Suppression of STING signaling through epigenetic silencing and missense mutation impedes DNA damage mediated cytokine production

Hiroyasu Konno, Shota Yamauchi, Anders Berglund, Ryan M. Putney, James J. Mulé, Glen N. Barber

Research output: Contribution to journalArticle

28 Scopus citations

Abstract

The production of cytokines in response to DNA-damage events may be an important host defense response to help prevent the escape of pre-cancerous cells. The innate immune pathways involved in these events are known to be regulated by cellular molecules such as stimulator of interferon genes (STING), which controls type I interferon and pro-inflammatory cytokine production in response to the presence of microbial DNA or cytosolic DNA that has escaped from the nucleus. STING signaling has been shown to be defective in a variety of cancers, such as colon cancer and melanoma, actions that may enable damaged cells to escape the immunosurveillance system. Here, we report through examination of databases that STING signaling may be commonly suppressed in a greater variety of tumors due to loss-of-function mutation or epigenetic silencing of the STING/cGAS promoter regions. In comparison, RNA activated innate immune pathways controlled by RIG-I/MDA5 were significantly less affected. Examination of reported missense STING variants confirmed that many exhibited a loss-of-function phenotype and could not activate cytokine production following exposure to cytosolic DNA or DNA-damage events. Our data imply that the STING signaling pathway may be recurrently suppressed by a number of mechanisms in a considerable variety of malignant disease and be a requirement for cellular transformation.

Original languageEnglish (US)
Pages (from-to)2037-2051
Number of pages15
JournalOncogene
Volume37
Issue number15
DOIs
StatePublished - Apr 1 2018

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Cancer Research

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