rs2294008T, a risk allele for gastric and gallbladder cancers, suppresses the PSCA promoter by recruiting the transcription factor YY1.
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.
Division of Genetics, National Cancer Center Research Institute, Tsukiji 5-1-1, Chuo-ku, Tokyo, 104-0045, Japan.
Norihisa
N
Saeki
Hiroe
H
Ono
Kazuyoshi
K
Yanagihara
Kazuhiko
K
Aoyagi
Hiroki
H
Sasaki
Hiromi
H
Sakamoto
Teruhiko
T
Yoshida
D000483:Alleles; D000951:Antigens, Neoplasm / Q000235:genetics*; D001483:Base Sequence; D001665:Binding Sites; D016384:Consensus Sequence; D058851:GPI-Linked Proteins / Q000235:genetics; D005706:Gallbladder Neoplasms / Q000235:genetics* / Q000378:metabolism*; D005753:Gastric Mucosa / Q000378:metabolism / Q000473:pathology; D015972:Gene Expression Regulation, Neoplastic; D023061:Gene Order; D006801:Humans; D008969:Molecular Sequence Data; D009363:Neoplasm Proteins / Q000235:genetics*; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D013274:Stomach Neoplasms / Q000235:genetics* / Q000378:metabolism*; D014158:Transcription, Genetic; D050986:YY1 Transcription Factor / Q000378:metabolism*
D000951:Antigens, Neoplasm; D058851:GPI-Linked Proteins; D009363:Neoplasm Proteins; C110843:PSCA protein, human; D050986:YY1 Transcription Factor