuronal formation (e.g., CAMP response element-binding protein [CREB] signaling), and cell death regulation (e.g., tumor protein(p)53 signaling).ConclusionsWe identify novel molecular mechanisms mediating the effects of interferon-α on the human hippocampus potentially involved in inflammation-induced neuropsychiatric symptoms.

Dataset Information

CD95/Fas Increases Stemness in Cancer Cells by Inducing a STAT1-Dependent Type I Interferon Response.

Publications

CD95/Fas Increases Stemness in Cancer Cells by Inducing a STAT1-Dependent Type I Interferon Response.

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