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Type I Interferon Regulates a Coordinated Gene Network to Enhance Cytotoxic T Cell-Mediated Tumor Killing

Fan, JB;Miyauchi, S;Xu, HZ;Liu, D;Kim, LJY;Burkart, C;Cheng, H;Arimoto, KI;Yan, M;Zhou, Y;Gyorffy, B;Knobeloch, KP;Rich, JN;Cang, H;Fu, XD;Zhang, DE;

Type I interferons (IFNs), which activate many IFN-stimulated genes (ISGs), are known to regulate tumorigenesis. However, little is known regarding how various ISGs coordinate with one another in developing anti-tumor 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 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 breast cancer patients. These findings reveal a cooperative IFN-inducible gene network in orchestrating a tumor suppressive microenvironment. Copyright 2020, American Association for Cancer Research.

  • PubMed ID: 31974171