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

Autor:	Augspach A; Department for BioMedical Research, University of Bern, 3008 Bern, Switzerland., Drake KD; Physiology and Neurobiology Department, University of Connecticut, Storrs, CT 06269, USA., Roma L; Institute of Pathology and Medical Genetics, University Hospital Basel, 4056 Basel, Switzerland., Qian E; Department of Computer Science, Yale University, New Haven, CT 06520, USA; Yale College, New Haven, CT 06520, USA., Lee SR; Department of Computer Science, Yale University, New Haven, CT 06520, USA; Yale College, New Haven, CT 06520, USA., Clarke D; 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., Kumar S; 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., Jaquet M; Department for BioMedical Research, University of Bern, 3008 Bern, Switzerland., Gallon J; Institute of Pathology and Medical Genetics, University Hospital Basel, 4056 Basel, Switzerland., Bolis M; Institute of Oncology Research, 6500 Bellinzona, Switzerland; Computational Oncology Unit, Department of Oncology, Istituto di Ricerche Farmacologiche 'Mario Negri' IRCCS, 20156 Milano, Italy., Triscott J; Department for BioMedical Research, University of Bern, 3008 Bern, Switzerland., Galván JA; Institute of Pathology, University of Bern, Bern 3008, Switzerland., Chen Y; 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., Thalmann GN; Department for BioMedical Research, University of Bern, 3008 Bern, Switzerland; Department of Urology, Inselspital, Bern University Hospital, 3008 Bern, Switzerland., Kruithof-de Julio M; 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., Theurillat JP; Institute of Oncology Research, 6500 Bellinzona, Switzerland; Faculty of Biomedical Sciences, Università della Svizzera italiana, 6900 Lugano, Switzerland., Wuchty S; 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., Gerstein M; 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., Piscuoglio S; Institute of Pathology and Medical Genetics, University Hospital Basel, 4056 Basel, Switzerland; Department of Biomedicine, University of Basel, 4031 Basel, Switzerland., Kanadia RN; Physiology and Neurobiology Department, University of Connecticut, Storrs, CT 06269, USA; Institute for Systems Genomics, University of Connecticut, Storrs, CT, USA. Electronic address: rahul.kanadia@uconn.edu., Rubin MA; 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: mark.rubin@unibe.ch.
Jazyk:	angličtina
Zdroj:	Molecular cell [Mol Cell] 2023 Jun 15; Vol. 83 (12), pp. 1983-2002.e11. Date of Electronic Publication: 2023 Jun 08.
DOI:	10.1016/j.molcel.2023.05.017
Abstrakt:	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. Competing Interests: Declaration of interests The University of Bern has filed a patent around PCa treatment and diagnosis. A.A. and M.A.R. are listed as co-inventors. The University of Connecticut has filed a patent around diagnosis. R.N.K., K.D., A.A., and M.A.R. are listed as co-inventors. (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
Externí odkaz:	Zobrazit plný text záznamu