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IFNγ-Induced IFIT5 Promotes Epithelial-to-Mesenchymal Transition in Prostate Cancer via miRNA Processing

U‐Ging Lo1Department of Urology, University of Texas Southwestern Medical Center, Dallas, TexasRey-Chen Pong1Department of Urology, University of Texas Southwestern Medical Center, Dallas, TexasDiane Yang1Department of Urology, University of Texas Southwestern Medical Center, Dallas, TexasLeah Gandee1Department of Urology, University of Texas Southwestern Medical Center, Dallas, TexasElizabeth Hernandez1Department of Urology, University of Texas Southwestern Medical Center, Dallas, TexasAndrew Dang1Department of Urology, University of Texas Southwestern Medical Center, Dallas, TexasChung-Jung Lin1Department of Urology, University of Texas Southwestern Medical Center, Dallas, TexasJohn Santoyo1Department of Urology, University of Texas Southwestern Medical Center, Dallas, TexasShihong Ma1Department of Urology, University of Texas Southwestern Medical Center, Dallas, TexasRajni Sonavane1Department of Urology, University of Texas Southwestern Medical Center, Dallas, TexasJun Huang2Department of Urology, The First Affiliated Hospital, Medical School of Xi'an Jiaotong University, Xi'an ChinaShu-Fen Tseng3Department of Bioengineering, University of Texas at Arlington, Arlington, TexasLoredana Moro4Institute of Biomembranes, Bioenergetics and Molecular Biotechnologies, National Research Council, Bari, ItalyArnaldo Arbini5Department of Pathology, NYU Langone Medical Center, New York, New YorkPayal Kapur6Department of Pathology, University of Texas Southwestern Medical Center, Dallas, TexasGanesh V. Raj1Department of Urology, University of Texas Southwestern Medical Center, Dallas, TexasDalin He2Department of Urology, The First Affiliated Hospital, Medical School of Xi'an Jiaotong University, Xi'an ChinaChih‐Ho Lai7Department of Microbiology and Immunology, Graduate Institute of Biomedical Sciences, College of Medicine, Chang Gung University, Taoyuan, TaiwanHo Lin8Department of Life Sciences, National Chung Hsing University, Taichung, TaiwanJer‐Tsong Hsieh1Department of Urology, University of Texas Southwestern Medical Center, Dallas, Texas

2018en

ABI

Annotatsiya

Abstract IFNγ, a potent cytokine known to modulate tumor immunity and tumoricidal effects, is highly elevated in patients with prostate cancer after radiation. In this study, we demonstrate that IFNγ can induce epithelial-to-mesenchymal transition (EMT) in prostate cancer cells via the JAK–STAT signaling pathway, leading to the transcription of IFN-stimulated genes (ISG) such as IFN-induced tetratricopeptide repeat 5 (IFIT5). We unveil a new function of IFIT5 complex in degrading precursor miRNAs (pre-miRNA) that includes 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 prostate cancer cells. Depletion of IFIT5 decreased IFNγ-induced cell invasiveness in vitro and lung metastasis in vivo. IFIT5 was highly elevated in high-grade prostate cancer and its expression inversely correlated with these suppressive miRNAs. Altogether, this study unveils a prometastatic role of the IFNγ pathway via a new mechanism of action, which raises concerns about its clinical application. Significance: A unique IFIT5–XRN1 complex involved in the turnover of specific tumor suppressive microRNAs is the underlying mechanism of IFNγ-induced epithelial-to-mesenchymal transition in prostate cancer. See related commentary by Liu and Gao, p. 1032

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DOI: 10.1158/0008-5472.can-18-2207

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