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Nat Genet. 2014 Feb;46(2):126-35. doi: 10.1038/ng.2862. Epub 2014 Jan 5.

A prostate cancer susceptibility allele at 6q22 increases RFX6 expression by modulating HOXB13 chromatin binding.

Author information

1
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].
2
1] Department of Biosciences and Nutrition, Karolinska Institutet, Stockholm, Sweden. [2] Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden. [3].
3
1] Biocenter Oulu, University of Oulu, Oulu, Finland. [2] Department of Medical Biochemistry and Molecular Biology, Institute of Biomedicine, University of Oulu, Oulu, Finland.
4
Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
5
Fudan Institute of Urology, Huashan Hospital, Fudan University, Shanghai, China.
6
Department of Pathology, Oulu University Hospital, Oulu, Finland.
7
Prostate Cancer Research Center, Institute of Biomedical Technology and BioMediTech, University of Tampere and Tampere University Hospital, Tampere, Finland.
8
Department of Biosciences and Nutrition, Karolinska Institutet, Stockholm, Sweden.
9
Department of Pathology and Cytology, Karolinska University Hospital, Stockholm, Sweden.
10
1] Department of Biosciences and Nutrition, Karolinska Institutet, Stockholm, Sweden. [2] Genome-Scale Biology Program, University of Helsinki, Helsinki, Finland.
11
1] Department of Pathology, Oulu University Hospital, Oulu, Finland. [2] Medical Research Center, University of Oulu, Oulu, Finland.

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.

PMID:
24390282
DOI:
10.1038/ng.2862
[Indexed for MEDLINE]

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