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

• Published in: Nature genetics Vol. 48; no. 10; pp. 1142 - 1150
• Main Authors: Guo, Haiyang, Ahmed, Musaddeque, Zhang, Fan, Yao, Cindy Q, Li, SiDe, Liang, Yi, Hua, Junjie, Soares, Fraser, Sun, Yifei, Langstein, Jens, Li, Yuchen, Poon, Christine, Bailey, Swneke D, Desai, Kinjal, Fei, Teng, Li, Qiyuan, Sendorek, Dorota H, Fraser, Michael, Prensner, John R, Pugh, Trevor J, Pomerantz, Mark, Bristow, Robert G, Lupien, Mathieu, Feng, Felix Y, Boutros, Paul C, Freedman, Matthew L, Walsh, Martin J, He, Housheng Hansen
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01.10.2016; Nature Publishing Group
• Subjects: 13/1; 13/106; 38; 38/23; 38/43; 38/77; 631/208/205/2138; 631/67/589/466; Agriculture; Androgens; Animal Genetics and Genomics; Animals; Binding sites; Biomedicine; Cancer genetics; Cancer Research; Cell growth; Cell Line, Tumor; Chromatin - metabolism; Development and progression; Enhancer Elements, Genetic; Epigenetics; Gene Expression Regulation, Neoplastic; Gene Function; Genes; Genetic aspects; Genetic Predisposition to Disease; Genetic research; Genome-Wide Association Study; Genomes; Genomics; Genotype; Grants; Health aspects; Health risks; Human Genetics; Humans; Male; Mice; Mice, Inbred NOD; Polymorphism, Single Nucleotide; Prostate cancer; Prostatic Neoplasms - genetics; Proteins; Receptors, Androgen - metabolism; Regulation; Risk Factors; RNA polymerase; RNA, Long Noncoding - genetics; Signal Transduction; Single nucleotide polymorphisms; Studies; Transcription factors; Transcription Factors - metabolism; Xenograft Model Antitumor Assays
• ISSN: 1061-4036; 1546-1718
• DOI: 10.1038/ng.3637

Housheng Hansen He and colleagues perform an integrated analysis and identify 45 candidate long noncoding RNAs (lncRNAs) associated with prostate cancer risk. They further show that a prostate cancer risk allele in the 8q24 region results in upregulation of the lncRNA PCAT1, which promotes prostate cancer cell proliferation and tumor growth. 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.