Minor intron splicing is critical for survival of lethal prostate cancer

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

doi:10.1016/j.molcel.2023.05.017

Minor intron splicing is critical for survival of lethal prostate cancer

Mol Cell. 2023 Jun 15;83(12):1983-2002.e11. doi: 10.1016/j.molcel.2023.05.017. Epub 2023 Jun 8.

Authors

Anke Augspach¹, Kyle D Drake², Luca Roma³, Ellen Qian⁴, Se Ri Lee⁴, Declan Clarke⁵, Sushant Kumar⁵, Muriel Jaquet¹, John Gallon³, Marco Bolis⁶, Joanna Triscott¹, José A Galván⁷, Yu Chen⁸, George N Thalmann⁹, Marianna Kruithof-de Julio¹⁰, Jean-Philippe P Theurillat¹¹, Stefan Wuchty¹², Mark Gerstein¹³, Salvatore Piscuoglio¹⁴, Rahul N Kanadia¹⁵, Mark A Rubin¹⁶

Affiliations

¹ Department for BioMedical Research, University of Bern, 3008 Bern, Switzerland.
² Physiology and Neurobiology Department, University of Connecticut, Storrs, CT 06269, USA.
³ Institute of Pathology and Medical Genetics, University Hospital Basel, 4056 Basel, Switzerland.
⁴ Department of Computer Science, Yale University, New Haven, CT 06520, USA; Yale College, New Haven, CT 06520, USA.
⁵ 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.
⁶ Institute of Oncology Research, 6500 Bellinzona, Switzerland; Computational Oncology Unit, Department of Oncology, Istituto di Ricerche Farmacologiche "Mario Negri" IRCCS, 20156 Milano, Italy.
⁷ Institute of Pathology, University of Bern, Bern 3008, Switzerland.
⁸ 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.
⁹ Department for BioMedical Research, University of Bern, 3008 Bern, Switzerland; Department of Urology, Inselspital, Bern University Hospital, 3008 Bern, Switzerland.
¹⁰ 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.
¹¹ Institute of Oncology Research, 6500 Bellinzona, Switzerland; Faculty of Biomedical Sciences, Università della Svizzera italiana, 6900 Lugano, Switzerland.
¹² 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.
¹³ 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.
¹⁴ Institute of Pathology and Medical Genetics, University Hospital Basel, 4056 Basel, Switzerland; Department of Biomedicine, University of Basel, 4031 Basel, Switzerland.
¹⁵ 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.
¹⁶ 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.

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.

Keywords: CRPC; REST; U6atac siRNA; androgen receptor; castration-resistant prostate cancer; lineage plasticity; minor intron splicing; minor spliceosome; neuroendocrine prostate cancer; prostate cancer; small-cell prostate cancer; snRNAs; splicing; therapeutics; therapy resistance.

MeSH terms

Cell Line, Tumor
Humans
Introns / genetics
Male
Prostatic Neoplasms* / metabolism
Prostatic Neoplasms, Castration-Resistant* / genetics
RNA Splicing / genetics
Receptors, Androgen / genetics
Receptors, Androgen / metabolism
Signal Transduction
Spliceosomes / metabolism

Substances

Receptors, Androgen

Abstract

MeSH terms

Substances

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