Coordinated Splicing of Regulatory Detained Introns within Oncogenic Transcripts Creates an Exploitable Vulnerability in Malignant Glioma

• Main Authors: Braun, Christian J. (Author), Stanciu, Monica (Contributor), Boutz, Paul L. (Author), Patterson, Jesse C. (Author), Calligaris, David (Author), Higuchi, Fumi (Author), Neupane, Rachit (Contributor), Fenoglio, Silvia (Contributor), Cahill, Daniel P. (Author), Wakimoto, Hiroaki (Author), Agar, Nathalie Y.R (Author), Yaffe, Michael B. (Author), Sharp, Phillip A. (Author), Hemann, Michael T. (Author), Lees, Jacqueline A. (Author), Boutz, Paul (Contributor), Patterson, Jesse C (Contributor), Yaffe, Michael B (Contributor), Hemann, Michael (Contributor), Lees, Jacqueline (Contributor), Braun, Christian Joerg (Author)
• Other Authors: Massachusetts Institute of Technology. Department of Biological Engineering (Contributor), Koch Institute for Integrative Cancer Research at MIT (Contributor), Braun, Christian Jorg (Contributor), Sharp, Phillip A (Contributor)
• Format: Article
• Language: English
• Published: Elsevier BV, 2018-10-31T19:11:29Z.
• Subjects: Article
• Online Access: Get fulltext

Glioblastoma (GBM) is a devastating malignancy with few therapeutic options. We identify PRMT5 in an in vivo GBM shRNA screen and show that PRMT5 knockdown or inhibition potently suppresses in vivo GBM tumors, including patient-derived xenografts. Pathway analysis implicates splicing in cellular PRMT5 dependency, and we identify a biomarker that predicts sensitivity to PRMT5 inhibition. We find that PRMT5 deficiency primarily disrupts the removal of detained introns (DIs). This impaired DI splicing affects proliferation genes, whose downregulation coincides with cell cycle defects, senescence and/or apoptosis. We further show that DI programs are evolutionarily conserved and operate during neurogenesis, suggesting that they represent a physiological regulatory mechanism. Collectively, these findings reveal a PRMT5-regulated DI-splicing program as an exploitable cancer vulnerability. Braun et al. show that glioblastoma is selectively sensitive to the inhibition of PRMT5 and identify a predictive biomarker for this sensitivity. PRMT5 inhibition primarily disrupts the removal of detained introns, which results in the reduction of functional transcripts of mainly proliferation-associated genes. Keywords: splicing addiction; GBM; PRMT5; EPZ015666; biomarker; CLNS1A; RIOK1
National Institutes of Health (U.S.) (Grant PO1-CA42063)
National Cancer Institute (U.S.) (Grant PO1-CA42063)
National Institutes of Health (U.S.) (Grant R01GM034277)
National Cancer Institute (U.S.) (Grant R01GM034277)
National Institutes of Health (U.S.) (Grant P30-CA14051)