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 depen-dency factor, the RE1-silencing factor (REST). Taken together, we have nominated MiS as a vulnerability for lethal PCa and potentially other cancers.

Automated summary

The evolutionarily conserved minor spliceosome (MiS) is essential for the expression of -714 minor intron-containing genes (MIGs) involved in important cellular processes. In prostate cancer (PCa), MiS activity is regulated by androgen receptor signaling and elevated levels of U6atac. Inhibition of MiS through siU6atac disrupts minor intron splicing and has a potent effect on inhibiting tumor growth, especially in advanced therapy-resistant PCa. MiS is identified as a vulnerability in lethal PCa and potentially other cancers.