A Prostate Cancer–Associated SNP Increases HOXB13 Binding

Germline mutations in HOXB13, encoding a homeobox transcription factor that is expressed during prostate development, are associated with an increased risk of hereditary prostate cancer. To identify HOXB13 targets in prostate cancer cells, Huang and colleagues performed chromatin immunoprecipitation sequencing and observed that prostate cancer susceptibility alleles identified by genome-wide association studies (GWAS) were significantly enriched for HOXB13-occupied sites. One such prostate cancer risk–associated single-nucleotide polymorphism (SNP), rs339331, was located on chromosome 6q22 in a highly conserved active enhancer region within intron 4 of RFX6. The risk-associated T allele strongly increased the DNA-binding affinity of HOXB13 compared with the reference C allele in vitro, and HOXB13 preferentially bound the risk allele in prostate cancer cell lines that were heterozygous at rs339331. Moreover, HOXB13 was required for risk-associated allele-specific RFX6 expression in prostate cancer cell lines, suggesting that the prostate cancer susceptibility allele at 6q22 promotes RFX6 expression by increasing HOXB13 binding to the transcriptional enhancer within this locus. Knockdown of either HOXB13 or RFX6 significantly reduced prostate cancer cell proliferation, migration, and invasion, raising the possibility that increased RFX6 expression may underlie the increased prostate cancer risk conferred by the T allele of rs339331. In prostate cancer samples, the risk-associated T allele was significantly associated with elevated RFX6 expression, and, consistent with the findings suggesting that RFX6 upregulation promotes phenotypes associated with prostate cancer progression, RFX6 expression was significantly higher in prostate cancer samples than in benign or normal prostate samples and was significantly correlated with Gleason score, prostate-specific antigen level, and increased probability of biochemical recurrence. Together, these findings not only identify RFX6 as a potential prostate cancer susceptibility gene but also uncover a functional interaction between HOXB13 and GWAS-identified SNPs that may explain mechanisms underlying hereditary prostate cancer risk.

Huang Q, Whitington T, Gao P, Lindberg JF, Yang Y, Sun J, et al. A prostate cancer susceptibility allele at 6q22 increases RFX6 expression by modulating HOXB13 chromatin binding. Nat Genet 2013;46:126–35.

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