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

Haiyang Guo, Musaddeque Ahmed, Fan Zhang, Cindy Q. Yao, Side Li, Yi Liang, Junjie Hua, Fraser Soares, Yifei Sun, Jens Langstein, Yuchen Li, Christine Poon, Swneke D. Bailey, Kinjal Desai, Teng Fei, Qiyuan Li, Dorota H. Sendorek, Michael Fraser, John R. Prensner, Trevor J. PughMark Pomerantz, Robert G. Bristow, Mathieu Lupien, Felix Y. Feng, Paul C. Boutros, Matthew L. Freedman, Martin J. Walsh, Housheng Hansen He

Research output: Contribution to journalArticlepeer-review

181 Scopus citations

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.

Original languageEnglish
Pages (from-to)1142-1150
Number of pages9
JournalNature Genetics
Volume48
Issue number10
DOIs
StatePublished - 1 Oct 2016

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