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

Augspach, Anke Katharina; Drake, Kyle D; Roma, Luca; Qian, Ellen; Lee, Se Ri; Clarke, Declan; Kumar, Sushant; Jaquet, Muriel; Gallon, John; Bolis, Marco; Triscott, Joanna Catherine Caprio; Galván, José A; Chen, Yu; Thalmann, George N; Kruithof-de Julio, Marianna; Theurillat, Jean-Philippe P; Wuchty, Stefan; Gerstein, Mark; Piscuoglio, Salvatore; Kanadia, Rahul N; ... (2023). Minor intron splicing is critical for survival of lethal prostate cancer. Molecular cell, 83(12), 1983-2002.e11. Cell Press 10.1016/j.molcel.2023.05.017

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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.

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