rs2294008T, a risk allele for gastric and gallbladder cancers, suppresses the PSCA promoter by recruiting the transcription factor YY 1

Previous genomewide association studies identified prostate stem cell antigen ( PSCA ) as a gastric cancer ( GC ) susceptibility gene and showed an association between GC and the T allele of the single nucleotide polymorphism rs2294008 (C/T) in this gene. The protein product of this gene inhibits cell growth, and the T allele significantly suppresses the transcriptional activity of the −3.2 kb PSCA upstream region. However, the mechanism remains unknown. In this study, we conducted reporter assays using the PSCA upstream region containing the C allele and identified the region from −200 to +38 bp of the transcription initiation site of the gene as a critical region of the −3.2 kb PSCA upstream region. We found that introducing the T allele at rs2294008 generated a consensus binding sequence for the Polycomb group transcription factor Yin Yang 1 ( YY 1) and that disruption of the consensus sequence restored the transcriptional activity to the −3.2 kb PSCA upstream region. These findings imply that the T allele significantly suppresses PSCA expression in vivo by recruiting YY 1 to its promoter, which eventually predisposes gastric epithelial cells to GC development.