Clioquinol Suppresses Cyclin D1 Gene Expression through Transcriptional and Post-transcriptional Mechanisms

Clioquinol, a metal-binding compound, has been shown to have anticancer activity in in vitro and in vivo model systems. This study investigated the effects of clioquinol on cyclin D1 gene expression in breast cancer cells. Treatment with clioquinol significantly reduced cyclin D1 protein levels in a concentration-dependent manner, effects being more pronounced in the presence of zinc. Clioquinol reduced cyclin D1 mRNA contents in cells that had been pre-treated with actinomycin D, indicating that this compound alters cyclin D1 mRNA stability, an event associated with post-transcriptional regulation. Using a cyclin D1 3'-UTR reporter construct (CCND1-3'-UTR), we confirmed that this 3'-UTR mediates the inhibitory action of clioquinol, likely through miR-302C. This study demonstrates for the first time that clioquinol targets post-transcriptional steps of cyclin D1 gene expression in cancer cells, adding new insight into our understanding of its mechanisms of anticancer action.