Leveraging Poison Introns for Therapeutics and Diagnostics of Lethal Prostate Cancer

Principal Investigators: Mark Rubin, MD (University of Bern), Gunnar Rätsch, PhD (ETH Zurich), Rahul Kanadia, PhD (University of Connecticut)

Co-Investigators: Anke Augspach, PhD (University of Bern), Andre Kahles, PhD (ETH Zurich), Takemoto Kazumasa, PhD (University of Connecticut)

Description:

• Genes are encoded in the genome in a non-contiguous fashion. During the RNA transcription process, various pieces of RNA code, called introns are removed, and other pieces called exons are spliced together to form the final messenger RNA code that is translated into proteins. Minor introns (often called “poison introns” because failure to remove them will result in significant protein alterations) are present in a small number of genes and a unique splicing complex called the minor spliceosome must splice them out.
• Dr. Mark Rubin and team are studying the biological processes by which altered RNA splicing contributes to prostate cancer pathogenesis.  They previously found that minor intron-containing genes enrich as direct interactors of prostate cancer-causing proteins. In addition, components of the minor spliceosome such as U6atac correlate with prostate cancer progression and represent a vulnerability of advanced prostate cancer. Importantly, prostate cancer cells were vulnerable to the inhibition of the minor spliceosome that was achieved through downregulation of U6atac.  These data suggest that the minor spliceosome and minor intron splicing may be a master regulator of prostate cancer.
• In this project, Dr. Rubin and the team will investigate the biology of minor RNA intron splicing in prostate cancer.
• The team will design novel strategies to downregulate U6atac to inhibit minor spliceosome and block minor intron splicing
• The molecular mechanisms by which the minor intron splicing complex, the minor spliceosome, contributes to splicing of minor and major intron during prostate cancer progression will be investigated.
• The team will also develop a prostate cancer risk assessment biomarker using differential minor spliceosome intron splicing complex component expression and activity.
• If successful, this project will define the biological role of minor splicing in prostate cancer, determine the therapeutic potential of targeting this process and develop a biomarker-based on this process to inform on prostate cancer progression and diagnosis.

What this means to patients: The role of minor intron splicing in prostate cancer is unclear but may be a crucial regulator of disease progression and therapy resistance. This project will provide a comprehensive insight into the impact of minor splicing on prostate cancer biology and therapy resistance and its potential as a risk assessment biomarker. This may ultimately lead to the development of new treatments targeting this pathway for patients with incurable, lethal prostate cancer.