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.
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•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
Augspach et al. discover a significant vulnerability in therapy-resistant prostate cancer. They show that RNAi-based inhibition of the minor spliceosome blocked the cell cycle and reduced survival in cancer cells, whereas it did not affect non-cancer cells. This approach was more effective than current state-of-the-art therapies.