Title: ISG15 and protein ISGylation in cancer Summary The long-term goal of this study is to understand the role of ISG15-related protein posttranslational modification (ISGylation, a ubiquitin-like modification) in cancer development and prognosis. In recent years our knowledge about type I interferon (IFN) signaling in cancer has expanded rapidly. It is now recognized that IFN plays important roles during cancer development and in the efficacy of cancer therapies. The bioactivity of IFN relies on the expression of many IFN-stimulated genes (ISGs). However, the functions of different ISGs associated with the effect of IFN in cancer remain largely unknown. ISG15 is one of the major ISGs. Its expression is strongly upregulated by IFN and by any cellular stress that promotes IFN production. Furthermore, most of the enzymes involved in protein ISGylation are also encoded by ISGs. Therefore, protein ISGylation is tightly regulated by IFN signaling. Since ISG15 is not found in simple eukaryotic organisms, such as yeast and nematodes, it is likely involved in specialized functions in complex organisms, such as human and mouse. Our lab is among a few pioneer groups that identified key enzymes, protein targets, and biochemical effects of protein ISGylation. Furthermore, we generated the ISG15 E1 enzyme,Uba7, knockout and ISG15 deconjugating enzyme, Usp18, knockout mouse models, which lack protein ISGylation and accumulate ISGylated proteins, respectively. ISG15 expression is upregulated in many human cancers. More importantly, expression of UBA7 is associated with favorable patient survival in multiple types of human cancer. During the previous funding period, we discovered that Uba7-mediated protein ISGylation had a previously unrecognized function in the fine tuning of IFN-related tumor-immune crosstalk by facilitating expression of key cytokines and chemokines. Based on current knowledge and our preliminary data, we hypothesize that protein ISGylation contributes to IFN-mediated chromatin remodeling, restriction of cancer cell stemness, and efficacy of cancer therapies. To test this hypothesis, we will perform the following studies:
Aim 1. Examine protein ISGylation in IFN-mediated chromatin remodeling;
Aim 2. Analyze protein ISGylation in IFN-mediated restriction of cancer stem cells;
Aim 3. Investigate the cancer therapeutic potential of blocking the ISG15-deconjugating enzyme activity of Usp18.

Public Health Relevance

Cancer is the most devastating human disease in the world. Expression of the ubiquitin like protein ISG15 is strongly increased in many types of cancer. The aim of this application is to provide molecular insights of how ISG15 is involved in cancer development in order to identification of novel and effective treatments of cancer.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project (R01)
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Molecular Oncogenesis Study Section (MONC)
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Hildesheim, Jeffrey
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University of California, San Diego
Schools of Medicine
La Jolla
United States
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Arimoto, Kei-Ichiro; Löchte, Sara; Stoner, Samuel A et al. (2017) STAT2 is an essential adaptor in USP18-mediated suppression of type I interferon signaling. Nat Struct Mol Biol 24:279-289
Arimoto, Kei-ichiro; Hishiki, Takayuki; Kiyonari, Hiroshi et al. (2015) Murine Herc6 Plays a Critical Role in Protein ISGylation In Vivo and Has an ISGylation-Independent Function in Seminal Vesicles. J Interferon Cytokine Res 35:351-8
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