1. ¹Department of Biochemistry and Cancer Biology, College of Medicine, University of Toledo, Toledo, OH, USA
2. ²University of Michigan Comprehensive Cancer Center, University of Michigan Health System, Ann Arbor, MI, USA
3. ³Department of Urology, University of Michigan Health System, Ann Arbor, MI, USA
4. ⁴The Beatson Institute for Cancer Research, Glasgow, UK
5. ⁵Sir Henry Wellcome Functional Genomic Facility, University of Glasgow, Glasgow, UK

Correspondence: Dr KC Yeung, Department of Biochemistry and Cancer Biology, College of Medicine, University of Toledo, Health Science Campus, BHSB Room 469, 3035 Arlington Avenue, Toledo, OH 43614-5804, USA. E-mail: kam.yeung@utoledo.edu

⁶These authors contributed equally to this work.

Received 29 August 2007; Revised 18 September 2007; Accepted 18 September 2007; Published online 22 October 2007.

Abstract

Diminished expression of the metastasis suppressor protein RKIP was previously reported in a number of cancers. The underlying mechanism remains unknown. Here, we show that the expression of RKIP negatively correlates with that of Snail zinc-transcriptional repressor, a key modulator of normal and neoplastic epithelial–mesenchymal transition (EMT) program. With a combination of loss-of-function and gain-of-function approaches, we showed that Snail repressed the expression of RKIP in metastatic prostate cancer cell lines. The effect of Snail on RKIP was on the level of transcriptional initiation and mediated by a proximal E-box on the RKIP promoter. Our results therefore suggest that RKIP is a novel component of the Snail transcriptional regulatory network important for the progression and metastasis of cancer.