Minor intron splicing is critical for survival of lethal prostate cancer.

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. Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.

Citation

Anke Augspach, Kyle D Drake, Luca Roma, Ellen Qian, Se Ri Lee, Declan Clarke, Sushant Kumar, 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, Mark A Rubin. Minor intron splicing is critical for survival of lethal prostate cancer. Molecular cell. 2023 Jun 15;83(12):1983-2002.e11

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PMID: 37295433

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