An IFNg/STAT1/JMJD3 axis induces ZEB1 expression and promotes aggressiveness in lung adenocarcinoma

Abstract

Active IFNg signaling is a common feature of tumors responding to PD-1 checkpoint blockade. IFNg exhibits both anti- and protumor activities. Here, we show that the treatment of lung adenocarcinoma cells with IFNg led to a rapid increase of ZEB1 expression and a significant change in epithelial-to-mesenchymal transition (EMT)-associated gene expression pattern. Moreover, functional analyses show that IFNg promoted cell migration in vitro and metastasis in vivo. We demonstrate that ZEB1 is required for IFNg-promoted EMT, cell migration, and metastasis, as RNAi-mediated knockdown of ZEB1 abrogated EMT, cell migration, and metastasis induced by IFNg. We show that IFNg induced upregulation of JMJD3 significantly reduced H3K27 trimethylation in the promoter of the ZEB1 gene, which led to activation of ZEB1 gene transcription. IFNg-induced JMJD3 expression was JAK1/2-STAT1 dependent. Inhibition of JMJD3 abrogated IFNg-induced ZEB1 expression. IFNg-induced ZEB1 also reduced miR-200 expression. Downregulation of ZEB1 increased miR-200 expression, which led to a reduction of PD-L1 expression induced by IFNg. It is worth noting that knockdown of ZEB1 did not affect IFNg-mediated antiproliferation and induction of CXCL9 and CXCL10. Thus, downregulation of ZEB1 may prevent the protumor activity of IFNg while retaining its antitumor function. This study expands our understanding of IFNg-mediated signaling and helps to identify therapeutic targets to improve current immunotherapies. Implications: IFNg increases ZEB1 expression in a STAT1-JMJD3 dependent manner, and consequently promotes cancer cell aggressiveness. This study provides a potential target to minimize the procancer effect of IFNg while preserving its antitumor function.