Dataset Information

The mechanism of how CD95/Fas activates the Type I IFN/STAT1 axis, driving cancer stemness in breast cancer.

ABSTRACT: CD95/Fas is an apoptosis inducing death receptor. However, it also has multiple nonapoptotic activities that are tumorigenic. Chronic stimulation of CD95 on breast cancer cells can increase their cancer initiating capacity through activation of a type I interferon (IFN-I)/STAT1 pathway when caspases are inhibited. We now show that this activity relies on the canonical components of the CD95 death-inducing signaling complex, FADD and caspase-8, and on the activation of NF-?B. We identified caspase-2 as the antagonistic caspase that downregulates IFN-I production. Once produced, IFN-Is bind to their receptors activating both STAT1 and STAT2 resulting in upregulation of the double stranded (ds)RNA sensor proteins RIG-I and MDA5, and a release of a subset of endogenous retroviruses. Thus, CD95 is part of a complex cell autonomous regulatory network that involves activation of innate immune components that drive cancer stemness and contribute to therapy resistance.

SUBMITTER: Qadir AS

PROVIDER: S-EPMC6987111 | biostudies-literature | 2020 Jan

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

The mechanism of how CD95/Fas activates the Type I IFN/STAT1 axis, driving cancer stemness in breast cancer.

Qadir Abdul S AS Stults Austin M AM Murmann Andrea E AE Peter Marcus E ME

Scientific reports 20200128 1

CD95/Fas is an apoptosis inducing death receptor. However, it also has multiple nonapoptotic activities that are tumorigenic. Chronic stimulation of CD95 on breast cancer cells can increase their cancer initiating capacity through activation of a type I interferon (IFN-I)/STAT1 pathway when caspases are inhibited. We now show that this activity relies on the canonical components of the CD95 death-inducing signaling complex, FADD and caspase-8, and on the activation of NF-κB. We identified caspas ...[more]

PMID: 31992798

Similar Datasets

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.

Dataset Information

The mechanism of how CD95/Fas activates the Type I IFN/STAT1 axis, driving cancer stemness in breast cancer.

Publications

The mechanism of how CD95/Fas activates the Type I IFN/STAT1 axis, driving cancer stemness in breast cancer.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets