AZI1 RNA-Driven Gene Fusion in Prostate Cancer
Abstract
One common genetic alteration in prostate cancer is gene fusion resulting from chromosomal translocations. Fusion gene formation requires genomic DNA break in gene “A” and gene “B.” The genomic DNA breaks then join together in the wrong way to become an aberrant fusion gene A-B. Gene fusion between TMPRSS2 and ERG was present in 50% of prostate patient population, leading to increased cell proliferation and invasion. Fusion genes have been proven very useful for patient care, as they provide a means for accurate cancer diagnosis and drug targets for developing anti-cancer therapies. Fusion gene formations through chromosomal translocations are presumed to occur prior to fusion RNA expression. However, studies have reported the presence of fusion RNAs in individuals who were negative for chromosomal translocations. The observation, that fusion RNA could be present prior to fusion gene, raises the possibility that fusion RNAs act as a guide RNA to mediate genomic rearrangement by annealing to their parental genes in the genome. Rowley and Blumenthal (Science, 2008) called this “the cart before the horse” hypothesis, in that “RNA before DNA” defies the conventional order of the central dogma of biology: DNA to RNA to protein. Despite the fundamental implications in cancer, RNA-driven fusion gene has not been demonstrated in mammalian cells until now. In a recent published study (PNAS 2018), we identified a cellular RNA “AZI1” with sequence “partially” resembling that of TMPRSS2-ERG fusion RNA found in prostate cancer. Strikingly, when this RNA, but not its protein, was expressed in a prostate cell line, it induced new gene fusion between TMPRSS2 and ERG at the genomic DNA level. The results strongly support the provocative model that aberrant cellular RNAs play a pivotal role in initiating and specifying gene pairs to undergo fusion in prostate cancer. To widen the impacts of this fundamental discovery to patient care, we aim to (1) investigate the pathological association of AZI1 with TMPRSS2-ERG fusion in human prostate cancer specimens, (2) dissect the mechanisms that govern AZI1 RNA-mediated gene fusion so that it can be targeted for improved cancer prevention and therapy. Our proposal differs from others in that it challenges current paradigms and looks at existing problems from a new perspective. It is innovative in concept, as it goes against existing models and defies the conventional order of the central dogma of biology: DNA to RNA to protein. If successful, it will (1) provide important insight in early disease mechanism, (2) guide design strategies to inhibit the development of prostate cancer, and (3) provide insight in cancer ethnic disparities because fusion genes affects different ethnic groups disproportionately. The research team we assembled brings together expertise in cancer genomics (Dr. Laising Yen) and prostate oncology (Dr. Mike Ittmann) to form an effective collaboration.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Mar 10, 2021
- Source ID
- W81XWH2010926
Entities
People
- Laising Yen
Organizations
- Baylor College of Medicine
- United States Army