ena-STUDY-BCO-24-10-2013-09:57:34:608-12
A prostate cancer susceptibility allele at 6q22 increases RFX6 expression by modulating HOXB13 chromatin binding
Genome-wide association studies (GWAS) have identified thousands of single nucleotide polymorphisms (SNP) associated with predisposition for various diseases including prostate cancer. However, the mechanistic roles of these SNPs remain poorly defined, particularly for noncoding polymorphisms. Here we profiled the genome-wide chromatin binding location of transcription factor HOXB13 and mapped common genetic variant rs339331 at the 6q22 prostate cancer susceptibility locus to a HOXB13 binding site. The rs339331 T risk allele increases binding of HOXB13 to a newly discovered transcriptional enhancer, conferring allele-specific upregulation of rs339331-associated gene RFX6. Depletion of HOXB13 reduces its chromatin occupancy and the transcription of RFX6 selectively at the rs339331 T allele in human prostate cancer cells that are heterozygous for rs339331. Our functional study reveals that suppression of RFX6 greatly diminishes prostate cancer cell proliferation, migration and invasion. Clinical evidence indicates that RFX6 upregulation in human prostate cancers correlates with tumor progression, metastasis and risk of biochemical relapse. Finally, we observed a significant association between the rs339331 T risk allele and higher RFX6 mRNA level in human prostate tumors (P = 2.95 x 10-4). These results suggest that rs339331 impacts prostate cancer risk by affecting expression of RFX6. Together, our study provides compelling evidence to substantiate the causality of rs339331 and highlights a novel functional interaction between this risk variant and another prostate cancer susceptibility gene HOXB13.
Genome-wide association studies (GWAS) have identified thousands of single nucleotide polymorphisms (SNP) associated with predisposition for various diseases including prostate cancer. However, the mechanistic roles of these SNPs remain poorly defined, particularly for noncoding polymorphisms. Here we profiled the genome-wide chromatin binding location of transcription factor HOXB13 and mapped common genetic variant rs339331 at the 6q22 prostate cancer susceptibility locus to a HOXB13 binding site. The rs339331 T risk allele increases binding of HOXB13 to a newly discovered transcriptional enhancer, conferring allele-specific upregulation of rs339331-associated gene RFX6. Depletion of HOXB13 reduces its chromatin occupancy and the transcription of RFX6 selectively at the rs339331 T allele in human prostate cancer cells that are heterozygous for rs339331. Our functional study reveals that suppression of RFX6 greatly diminishes prostate cancer cell proliferation, migration and invasion. Clinical evidence indicates that RFX6 upregulation in human prostate cancers correlates with tumor progression, metastasis and risk of biochemical relapse. Finally, we observed a significant association between the rs339331 T risk allele and higher RFX6 mRNA level in human prostate tumors (P = 2.95 x 10-4). These results suggest that rs339331 impacts prostate cancer risk by affecting expression of RFX6. Together, our study provides compelling evidence to substantiate the causality of rs339331 and highlights a novel functional interaction between this risk variant and another prostate cancer susceptibility gene HOXB13.