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

被引：157

作者：

Braun, Christian J. ^{[1
,2
]}

Stanciu, Monica ^{[1
,2
]}

Boutz, Paul L. ^{[1
,2
]}

Patterson, Jesse C. ^{[1
,2
]}

Calligaris, David ^{[3
]}

Higuchi, Fumi ^{[4
]}

Neupane, Rachit ^{[1
,2
]}

Fenoglio, Silvia ^{[1
,2
]}

Cahill, Daniel P. ^{[4
]}

Wakimoto, Hiroaki ^{[4
]}

Agar, Nathalie Y. R. ^{[3
,5
,6
]}

Yaffe, Michael B. ^{[1
,2
,7
,8
]}

Sharp, Phillip A. ^{[1
,2
]}

Hemann, Michael T. ^{[1
,2
]}

Lees, Jacqueline A. ^{[1
,2
]}

机构：

[1] MIT, David H Koch Inst Integrat Canc Res, 77 Massachusetts Ave, Cambridge, MA 02139 USA

[2] MIT, Dept Biol, 77 Massachusetts Ave, Cambridge, MA 02139 USA

[3] Harvard Med Sch, Brigham & Womens Hosp, Dept Neurosurg, Boston, MA 02115 USA

[4] Harvard Med Sch, Massachusetts Gen Hosp, Dept Neurosurg, Boston, MA 02115 USA

[5] Harvard Med Sch, Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02215 USA

[6] Harvard Med Sch, Dept Radiol, Boston, MA 02115 USA

[7] MIT, Dept Biol Engn, Cambridge, MA 02139 USA

[8] Harvard Med Sch, Div Acute Care Surg Trauma & Crit Care, Dept Surg, Beth Israel Deaconess Med Ctr, Boston, MA 02215 USA

来源：

CANCER CELL | 2017年 / 32卷 / 04期

关键词：

PRMT5 ARGININE METHYLTRANSFERASE; PRE-MESSENGER-RNA; IN-VIVO; TEMOZOLOMIDE; MODELS; SMN;

D O I：

10.1016/j.ccell.2017.08.018

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

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.

引用

页码：411 / +

页数：27

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