Minor intron splicing is critical for survival of lethal prostate cancer Journal Article
| Authors: | Augspach, A.; Drake, K. D.; Roma, L.; Qian, E.; Lee, S. R.; Clarke, D.; Kumar, S.; Jaquet, M.; Gallon, J.; Bolis, M.; Triscott, J.; Galván, J. A.; Chen, Y.; Thalmann, G. N.; Kruithof-de Julio, M.; Theurillat, J. P. P.; Wuchty, S.; Gerstein, M.; Piscuoglio, S.; Kanadia, R. N.; Rubin, M. A. |
| Article Title: | Minor intron splicing is critical for survival of lethal prostate cancer |
| Abstract: | 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. © 2023 The Author(s) |
| Keywords: | prostate cancer; androgen receptor; therapy resistance; therapeutics; splicing; castration-resistant prostate cancer; snrnas; crpc; rest; neuroendocrine prostate cancer; lineage plasticity; minor spliceosome; minor intron splicing; small-cell prostate cancer; u6atac sirna |
| Journal Title: | Molecular Cell |
| Volume: | 83 |
| Issue: | 12 |
| ISSN: | 1097-2765 |
| Publisher: | Cell Press |
| Date Published: | 2023-06-15 |
| Start Page: | 1983 |
| End Page: | 2002.e11 |
| Language: | English |
| DOI: | 10.1016/j.molcel.2023.05.017 |
| PUBMED: | 37295433 |
| PROVIDER: | scopus |
| PMCID: | PMC10637423 |
| DOI/URL: | |
| Notes: | Article -- Source: Scopus |
