The BRCA1 Pseudogene Negatively Regulates Antitumor Responses through Inhibition of Innate Immune Defense Mechanisms.

Autor:	Han YJ; Department of Medicine, Center for Clinical Cancer Genetics and Global Health, University of Chicago, Chicago, Illinois. yjhan@medicine.bsd.uchicago.edu folopade@medicine.bsd.uchicago.edu., Zhang J; Department of Medicine, Center for Clinical Cancer Genetics and Global Health, University of Chicago, Chicago, Illinois., Lee JH; Department of Microbiology, University of Chicago, Chicago, Illinois.; Florida Research and Innovation Center, Cleveland Clinic, Florida, Port Saint Lucie, Florida., Mason JM; Department of Genetics and Biochemistry, Clemson University, Clemson, South Carolina., Karginova O; Department of Medicine, Center for Clinical Cancer Genetics and Global Health, University of Chicago, Chicago, Illinois., Yoshimatsu TF; Department of Medicine, Center for Clinical Cancer Genetics and Global Health, University of Chicago, Chicago, Illinois., Hao Q; Department of Cell and Developmental Biology, Cancer Center at Illinois, University of Illinois at Urbana-Champaign, Urbana, Illinois., Hurley I; Department of Medicine, Center for Clinical Cancer Genetics and Global Health, University of Chicago, Chicago, Illinois., Brunet LP; Translational Genomics and Targeted Therapies in Solid Tumors, IDIBAPS, Barcelona, Spain.; Department of Medicine, University of Barcelona, Barcelona, Spain., Prat A; Translational Genomics and Targeted Therapies in Solid Tumors, IDIBAPS, Barcelona, Spain.; Department of Medicine, University of Barcelona, Barcelona, Spain., Prasanth KV; Department of Cell and Developmental Biology, Cancer Center at Illinois, University of Illinois at Urbana-Champaign, Urbana, Illinois., Gack MU; Department of Microbiology, University of Chicago, Chicago, Illinois.; Florida Research and Innovation Center, Cleveland Clinic, Florida, Port Saint Lucie, Florida., Olopade OI; Department of Medicine, Center for Clinical Cancer Genetics and Global Health, University of Chicago, Chicago, Illinois. yjhan@medicine.bsd.uchicago.edu folopade@medicine.bsd.uchicago.edu.
Jazyk:	angličtina
Zdroj:	Cancer research [Cancer Res] 2021 Mar 15; Vol. 81 (6), pp. 1540-1551. Date of Electronic Publication: 2021 Jan 20.
DOI:	10.1158/0008-5472.CAN-20-1959
Abstrakt:	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 BRCA1P1 , the pseudogene of the BRCA1 tumor-suppressor gene, in regulating innate immune defense mechanisms in breast cancer cells. BRCA1P1 expresses a long-noncoding RNA (lncRNA) in breast cancer cells through divergent transcription. Expression of lncRNA- BRCA1P1 is increased in breast tumors compared with normal breast tissues. Depletion of BRCA1P1 induces an antiviral defense-like program, including the expression of antiviral genes in breast cancer cells. Furthermore, BRCA1P1 -deficient cancer cells mimic virus-infected cells by stimulating cytokines and inducing cell apoptosis. Accordingly, depletion of BRCA1P1 increases host innate immune responses and restricts virus replication. In converse, overexpression of BRCA1P1 reduces cytokine expression in breast cancer cells. Mechanistically, lncRNA- BRCA1P1 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 BRCA1P1 stimulates cytokine expression and local immunity, and suppresses tumor growth. Our results suggest an important role for BRCA1P1 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. (©2021 American Association for Cancer Research.)
Databáze:	MEDLINE
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