期刊
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
卷 114, 期 26, 页码 E5207-E5215出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1617467114
关键词
CRISPR screen; HNRNPL; prostate cancer; RNA binding protein; alternative splicing
资金
- Department of Defense Prostate Cancer Research Program Postdoctoral Training Award [W81XWH-14-1-0513]
- National Cancer Institute [P50 CA090381-13, 5P01 CA163227]
- NIH [R01 HG008927]
- DOD [PC140817P1]
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.
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