1. Type I Interferon Regulates a Coordinated Gene Network to Enhance Cytotoxic T Cell-Mediated Tumor Killing.
- Author
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Fan JB, Miyauchi S, Xu HZ, Liu D, Kim LJY, Burkart C, Cheng H, Arimoto KI, Yan M, Zhou Y, Győrffy B, Knobeloch KP, Rich JN, Cang H, Fu XD, and Zhang DE
- Subjects
- Animals, Breast Neoplasms immunology, Breast Neoplasms pathology, Cell Proliferation genetics, Female, Gene Expression Regulation, Neoplastic genetics, Gene Regulatory Networks immunology, Humans, Mice, T-Lymphocytes immunology, Transcription Factors genetics, Ubiquitins genetics, Ubiquitins immunology, Breast Neoplasms genetics, Interferon Type I genetics, STAT1 Transcription Factor genetics, STAT2 Transcription Factor genetics, Ubiquitin-Activating Enzymes genetics
- 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. 327 ., (©2020 American Association for Cancer Research.)
- Published
- 2020
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