Methyltransferase SETD7 as a Regulator of STING-Dependent Cytokine Response in Lung Cancer Cells

The innate immune signaling pathway cGAS-STING plays an important role in the recognition of cytosolic nucleic acids and the induction of the interferon-dependent antiviral response. Despite the significant research interest in this cascade in the context of immune system function, the mechanisms regulating cGAS-STING signaling and the switch between its pro-inflammatory and pro-apoptotic effects remain largely underexplored. According to publicly available RNA-seq data and microarray analyses, SETD7 lysine methyltransferase participates in interferon signaling in cancer cells. This study aims to elucidate the role of SETD7 in the regulation of the STING-dependent immune response in human lung adenocarcinoma (LUAD) cells. For this purpose, we developed a reproducible and cost-effective method for inducing the STING cascade by transfecting cells with salmon sperm DNA (sspDNA). We demonstrated that sspDNA efficiently induces phosphorylation of the key components of the STING-TBK1-IRF3 signaling pathway and activates the expression of interferons and pro-inflammatory cytokines. Using this approach, we further demonstrated that SETD7 is involved in the regulation of the IRF3-dependent transcriptional program. Suppression of SETD7 was associated with changes in the expression of genes related to innate immune response and apoptosis, including increased levels of <i>IFNA1</i>, <i>IL1B</i>, <i>BAK1</i>, <i>BBC3</i> (PUMA), and <i>BCL2</i>. Furthermore, attenuation of SETD7 expression reduced the lentiviral transduction efficacy in H1299 cells. These results suggest that SETD7 may play a role in regulating the switch in STING signaling between pro-inflammatory and pro-apoptotic responses in LUAD cells.