Expression of metastasis suppressor gene AES driven by a 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 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.