title: Expression of metastasis suppressor gene AES driven by a Yin Yang (YY) element in a CpG island promoter and transcription factor YY2.
abstract: We recently found that the product of the AES gene functions as a metastasis suppressor of colorectal cancer (CRC) in both humans and mice. Expression of amino-terminal enhancer of split (AES) protein is significantly decreased in liver metastatic lesions compared with primary colon tumors. To investigate its downregulation mechanism in metastases, we searched for transcriptional regulators of AES in human CRC and found that its expression is reduced mainly by transcriptional dysregulation and, in some cases, by additional haploidization of its coding gene. The AES promoter-enhancer is in a typical CpG island, and contains a Yin-Yang transcription factor recognition sequence (YY element). In human epithelial cells of normal colon and primary tumors, transcription 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 liver metastases, however, expression of Yy2 (and therefore of Aes) is downregulated. In human CRC metastases to the liver, the levels of AES protein are correlated with those of YY2. In addition, we noticed copy-number reduction for the AES coding gene in chromosome 19p13.3 in 12% (5/42) of human CRC cell lines. We excluded other mechanisms such as point or indel mutations in the coding or regulatory regions of the AES gene, CpG methylation in the AES promoter enhancer, expression of microRNAs, and chromatin histone modifications. These results indicate that Aes may belong to a novel family of metastasis suppressors with a CpG-island promoter enhancer, and it is regulated transcriptionally.
authors: Department of Pharmacology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.|Division of Experimental Therapeutics, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
authors: Fumihiko
authors: F
authors: Kakizaki
authors: Department of Pharmacology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.|Department of Developmental and Regenerative Biology, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
authors: Masahiro
authors: M
authors: Sonoshita
authors: Division of Experimental Therapeutics, Graduate School of Medicine, Kyoto University, Kyoto, Japan.|Gastrointestinal Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
authors: Hiroyuki
authors: H
authors: Miyoshi
authors: Department of Pharmacology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.|Gastrointestinal Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan.|Moores Cancer Center, University of California San Diego, La Jolla, California, USA.
authors: Yoshiro
authors: Y
authors: Itatani
authors: Medical Research Support Center, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
authors: Shinji
authors: S
authors: Ito
authors: Gastrointestinal Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
authors: Kenji
authors: K
authors: Kawada
authors: Gastrointestinal Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
authors: Yoshiharu
authors: Y
authors: Sakai
authors: Department of Pharmacology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.|Division of Experimental Therapeutics, Graduate School of Medicine, Kyoto University, Kyoto, Japan.|Gastrointestinal Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
authors: M Mark
authors: MM
authors: Taketo
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D056970:Co-Repressor Proteins; D015179:Colorectal Neoplasms / Q000235:genetics* / Q000473:pathology*; D018899:CpG Islands / Q000235:genetics*; D019175:DNA Methylation / Q000235:genetics; D015536:Down-Regulation; D016147:Genes, Tumor Suppressor; D006801:Humans; D008113:Liver Neoplasms / Q000235:genetics / Q000556:secondary; D051379:Mice; D009154:Mutation / Q000235:genetics; D009362:Neoplasm Metastasis / Q000235:genetics*; D011401:Promoter Regions, Genetic / Q000235:genetics*; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D012097:Repressor Proteins / Q000235:genetics*; D020218:Response Elements / Q000235:genetics; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D014158:Transcription, Genetic / Q000235:genetics; D050986:YY1 Transcription Factor / Q000378:metabolism
chemical_list: D056970:Co-Repressor Proteins; D012333:RNA, Messenger; D012097:Repressor Proteins; C498445:TLE5 protein, human; C089462:Tle5 protein, mouse; D014157:Transcription Factors; D050986:YY1 Transcription Factor; C494698:YY1 protein, human; C506066:YY2 protein, human; C509847:YY2 protein, mouse
keywords: 
  AES
  ; CpG island; YY2; colon cancer; transcription