title: 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.
authors.affiliation: Princess Margaret Cancer Center, University Health Network, Toronto, Ontario, Canada.
authors.forename: Haiyang
authors.initials: H
authors.lastname: Guo
authors.affiliation: Princess Margaret Cancer Center, University Health Network, Toronto, Ontario, Canada.
authors.forename: Musaddeque
authors.initials: M
authors.lastname: Ahmed
authors.affiliation: Department of Pharmacological Sciences, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
authors.forename: Fan
authors.initials: F
authors.lastname: Zhang
authors.affiliation: Ontario Institute for Cancer Research, Toronto, Ontario, Canada.
authors.forename: Cindy Q
authors.initials: CQ
authors.lastname: Yao
authors.affiliation: Department of Pharmacological Sciences, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
authors.forename: SiDe
authors.initials: S
authors.lastname: Li
authors.affiliation: Princess Margaret Cancer Center, University Health Network, Toronto, Ontario, Canada.
authors.forename: Yi
authors.initials: Y
authors.lastname: Liang
authors.affiliation: Princess Margaret Cancer Center, University Health Network, Toronto, Ontario, Canada.|Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Junjie
authors.initials: J
authors.lastname: Hua
authors.affiliation: Princess Margaret Cancer Center, University Health Network, Toronto, Ontario, Canada.
authors.forename: Fraser
authors.initials: F
authors.lastname: Soares
authors.affiliation: Department of Pharmacological Sciences, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
authors.forename: Yifei
authors.initials: Y
authors.lastname: Sun
authors.affiliation: Princess Margaret Cancer Center, University Health Network, Toronto, Ontario, Canada.|German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: Jens
authors.initials: J
authors.lastname: Langstein
authors.affiliation: Princess Margaret Cancer Center, University Health Network, Toronto, Ontario, Canada.
authors.forename: Yuchen
authors.initials: Y
authors.lastname: Li
authors.affiliation: Princess Margaret Cancer Center, University Health Network, Toronto, Ontario, Canada.
authors.forename: Christine
authors.initials: C
authors.lastname: Poon
authors.affiliation: Princess Margaret Cancer Center, University Health Network, Toronto, Ontario, Canada.
authors.forename: Swneke D
authors.initials: SD
authors.lastname: Bailey
authors.affiliation: Department of Genetics, Norris Cotton Cancer Center, Dartmouth Medical School, Lebanon, New Hampshire, USA.
authors.forename: Kinjal
authors.initials: K
authors.lastname: Desai
authors.affiliation: Department of Medical Oncology, Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.
authors.forename: Teng
authors.initials: T
authors.lastname: Fei
authors.affiliation: Medical College of Xiamen University, Xiamen, China.
authors.forename: Qiyuan
authors.initials: Q
authors.lastname: Li
authors.affiliation: Ontario Institute for Cancer Research, Toronto, Ontario, Canada.
authors.forename: Dorota H
authors.initials: DH
authors.lastname: Sendorek
authors.affiliation: Princess Margaret Cancer Center, University Health Network, Toronto, Ontario, Canada.
authors.forename: Michael
authors.initials: M
authors.lastname: Fraser
authors.affiliation: Michigan Center for Translational Pathology, University of Michigan Medical School, Ann Arbor, Michigan, USA.
authors.forename: John R
authors.initials: JR
authors.lastname: Prensner
authors.affiliation: Princess Margaret Cancer Center, University Health Network, Toronto, Ontario, Canada.|Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Trevor J
authors.identifier: 0000-0002-8073-5888
authors.initials: TJ
authors.lastname: Pugh
authors.affiliation: Department of Medical Oncology, Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.
authors.forename: Mark
authors.initials: M
authors.lastname: Pomerantz
authors.affiliation: Princess Margaret Cancer Center, University Health Network, Toronto, Ontario, Canada.|Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Robert G
authors.initials: RG
authors.lastname: Bristow
authors.affiliation: Princess Margaret Cancer Center, University Health Network, Toronto, Ontario, Canada.|Ontario Institute for Cancer Research, Toronto, Ontario, Canada.|Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Mathieu
authors.identifier: 0000-0003-0929-9478
authors.initials: M
authors.lastname: Lupien
authors.affiliation: Department of Radiation Oncology, University of California at San Francisco, San Francisco, California, USA.|Department of Urology, University of California at San Francisco, San Francisco, California, USA.|Department of Medicine, University of California at San Francisco, San Francisco, California, USA.|Helen Diller Family Comprehensive Cancer Center, University of California at San Francisco, San Francisco, California, USA.
authors.forename: Felix Y
authors.initials: FY
authors.lastname: Feng
authors.affiliation: Ontario Institute for Cancer Research, Toronto, Ontario, Canada.|Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada.|Department of Pharmacology and Toxicology, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Paul C
authors.identifier: 0000-0003-0553-7520
authors.initials: PC
authors.lastname: Boutros
authors.affiliation: Department of Medical Oncology, Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.|Eli and Edythe L. Broad Institute, Cambridge, Massachusetts, USA.
authors.forename: Matthew L
authors.initials: ML
authors.lastname: Freedman
authors.affiliation: Department of Pharmacological Sciences, Icahn School of Medicine at Mount Sinai, New York, New York, USA.|Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
authors.forename: Martin J
authors.initials: MJ
authors.lastname: Walsh
authors.affiliation: Princess Margaret Cancer Center, University Health Network, Toronto, Ontario, Canada.|Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Housheng Hansen
authors.identifier: 0000-0003-2898-3363
authors.initials: HH
authors.lastname: He
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D002843:Chromatin / Q000378:metabolism; D004742:Enhancer Elements, Genetic; D015972:Gene Expression Regulation, Neoplastic; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D005838:Genotype; D006801:Humans; D008297:Male; D051379:Mice; D016688:Mice, Inbred NOD; D020641:Polymorphism, Single Nucleotide; D011471:Prostatic Neoplasms / Q000235:genetics*; D062085:RNA, Long Noncoding / Q000235:genetics; D011944:Receptors, Androgen / Q000378:metabolism; D012307:Risk Factors; D015398:Signal Transduction; D014157:Transcription Factors / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
chemical_list: D002843:Chromatin; C588212:PCAT-1 lncRNA, human; D062085:RNA, Long Noncoding; D011944:Receptors, Androgen; D014157:Transcription Factors