title: A prostate cancer susceptibility allele at 6q22 increases RFX6 expression by modulating HOXB13 chromatin binding.
abstract: Genome-wide association studies have identified thousands of SNPs associated with predisposition to various diseases, including prostate cancer. However, the mechanistic roles of these SNPs remain poorly defined, particularly for noncoding polymorphisms. Here we find that the prostate cancer risk-associated SNP rs339331 at 6q22 lies within a functional HOXB13-binding site. The risk-associated T allele at rs339331 increases binding of HOXB13 to a transcriptional enhancer, conferring allele-specific upregulation of the rs339331-associated gene RFX6. Suppression of RFX6 diminishes prostate cancer cell proliferation, migration and invasion. Clinical data indicate that RFX6 upregulation in human prostate cancers correlates with tumor progression, metastasis and risk of biochemical relapse. Finally, we observe a significant association between the risk-associated T allele at rs339331 and increased RFX6 mRNA levels in human prostate tumors. Together, our results suggest that rs339331 affects prostate cancer risk by altering RFX6 expression through a functional interaction with the prostate cancer susceptibility gene HOXB13.
authors.affiliation: 1] Biocenter Oulu, University of Oulu, Oulu, Finland. [2] Department of Medical Biochemistry and Molecular Biology, Institute of Biomedicine, University of Oulu, Oulu, Finland. [3].
authors.forename: Qilai
authors.initials: Q
authors.lastname: Huang
authors.affiliation: 1] Department of Biosciences and Nutrition, Karolinska Institutet, Stockholm, Sweden. [2] Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden. [3].
authors.forename: Thomas
authors.initials: T
authors.lastname: Whitington
authors.affiliation: 1] Biocenter Oulu, University of Oulu, Oulu, Finland. [2] Department of Medical Biochemistry and Molecular Biology, Institute of Biomedicine, University of Oulu, Oulu, Finland.
authors.forename: Ping
authors.initials: P
authors.lastname: Gao
authors.affiliation: Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Johan F
authors.initials: JF
authors.lastname: Lindberg
authors.affiliation: 1] Biocenter Oulu, University of Oulu, Oulu, Finland. [2] Department of Medical Biochemistry and Molecular Biology, Institute of Biomedicine, University of Oulu, Oulu, Finland.
authors.forename: Yuehong
authors.initials: Y
authors.lastname: Yang
authors.affiliation: Fudan Institute of Urology, Huashan Hospital, Fudan University, Shanghai, China.
authors.forename: Jielin
authors.initials: J
authors.lastname: Sun
authors.affiliation: Department of Pathology, Oulu University Hospital, Oulu, Finland.
authors.forename: Marja-Riitta
authors.initials: MR
authors.lastname: Väisänen
authors.affiliation: Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Robert
authors.initials: R
authors.lastname: Szulkin
authors.affiliation: Prostate Cancer Research Center, Institute of Biomedical Technology and BioMediTech, University of Tampere and Tampere University Hospital, Tampere, Finland.
authors.forename: Matti
authors.initials: M
authors.lastname: Annala
authors.affiliation: Department of Biosciences and Nutrition, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Jian
authors.initials: J
authors.lastname: Yan
authors.affiliation: Department of Pathology and Cytology, Karolinska University Hospital, Stockholm, Sweden.
authors.forename: Lars A
authors.initials: LA
authors.lastname: Egevad
authors.affiliation: 1] Biocenter Oulu, University of Oulu, Oulu, Finland. [2] Department of Medical Biochemistry and Molecular Biology, Institute of Biomedicine, University of Oulu, Oulu, Finland.
authors.forename: Kai
authors.initials: K
authors.lastname: Zhang
authors.affiliation: 1] Biocenter Oulu, University of Oulu, Oulu, Finland. [2] Department of Medical Biochemistry and Molecular Biology, Institute of Biomedicine, University of Oulu, Oulu, Finland.
authors.forename: Ruizhu
authors.initials: R
authors.lastname: Lin
authors.affiliation: 1] Department of Biosciences and Nutrition, Karolinska Institutet, Stockholm, Sweden. [2] Genome-Scale Biology Program, University of Helsinki, Helsinki, Finland.
authors.forename: Arttu
authors.initials: A
authors.lastname: Jolma
authors.affiliation: Prostate Cancer Research Center, Institute of Biomedical Technology and BioMediTech, University of Tampere and Tampere University Hospital, Tampere, Finland.
authors.forename: Matti
authors.initials: M
authors.lastname: Nykter
authors.affiliation: 1] Biocenter Oulu, University of Oulu, Oulu, Finland. [2] Department of Medical Biochemistry and Molecular Biology, Institute of Biomedicine, University of Oulu, Oulu, Finland.
authors.forename: Aki
authors.initials: A
authors.lastname: Manninen
authors.affiliation: Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Fredrik
authors.initials: F
authors.lastname: Wiklund
authors.affiliation: 1] Department of Pathology, Oulu University Hospital, Oulu, Finland. [2] Medical Research Center, University of Oulu, Oulu, Finland.
authors.forename: Markku H
authors.initials: MH
authors.lastname: Vaarala
authors.affiliation: Prostate Cancer Research Center, Institute of Biomedical Technology and BioMediTech, University of Tampere and Tampere University Hospital, Tampere, Finland.
authors.forename: Tapio
authors.initials: T
authors.lastname: Visakorpi
authors.affiliation: Fudan Institute of Urology, Huashan Hospital, Fudan University, Shanghai, China.
authors.forename: Jianfeng
authors.initials: J
authors.lastname: Xu
authors.affiliation: 1] Department of Biosciences and Nutrition, Karolinska Institutet, Stockholm, Sweden. [2] Genome-Scale Biology Program, University of Helsinki, Helsinki, Finland.
authors.forename: Jussi
authors.initials: J
authors.lastname: Taipale
authors.affiliation: 1] Biocenter Oulu, University of Oulu, Oulu, Finland. [2] Department of Medical Biochemistry and Molecular Biology, Institute of Biomedicine, University of Oulu, Oulu, Finland.
authors.forename: Gong-Hong
authors.initials: GH
authors.lastname: Wei
mesh_terms: D001483:Base Sequence; D002843:Chromatin / Q000378:metabolism*; D047369:Chromatin Immunoprecipitation; D002874:Chromosome Mapping; D002896:Chromosomes, Human, Pair 6 / Q000235:genetics*; D003001:Cloning, Molecular; D015331:Cohort Studies; D004268:DNA-Binding Proteins / Q000235:genetics*; D024202:Electrophoretic Mobility Shift Assay; D005387:Finland; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics*; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D005838:Genotype; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008297:Male; D008969:Molecular Sequence Data; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D011471:Prostatic Neoplasms / Q000235:genetics*; D034741:RNA, Small Interfering / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D000071701:Regulatory Factor X Transcription Factors; D017422:Sequence Analysis, DNA; D013548:Sweden; D014157:Transcription Factors / Q000235:genetics*
chemical_list: D002843:Chromatin; D004268:DNA-Binding Proteins; C484414:HOXB13 protein, human; D018398:Homeodomain Proteins; D034741:RNA, Small Interfering; D000071701:Regulatory Factor X Transcription Factors; C547964:Rfx6 protein, human; D014157:Transcription Factors