Expression of metastasis suppressor gene AES driven by a YY element in a CpG island promoter and transcription factor YY2

Abstract

We have recently found that the product of Amino-terminal enhancer of split (AES) gene functions as a metastasis suppressor of colorectal cancer (CRC) in both humans and mice. Expression of AES protein is significantly decreased in liver metastatic lesions compared with primary colon tumors. To investigate its down-regulation mechanism in metastases, we have searched for transcriptional regulators of AES in human CRC, and show 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 down-regulated. 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 in-del mutations in the coding or regulatory regions of the AES gene, CpG methylation in the AES promoter-enhancer, expression of microRNAs (miRNAs), chromatin histone modifications etc. 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.

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