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

Cancer cell | Oct 9, 2017

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.

Pubmed ID: 28966034 RIS Download

Mesh terms: Animals | Brain Neoplasms | Cell Cycle | Cell Differentiation | Cell Line, Tumor | Cell Proliferation | Glioma | High-Throughput Screening Assays | Humans | Introns | Isoquinolines | Mice | Protein-Arginine N-Methyltransferases | Pyrimidines | RNA Splicing

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Associated grants

  • Agency: NCI NIH HHS, Id: R01 CA128803

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