An IFNγ/STAT1/JMJD3 Axis Induces ZEB1 Expression and Promotes Aggressiveness in Lung Adenocarcinoma

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