# ISG15 and Protein ISGylation in Cancer

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA, SAN DIEGO · 2020 · $412,014

## Abstract

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.

## Key facts

- **NIH application ID:** 9852988
- **Project number:** 5R01CA177305-07
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN DIEGO
- **Principal Investigator:** DONG-ER ZHANG
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $412,014
- **Award type:** 5
- **Project period:** 2013-03-01 → 2024-02-29

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9852988

## Citation

> US National Institutes of Health, RePORTER application 9852988, ISG15 and Protein ISGylation in Cancer (5R01CA177305-07). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9852988. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*