The Pseudogene Negatively Regulates Antitumor Responses through Inhibition of Innate Immune Defense Mechanisms.

Innate immune defense mechanisms play a pivotal role in antitumor responses. Recent evidence suggests that antiviral innate immunity is regulated not only by exogenous non-self-RNA but also by host-derived pseudogene RNAs. A growing body of evidence also indicates a biological role for pseudogenes as gene expression regulators or immune modulators. Here, we report an important role for , the pseudogene of the tumor-suppressor gene, in regulating innate immune defense mechanisms in breast cancer cells. expresses a long-noncoding RNA (lncRNA) in breast cancer cells through divergent transcription. Expression of lncRNA- is increased in breast tumors compared with normal breast tissues. Depletion of induces an antiviral defense-like program, including the expression of antiviral genes in breast cancer cells. Furthermore, -deficient cancer cells mimic virus-infected cells by stimulating cytokines and inducing cell apoptosis. Accordingly, depletion of increases host innate immune responses and restricts virus replication. In converse, overexpression of reduces cytokine expression in breast cancer cells. Mechanistically, lncRNA- is localized in the nucleus, binds to the NF-κB subunit RelA, and negatively regulates antiviral gene expression. Finally, in a xenograft mouse model of breast cancer, depletion of stimulates cytokine expression and local immunity, and suppresses tumor growth. Our results suggest an important role for in innate immune defense mechanisms and antitumor responses. This mechanism of antiviral immunity regulated by a host-derived pseudogene RNA may guide the development of novel therapies targeting immune responses in breast cancer. SIGNIFICANCE: This study identifies a novel mechanism of innate immunity driven by a host pseudogene RNA that inhibits innate immune defense mechanisms and antitumor responses through regulation of antiviral gene expression.