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Minor Intron Splicing Is Critical for Survival of Lethal Prostate Cancer

Highlights
  • Increased minor spliceosome activity is associated with prostate cancer progression
  • Minor intron-containing genes are overrepresented as direct interactors with oncogenes
  • Minor splicing alters splice patterns of important prostate cancer drivers
  • Downregulating the minor spliceosome creates a prostate cancer vulnerability


Summary: The evolutionarily conserved minor spliceosome (MiS) is required for protein expression of ∼714 minor intron-containing genes (MIGs) crucial for cell-cycle regulation, DNA repair, and MAP-kinase signaling. We explored the role of MIGs and MiS in cancer, taking prostate cancer (PCa) as an exemplar. Both androgen receptor signaling and elevated levels of U6atac, a MiS small nuclear RNA, regulate MiS activity, which is highest in advanced metastatic PCa. siU6atac-mediated MiS inhibition in PCa in vitro model systems resulted in aberrant minor intron splicing leading to cell-cycle G1 arrest. Small interfering RNA knocking down U6atac was ∼50% more efficient in lowering tumor burden in models of advanced therapy-resistant PCa compared with standard antiandrogen therapy. In lethal PCa, siU6atac disrupted the splicing of a crucial lineage dependency factor, the RE1-silencing factor (REST). Taken together, we have nominated MiS as a vulnerability for lethal PCa and potentially other cancers.

Anke Augspach, Kyle D. Drake, Luca Roma, Ellen Qian, Se Ri Lee, Declan Clarke, Sushant Kumar22, 23, Muriel Jaquet, John Gallon, Marco Bolis, Joanna Triscott, José A. Galván, Yu Chen
George N. Thalmann, Marianna Kruithof-de Julio, Jean-Philippe P. Theurillat, Stefan Wuchty, Mark Gerstein, Salvatore Piscuoglio, Rahul N. Kanadia 24, Mark A. Rubin 24, 25

Author Footnotes:  
  1. 22 Present address: Department of Medical Biophysics, University of Toronto, Toronto, ON M5G 1L7, Canada
  2. 23 Present address: Princess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 0A3, Canada
  3. 24 Senior author
  4. 25 Lead contact
Source: Augspach A, Drake K, Roma L., Minor Intron Splicing Is Critical for Survival of Lethal Prostate Cancer. Molecular Cell. 2023; DOI:https://doi.org/10.1016/j.molcel.2023.05.017

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Unlocking Prostate Cancer Therapeutics: The Potential of Minor Spliceosome Inhibition - Mark Rubin