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Title: Expression of metastasis suppressor gene AES driven by a YY element in a CpG island promoter and transcription factor YY2.
Authors: F, Kakizaki
M, Sonoshita
H, Miyoshi
Y, Itatani
S, Ito
K, Kawada
Y, Sakai
MM, Taketo
Author's alias: 柿崎, 文彦
園下, 将大
三好, 弘之
河田, 健二
伊藤, 慎二
Keywords: AES
colon cancer
CpG island
Issue Date: Aug-2016
Publisher: Wiley-Blackwell
Journal title: Cancer science
Volume: 107
Start page: 1622
End page: 1631
Abstract: We recently found that the product of the AES gene functions as a metastasissuppressor of colorectal cancer (CRC) in both humans and mice. Expression ofamino-terminal enhancer of split (AES) protein is signi?cantly decreased in livermetastatic lesions compared with primary colon tumors. To investigate itsdownregulation mechanism in metastases, we searched for transcriptional reg-ulators of AES in human CRC and found that its expression is reduced mainlyby transcriptional dysregulation and, in some cases, by additional haploidiza-tion of its coding gene. The AES promoter-enhancer is in a typical CpG island, and contains a Yin-Yang transcription factor recognition sequence (YY ele-ment). In human epithelial cells of normal colon and primary tumors, transcrip-tion factor YY2, a member of the YY family, binds directly to the YY element, and stimulates expression of AES. In a transplantation mouse model of livermetastases, however, expression of Yy2 (and therefore of Aes) is downregu-lated. In human CRC metastases to the liver, the levels of AES protein are cor-related with those of YY2. In addition, we noticed copy-number reduction forthe AES coding gene in chromosome 19p13.3 in 12% (5/42) of human CRC celllines. We excluded other mechanisms such as point or indel mutations in thecoding or regulatory regions of the AES gene, CpG methylation in the AESpromoter enhancer, expression of microRNAs, and chromatin histone modi?ca-tions. These results indicate that Aes may belong to a novel family of metas-tasis suppressors with a CpG-island promoter enhancer, and it is regulatedtranscriptionally.
Rights: © 2016 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltdon behalf of Japanese Cancer Association.This is an open access article under the terms of the Creative CommonsAttribution-NonCommercial-NoDerivs License, which permits use and distributionin any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.
DOI(Published Version): 10.1111/cas.13063
PubMed ID: 27561171
Appears in Collections:Journal Articles

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