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

Oncogene volume 37, pages 2037–2051 (2018)Cite this article

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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.

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Fig. 1: STING and cGAS genes are mutated in a variety of human tumors.
Fig. 2: STING mutants found in human tumors fail to activate dsDNA-induced inflammation.
Fig. 3: cGAS mutants, R376Q and E383K, found in human tumors cannot synthesize cGAMP.
Fig. 4: STING mutants are dominant-negative mutants.
Fig. 5: STING mutants fail to respond to DNA-adduct forming agents.
Fig. 6: cGAS and STING expression is suppressed by methylation in a pan-tumor analysis.
Fig. 7: cGAS and STING show a large variability in methylation for a variety of human tumors.

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Acknowledgements

This work was supported by grants from NCI (R01CA194404) (G.N. Barber) and NCI-NIH (1R01 CA148995, 1R01 CA184845, P30 CA076292, P50 CA168536), Cindy and Jon Gruden Fund, Chris Sullivan Fund, and Dr. Miriam and Sheldon G. Adelson Medical Research Foundation (J.J. Mulé). We thank the staff of the Moffitt Cancer Center Cancer Informatics and Collaborative Data Services.

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Authors and Affiliations

  1. Department of Cell Biology, University of Miami Miller School of Medicine, Miami, FL, USA

    Hiroyasu Konno, Shota Yamauchi & Glen N. Barber

  2. Department of Biostatistics and Bioinformatics, Moffitt Cancer Center, Tampa, FL, USA

    Anders Berglund & Ryan M. Putney

  3. Cutaneous Oncology, Moffitt Cancer Center, Tampa, FL, USA

    James J. Mulé

  4. Immunology Programs, Moffitt Cancer Center, Tampa, FL, USA

    James J. Mulé

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  1. Hiroyasu Konno
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Correspondence to Glen N. Barber.

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Konno, H., Yamauchi, S., Berglund, A. et al. Suppression of STING signaling through epigenetic silencing and missense mutation impedes DNA damage mediated cytokine production. Oncogene 37, 2037–2051 (2018). https://doi.org/10.1038/s41388-017-0120-0

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