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

Christian J Braun; Monica Stanciu; Paul L Boutz; Jesse C Patterson; David Calligaris; Fumi Higuchi; Rachit Neupane; Silvia Fenoglio; Daniel P Cahill; Hiroaki Wakimoto; Nathalie Y R Agar; Michael B Yaffe; Phillip A Sharp; Michael T Hemann; Jacqueline A Lees

doi:10.1016/j.ccell.2017.08.018

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

Cancer Cell. 2017 Oct 9;32(4):411-426.e11. doi: 10.1016/j.ccell.2017.08.018. Epub 2017 Sep 28.

Authors

Affiliations

¹ The David H. Koch Institute for Integrative Cancer Research and Department of Biology, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, MA 02139, USA.
² Department of Neurosurgery, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
³ Department of Neurosurgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA.
⁴ Department of Neurosurgery, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA; Department of Cancer Biology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA; Department of Radiology, Harvard Medical School, Boston, MA 02115, USA.
⁵ The David H. Koch Institute for Integrative Cancer Research and Department of Biology, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, MA 02139, USA; Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Division of Acute Care Surgery, Trauma, and Critical Care, Department of Surgery, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA.
⁶ The David H. Koch Institute for Integrative Cancer Research and Department of Biology, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, MA 02139, USA. Electronic address: hemann@mit.edu.
⁷ The David H. Koch Institute for Integrative Cancer Research and Department of Biology, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, MA 02139, USA. Electronic address: jalees@mit.edu.

Abstract

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.

Keywords: CLNS1A; EPZ015666; GBM; PRMT5; RIOK1; biomarker; splicing addiction.

Publication types

Research Support, Non-U.S. Gov't
Research Support, N.I.H., Extramural

MeSH terms

Animals
Brain Neoplasms / pathology*
Cell Cycle / drug effects
Cell Differentiation
Cell Line, Tumor
Cell Proliferation / drug effects
Glioma / drug therapy
Glioma / genetics
Glioma / pathology*
High-Throughput Screening Assays
Humans
Introns*
Isoquinolines / pharmacology
Mice
Protein-Arginine N-Methyltransferases / antagonists & inhibitors
Protein-Arginine N-Methyltransferases / physiology*
Pyrimidines / pharmacology
RNA Splicing

Substances

GSK3235025
Isoquinolines
Pyrimidines
PRMT5 protein, human
Protein-Arginine N-Methyltransferases

Abstract

Publication types

MeSH terms

Substances

Grants and funding