Modulation of long noncoding RNAs by risk SNPs underlying genetic predispositions to prostate cancer
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.
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Combining prostate cancer RNA-seq and SNP data from TCGA identified risk-modulating non-coding RNA.
“One group combined prostate cancer RNA-seq and SNP data to identify risk-modulating non-coding RNA, demonstrating the application of multi-omics TCGA data integration146,147.”
From The technological landscape and applications of single-cell multi-omics (2023) · cites this paper as [146]
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- Authors
- Guo, H., Ahmed, M., Zhang, F., Yao, C. Q., Li, S., Liang, Y., Hua, J., Soares, F., Sun, Y., Langstein, J., Li, Y., Poon, C., Bailey, S. D., Desai, K., Fei, T., Li, Q., Sendorek, D. H., Fraser, M., Prensner, J. R., Pugh, T. J., Pomerantz, M., Bristow, R. G., Lupien, M., Feng, F. Y., Boutros, P. C., Freedman, M. L., Walsh, M. J., & He, H. H.
- Affiliations
- University Health Network (CA)
- Icahn School of Medicine at Mount Sinai (US)
- Ontario Institute for Cancer Research (CA)
- Dartmouth Cancer Center (US)
- Dana-Farber Cancer Institute (US)
- Xiamen University (CN)
- University of Michigan (US)
- University of California, San Francisco (US)
- Broad Institute (US)
- Corresponding author
- He, Housheng Hansen
- ORCID
- Guo, Haiyang
- Ahmed, Musaddeque
- Zhang, Fan
- Liang, Yi
- Hua, Junjie
- Soares, Fraser
- Sun, Yifei
- Langstein, Jens
- Li, Yuchen
- Bailey, Swneke D
- Desai, Kinjal
- 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
- Venue
- Nature Genetics
- Published
- 2016-08-15
- Volume
- 48
- Issue
- 10
- Pages
- 1142-1150
- ISSN
- 1061-4036 (ISSN-L)
- 1546-1718
- OpenAlex
- W2511381148
- Cited by
- 226
- References
- 82
- Citations by year
- 2026: 8 · 2025: 8 · 2024: 9 · 2023: 21 · 2022: 19 · 2021: 27 · 2020: 35 · 2019: 38 · 2018: 32 · 2017: 24 · 2016: 5
- FWCI
- 13.74
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Genetics (publishedVersion)
- PubMed (publishedVersion)
- Research Explorer (The University of Manchester) (submittedVersion)
- Funders
- Canadian Institutes of Health Research (142246)
- National Heart, Lung, and Blood Institute (R01HL103967)
- National Cancer Institute (R01CA193910)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer-related molecular mechanisms research
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Prostate Cancer Treatment and Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
- Keywords
- long non-coding RNA, prostate cancer, PCAT1, 8q24, ONECUT2, androgen receptor, LSD1, distal enhancers, glycine N-methyltransferase, DHCR24, androgen response, tumor cell proliferation, tumor growth, genetic susceptibility
- MeSH terms
- Animals, Chromatin, Enhancer Elements, Genetic, Genotype, Humans, Male, Prostatic Neoplasms, Receptors, Androgen, Risk Factors, Transcription Factors, Signal Transduction, Gene Expression Regulation, Neoplastic, Mice, Inbred NOD, Genetic Predisposition to Disease, Polymorphism, Single Nucleotide, Xenograft Model Antitumor Assays, Cell Line, Tumor, Mice, Genome-Wide Association Study, RNA, Long Noncoding
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