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Proc Natl Acad Sci U S A. 2017 Jun 27;114(26):E5207-E5215. doi: 10.1073/pnas.1617467114. Epub 2017 Jun 13.

Genome-wide CRISPR screen identifies HNRNPL as a prostate cancer dependency regulating RNA splicing.

Fei T1,2,3,4, Chen Y5, Xiao T2,3,4, Li W4, Cato L2,3, Zhang P5, Cotter MB6,7, Bowden M6,7, Lis RT6,7, Zhao SG8,9, Wu Q10, Feng FY8,9, Loda M6,7,11,12, He HH13,14, Liu XS15, Brown M16,3.

Author information

1
College of Life and Health Sciences, Northeastern University, Shenyang 110819, People's Republic of China; feiteng@mail.neu.edu.cn xsliu@jimmy.harvard.edu myles_brown@dfci.harvard.edu.
2
Division of Molecular and Cellular Oncology, Department of Medical Oncology, Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Boston, MA 02215.
3
Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02215.
4
Department of Biostatistics and Computational Biology, Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute and Harvard School of Public Health, Boston, MA 02215.
5
Department of Bioinformatics and Computational Biology, Division of Quantitative Sciences, The University of Texas MD Anderson Cancer Center, Houston, TX 77030.
6
Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215.
7
Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02215.
8
Michigan Center for Translational Pathology, Comprehensive Cancer Center, University of Michigan, Ann Arbor, MI 48109.
9
Department of Radiation Oncology, University of Michigan, Ann Arbor, MI 48109.
10
Department of Bioinformatics, School of Life Sciences and Technology, Tongji University, Shanghai, 200092, China.
11
Department of Oncologic Pathology, Dana-Farber Cancer Institute, Boston, MA 02215.
12
Broad Institute of Harvard and MIT, Cambridge, MA 02142.
13
Princess Margaret Cancer Center, University Health Network, Toronto, ON, Canada M5G1L7.
14
Department of Medical Biophysics, University of Toronto, Toronto, ON, Canada M5G1L7.
15
Department of Biostatistics and Computational Biology, Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute and Harvard School of Public Health, Boston, MA 02215; feiteng@mail.neu.edu.cn xsliu@jimmy.harvard.edu myles_brown@dfci.harvard.edu.
16
Division of Molecular and Cellular Oncology, Department of Medical Oncology, Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Boston, MA 02215; feiteng@mail.neu.edu.cn xsliu@jimmy.harvard.edu myles_brown@dfci.harvard.edu.

Abstract

Alternative RNA splicing plays an important role in cancer. To determine which factors involved in RNA processing are essential in prostate cancer, we performed a genome-wide CRISPR/Cas9 knockout screen to identify the genes that are required for prostate cancer growth. Functional annotation defined a set of essential spliceosome and RNA binding protein (RBP) genes, including most notably heterogeneous nuclear ribonucleoprotein L (HNRNPL). We defined the HNRNPL-bound RNA landscape by RNA immunoprecipitation coupled with next-generation sequencing and linked these RBP-RNA interactions to changes in RNA processing. HNRNPL directly regulates the alternative splicing of a set of RNAs, including those encoding the androgen receptor, the key lineage-specific prostate cancer oncogene. HNRNPL also regulates circular RNA formation via back splicing. Importantly, both HNRNPL and its RNA targets are aberrantly expressed in human prostate tumors, supporting their clinical relevance. Collectively, our data reveal HNRNPL and its RNA clients as players in prostate cancer growth and potential therapeutic targets.

KEYWORDS:

CRISPR screen; HNRNPL; RNA binding protein; alternative splicing; prostate cancer

PMID:
28611215
PMCID:
PMC5495225
DOI:
10.1073/pnas.1617467114
[Indexed for MEDLINE]
Free PMC Article

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