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rs2294008T, a risk allele for gastric and gallbladder cancers, suppresses the PSCA promoter by recruiting the transcription factor YY 1
Author(s) -
Saeki Norihisa,
Ono Hiroe,
Yanagihara Kazuyoshi,
Aoyagi Kazuhiko,
Sasaki Hiroki,
Sakamoto Hiromi,
Yoshida Teruhiko
Publication year - 2015
Publication title -
genes to cells
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.912
H-Index - 115
eISSN - 1365-2443
pISSN - 1356-9597
DOI - 10.1111/gtc.12228
Subject(s) - biology , allele , promoter , gene , transcription factor , microbiology and biotechnology , yy1 , transcription (linguistics) , genetics , gene expression , linguistics , philosophy
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.