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.
Molecular cell. 2023 Jun 07 [Epub ahead of print]
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
Department for BioMedical Research, University of Bern, 3008 Bern, Switzerland., Physiology and Neurobiology Department, University of Connecticut, Storrs, CT 06269, USA., Institute of Pathology and Medical Genetics, University Hospital Basel, 4056 Basel, Switzerland., Department of Computer Science, Yale University, New Haven, CT 06520, USA; Yale College, New Haven, CT 06520, USA., Program in Computational Biology and Bioinformatics, Yale University, New Haven, CT 06520, USA; Department of Molecular Biophysics and Biochemistry, Yale University, New Haven, CT 06520, USA., Institute of Oncology Research, 6500 Bellinzona, Switzerland; Computational Oncology Unit, Department of Oncology, Istituto di Ricerche Farmacologiche "Mario Negri" IRCCS, 20156 Milano, Italy., Institute of Pathology, University of Bern, Bern 3008, Switzerland., Human Oncology and Pathogenesis Program (HOPP), Memorial Sloan Kettering, New York, NY 10065, USA; Department of Medicine, Memorial Sloan Kettering, New York, NY 10065, USA; Department of Medicine, Weill Cornell Medicine, New York, NY 10065, USA., Department for BioMedical Research, University of Bern, 3008 Bern, Switzerland; Department of Urology, Inselspital, Bern University Hospital, 3008 Bern, Switzerland., Department for BioMedical Research, University of Bern, 3008 Bern, Switzerland; Department of Urology, Inselspital, Bern University Hospital, 3008 Bern, Switzerland; Bern Center for Precision Medicine, University of Bern and Inselspital, 3008 Bern, Switzerland., Institute of Oncology Research, 6500 Bellinzona, Switzerland; Faculty of Biomedical Sciences, Università della Svizzera italiana, 6900 Lugano, Switzerland., Department of Computer Science, University of Miami, Coral Gables, FL 33146, USA; Sylvester Comprehensive Cancer Center, University of Miami, Coral Gables, FL 33136, USA; Department of Biology, University of Miami, Coral Gables, FL 33146, USA., Department of Computer Science, Yale University, New Haven, CT 06520, USA; Program in Computational Biology and Bioinformatics, Yale University, New Haven, CT 06520, USA; Department of Molecular Biophysics and Biochemistry, Yale University, New Haven, CT 06520, USA., Institute of Pathology and Medical Genetics, University Hospital Basel, 4056 Basel, Switzerland; Department of Biomedicine, University of Basel, 4031 Basel, Switzerland., Physiology and Neurobiology Department, University of Connecticut, Storrs, CT 06269, USA; Institute for Systems Genomics, University of Connecticut, Storrs, CT, USA. Electronic address: ., Department for BioMedical Research, University of Bern, 3008 Bern, Switzerland; Bern Center for Precision Medicine, University of Bern and Inselspital, 3008 Bern, Switzerland. Electronic address: .