rs2294008T, a risk allele for gastric and gallbladder cancers, suppresses the PSCA promoter by recruiting the transcription factor YY1

Abstract

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 (YY1) 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 YY1 to its promoter, which eventually predisposes gastric epithelial cells to GC development.