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Nat Genet. 2016 Oct;48(10):1142-50. doi: 10.1038/ng.3637. Epub 2016 Aug 15.

Modulation of long noncoding RNAs by risk SNPs underlying genetic predispositions to prostate cancer.

Author information

1
Princess Margaret Cancer Center, University Health Network, Toronto, Ontario, Canada.
2
Department of Pharmacological Sciences, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
3
Ontario Institute for Cancer Research, Toronto, Ontario, Canada.
4
Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada.
5
German Cancer Research Center (DKFZ), Heidelberg, Germany.
6
Department of Genetics, Norris Cotton Cancer Center, Dartmouth Medical School, Lebanon, New Hampshire, USA.
7
Department of Medical Oncology, Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.
8
Medical College of Xiamen University, Xiamen, China.
9
Michigan Center for Translational Pathology, University of Michigan Medical School, Ann Arbor, Michigan, USA.
10
Department of Radiation Oncology, University of California at San Francisco, San Francisco, California, USA.
11
Department of Urology, University of California at San Francisco, San Francisco, California, USA.
12
Department of Medicine, University of California at San Francisco, San Francisco, California, USA.
13
Helen Diller Family Comprehensive Cancer Center, University of California at San Francisco, San Francisco, California, USA.
14
Department of Pharmacology and Toxicology, University of Toronto, Toronto, Ontario, Canada.
15
Eli and Edythe L. Broad Institute, Cambridge, Massachusetts, USA.
16
Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York, USA.

Abstract

Long noncoding RNAs (lncRNAs) represent an attractive class of candidates to mediate cancer risk. Through integrative analysis of the lncRNA transcriptome with genomic data and SNP data from prostate cancer genome-wide association studies (GWAS), we identified 45 candidate lncRNAs associated with risk to prostate cancer. We further evaluated the mechanism underlying the top hit, PCAT1, and found that a risk-associated variant at rs7463708 increases binding of ONECUT2, a novel androgen receptor (AR)-interacting transcription factor, at a distal enhancer that loops to the PCAT1 promoter, resulting in upregulation of PCAT1 upon prolonged androgen treatment. In addition, PCAT1 interacts with AR and LSD1 and is required for their recruitment to the enhancers of GNMT and DHCR24, two androgen late-response genes implicated in prostate cancer development and progression. PCAT1 promotes prostate cancer cell proliferation and tumor growth in vitro and in vivo. These findings suggest that modulating lncRNA expression is an important mechanism for risk-associated SNPs in promoting prostate transformation.

PMID:
27526323
DOI:
10.1038/ng.3637
[Indexed for MEDLINE]

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