IFN-r-induced IFIT5 promotes epithelial-to-mesenchymal transition in prostate cancer via microRNA processing.

Interferon-γ (IFNγ), a potent cytokine known to modulate tumor immunity and tumoricidal effects, is highly elevated in prostate cancer (PCa) patients after radiation. In this study, we demonstrate that IFNγ can induce epithelial-to-mesenchymal transition (EMT) in PCa cells via the JAK-STAT signaling pathway, leading to the transcription of IFN-stimulated genes (ISG) such as interferon-induced tetratricopeptide repeat 5 (IFIT5). We unveil a new function of IFIT5 complex in degrading precursor microRNAs (pre-miRNA) that include pre-miR-363 from the miR-106a-363 cluster as well as pre-miR-101 and pre-miR-128, who share a similar 5'-end structure with pre-miR-363. These suppressive miRNAs exerted a similar function by targeting EMT transcription factors in PCa cells. Depletion of IFIT5 decreased IFNγ-induced cell invasiveness in vitro and lung metastasis in vivo. IFIT5 was highly elevated in high-grade PCa and its expression inversely correlated with these suppressive miRNAs. Altogether, this study unveils a pro-metastatic role of the IFNγ pathway via a new mechanism of action, which raises concerns about its clinical application.