Given the integral role of stimulator of
interferon genes (
STING, TMEM173) in the innate immune response, its loss or impairment in
cancer is thought to primarily affect antitumor immunity. Here we demonstrate a role for
STING in the maintenance of cellular homeostasis through regulation of the cell cycle. Depletion of
STING in human and murine
cancer cells and
tumors resulted in increased proliferation compared with wild-type controls. Microarray analysis revealed genes involved in cell-cycle regulation are differentially expressed in STINGko compared with WT MEFs.
STING-mediated regulation of the cell cycle converged on NFκB- and p53-driven activation of p21. The absence of
STING led to premature activation of
cyclin-dependent kinase 1 (CDK1), early onset to S-phase and mitosis, and increased
chromosome instability, which was enhanced by ionizing radiation. These results suggest a pivotal role for
STING in maintaining cellular homeostasis and response to genotoxic stress. SIGNIFICANCE: These findings provide clear mechanistic understanding of the role of
STING in cell-cycle regulation, which may be exploited in
cancer therapy because most normal cells express
STING, while many
tumor cells do not.See related commentary by Gius and Zhu, p. 1295.