The <i>BRCA1</i> Pseudogene Negatively Regulates Antitumor Responses through Inhibition of Innate Immune Defense Mechanisms.

Abstract

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 <i>BRCA1P1</i>, the pseudogene of the <i>BRCA1</i> tumor-suppressor gene, in regulating innate immune defense mechanisms in breast cancer cells. <i>BRCA1P1</i> expresses a long-noncoding RNA (lncRNA) in breast cancer cells through divergent transcription. Expression of lncRNA-<i>BRCA1P1</i> is increased in breast tumors compared with normal breast tissues. Depletion of <i>BRCA1P1</i> induces an antiviral defense-like program, including the expression of antiviral genes in breast cancer cells. Furthermore, <i>BRCA1P1</i>-deficient cancer cells mimic virus-infected cells by stimulating cytokines and inducing cell apoptosis. Accordingly, depletion of <i>BRCA1P1</i> increases host innate immune responses and restricts virus replication. In converse, overexpression of <i>BRCA1P1</i> reduces cytokine expression in breast cancer cells. Mechanistically, lncRNA-<i>BRCA1P1</i> 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 <i>BRCA1P1</i> stimulates cytokine expression and local immunity, and suppresses tumor growth. Our results suggest an important role for <i>BRCA1P1</i> 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.