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

• Published in: Nature genetics Vol. 46; no. 2; pp. 126 - 135
• Main Authors: Huang, Qilai, Whitington, Thomas, Gao, Ping, Lindberg, Johan F, Yang, Yuehong, Sun, Jielin, Väisänen, Marja-Riitta, Szulkin, Robert, Annala, Matti, Yan, Jian, Egevad, Lars A, Zhang, Kai, Lin, Ruizhu, Jolma, Arttu, Nykter, Matti, Manninen, Aki, Wiklund, Fredrik, Vaarala, Markku H, Visakorpi, Tapio, Xu, Jianfeng, Taipale, Jussi, Wei, Gong-Hong
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01.02.2014; Nature Publishing Group
• Subjects: 13/1; 13/109; 13/44; 13/89; 38/1; 38/15; 38/22; 38/23; 38/88; 38/90; 45/77; 631/208/200; 692/699/67/589/466; 9/10; Agriculture; Animal Genetics and Genomics; Base Sequence; Biomedicine; Cancer Research; Chromatin - metabolism; Chromatin Immunoprecipitation; Chromosome Mapping; Chromosomes, Human, Pair 6 - genetics; Cloning, Molecular; Cohort Studies; Confidence intervals; Deoxyribonucleic acid; Development and progression; Disease susceptibility; DNA; DNA-Binding Proteins - genetics; Electrophoretic Mobility Shift Assay; Finland; Gene expression; Gene Expression Regulation, Neoplastic - genetics; Gene Function; Genetic aspects; Genetic Predisposition to Disease - genetics; Genomes; Genomics; Genotype; Health aspects; Health risks; Homeodomain Proteins - genetics; Homeodomain Proteins - metabolism; Human Genetics; Humans; Male; Medicin och hälsovetenskap; Men; Molecular Sequence Data; Polymorphism, Single Nucleotide - genetics; Prostate cancer; Prostatic Neoplasms - genetics; Real-Time Polymerase Chain Reaction; Regulatory Factor X Transcription Factors; Risk factors; RNA, Small Interfering - genetics; Sequence Analysis, DNA; Sweden; Transcription factors; Transcription Factors - genetics; Sweden
• ISSN: 1061-4036; 1546-1718; 1546-1718
• DOI: 10.1038/ng.2862

Gong-Hong Wei, Jussi Taipale and colleagues show that a prostate cancer risk allele at 6q22 enhances HOXB13 chromatin binding at this locus, leading to increased allele-specific expression of RFX6 . They further show that RFX6 suppression reduces the proliferation, migration and invasion of prostate cancer cells and that RFX6 expression in clinical samples correlates with tumor progression and metastasis. 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 .