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

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...

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Published inNature 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
LanguageEnglish
Published New York Nature Publishing Group US 01.10.2016
Nature Publishing Group
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Abstract 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.
AbstractList 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.
Long noncoding RNAs (IncRNAs) 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.
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.
Audience Academic
Author Li, Qiyuan
Li, Yuchen
Pomerantz, Mark
Desai, Kinjal
Yao, Cindy Q
Walsh, Martin J
Bristow, Robert G
Poon, Christine
Prensner, John R
He, Housheng Hansen
Fei, Teng
Freedman, Matthew L
Liang, Yi
Feng, Felix Y
Ahmed, Musaddeque
Boutros, Paul C
Pugh, Trevor J
Soares, Fraser
Sun, Yifei
Lupien, Mathieu
Sendorek, Dorota H
Guo, Haiyang
Zhang, Fan
Li, SiDe
Langstein, Jens
Bailey, Swneke D
Fraser, Michael
Hua, Junjie
Author_xml – sequence: 1
  givenname: Haiyang
  surname: Guo
  fullname: Guo, Haiyang
  organization: Princess Margaret Cancer Center, University Health Network
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  organization: Princess Margaret Cancer Center, University Health Network
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  givenname: Fan
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  fullname: Zhang, Fan
  organization: Department of Pharmacological Sciences, Icahn School of Medicine at Mount Sinai
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  organization: Ontario Institute for Cancer Research
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  organization: Department of Pharmacological Sciences, Icahn School of Medicine at Mount Sinai
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  organization: Princess Margaret Cancer Center, University Health Network
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  organization: Princess Margaret Cancer Center, University Health Network
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  organization: Princess Margaret Cancer Center, University Health Network
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  organization: Princess Margaret Cancer Center, University Health Network
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  organization: Department of Genetics, Norris Cotton Cancer Center, Dartmouth Medical School
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  givenname: Teng
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  fullname: Fei, Teng
  organization: Department of Medical Oncology, Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute
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  fullname: Li, Qiyuan
  organization: Medical College of Xiamen University
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  organization: Princess Margaret Cancer Center, University Health Network
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  orcidid: 0000-0002-8073-5888
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  organization: Department of Medical Oncology, Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute
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  organization: Princess Margaret Cancer Center, University Health Network, Department of Medical Biophysics, University of Toronto
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  orcidid: 0000-0003-0929-9478
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  surname: Feng
  fullname: Feng, Felix Y
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  surname: He
  fullname: He, Housheng Hansen
  email: hansenhe@uhnresearch.ca
  organization: Princess Margaret Cancer Center, University Health Network, Department of Medical Biophysics, University of Toronto
BackLink https://www.ncbi.nlm.nih.gov/pubmed/27526323$$D View this record in MEDLINE/PubMed
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ContentType Journal Article
Copyright Springer Nature America, Inc. 2016
COPYRIGHT 2016 Nature Publishing Group
Copyright Nature Publishing Group Oct 2016
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– notice: COPYRIGHT 2016 Nature Publishing Group
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Snippet Housheng Hansen He and colleagues perform an integrated analysis and identify 45 candidate long noncoding RNAs (lncRNAs) associated with prostate cancer risk....
Long noncoding RNAs (lncRNAs) represent an attractive class of candidates to mediate cancer risk. Through integrative analysis of the lncRNA transcriptome with...
Long noncoding RNAs (IncRNAs) represent an attractive class of candidates to mediate cancer risk. Through integrative analysis of the lncRNA transcriptome with...
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StartPage 1142
SubjectTerms 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
Title Modulation of long noncoding RNAs by risk SNPs underlying genetic predispositions to prostate cancer
URI https://link.springer.com/article/10.1038/ng.3637
https://www.ncbi.nlm.nih.gov/pubmed/27526323
https://www.proquest.com/docview/1826400430
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