Type I Interferon Regulates a Coordinated Gene Network to Enhance Cytotoxic T Cell–Mediated Tumor Killing
- 1 March 2020
- journal article
- research article
- Published by American Association for Cancer Research (AACR) in Cancer Discovery
- Vol. 10 (3), 382-393
- https://doi.org/10.1158/2159-8290.cd-19-0608
Abstract
Type I interferons (IFN), which activate many IFN-stimulated genes (ISG), are known to regulate tumorigenesis. However, little is known regarding how various ISGs coordinate with one another in developing antitumor effects. Here, we report that the ISG UBA7 is a tumor suppressor in breast cancer. UBA7 encodes an enzyme that catalyzes the covalent conjugation of the ubiquitin-like protein product of another ISG (ISG15) to cellular proteins in a process known as “ISGylation.” ISGylation of other ISGs, including STAT1 and STAT2, synergistically facilitates production of chemokine-receptor ligands to attract cytotoxic T cells. These gene-activation events are further linked to clustering and nuclear relocalization of STAT1/2 within IFN-induced promyelocytic leukemia (PML) bodies. Importantly, this coordinated ISG–ISGylation network plays a central role in suppressing murine breast cancer growth and metastasis, which parallels improved survival in patients with breast cancer. These findings reveal a cooperative IFN-inducible gene network in orchestrating a tumor-suppressive microenvironment. Significance: We report a highly cooperative ISG network, in which UBA7-mediated ISGylation facilitates clustering of transcription factors and activates an antitumor gene-expression program. These findings provide mechanistic insights into immune evasion in breast cancer associated with UBA7 loss, emphasizing the importance of a functional ISG–ISGylation network in tumor suppression. This article is highlighted in the In This Issue feature, p. 327Other Versions
Funding Information
- NIH (-DP2-EB020400)
- NIH (R01CA177305)
This publication has 54 references indexed in Scilit:
- Usp18 deficient mammary epithelial cells create an antitumour environment driven by hypersensitivity to IFN‐λ and elevated secretion of Cxcl10EMBO Molecular Medicine, 2013
- Chemosensitivity is controlled by p63 modification with ubiquitin-like protein ISG15JCI Insight, 2012
- The cBio Cancer Genomics Portal: An Open Platform for Exploring Multidimensional Cancer Genomics DataCancer Discovery, 2012
- Implementing an online tool for genome-wide validation of survival-associated biomarkers in ovarian-cancer using microarray data from 1287 patientsEndocrine-Related Cancer, 2012
- Transgenic Expression of Polyomavirus Middle T Antigen in the Mouse Prostate Gives Rise to CarcinomaJournal of Virology, 2011
- Arsenic Trioxide Controls the Fate of the PML-RARα Oncoprotein by Directly Binding PMLScience, 2010
- An online survival analysis tool to rapidly assess the effect of 22,277 genes on breast cancer prognosis using microarray data of 1,809 patientsBreast Cancer Research and Treatment, 2009
- The ubiquitin-like molecule interferon-stimulated gene 15 (ISG15) is a potential prognostic marker in human breast cancerBreast Cancer Research, 2008
- Toll-like receptor 4–dependent contribution of the immune system to anticancer chemotherapy and radiotherapyNature Medicine, 2007
- Cloning of a breast cancer homozygous deletion junction narrows the region of search for a 3p21.3 tumor suppressor geneOncogene, 1998