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

Cell Rep. 2017 Mar 7;18(10):2373-2386. doi: 10.1016/j.celrep.2017.02.037.

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.

Keywords: Fas; STAT1; breast cancer; cancer stem cells; head and neck cancer; type I interferons.

Publication types

  • Research Support, U.S. Gov't, Non-P.H.S.
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Breast Neoplasms / genetics
  • Breast Neoplasms / pathology
  • Caspase 3 / metabolism
  • Cell Line, Tumor
  • Down-Regulation
  • Female
  • Gene Expression Regulation, Neoplastic
  • Gene Knockout Techniques
  • Humans
  • Interferon Type I / metabolism*
  • Isotope Labeling
  • Neoplastic Stem Cells / metabolism*
  • Neoplastic Stem Cells / pathology*
  • Phosphorylation
  • RNA, Small Interfering / metabolism
  • STAT1 Transcription Factor / metabolism*
  • Signal Transduction
  • Up-Regulation
  • fas Receptor / metabolism*

Substances

  • FAS protein, human
  • Interferon Type I
  • RNA, Small Interfering
  • STAT1 Transcription Factor
  • fas Receptor
  • Caspase 3