Metastasis is a major cause of morbidity and mortality in solid cancers. Thus, delineating the molecular mechanisms that underpin the processes that enable tumour cells to spread to secondary organs is vital to fully understanding tumour progression and to the development of novel therapeutics. Epithelial to Mesenchymal Transition (EMT), a highly conserved developmental program, has been shown to facilitate the dissemination of tumour cells. By undergoing EMT, tumour cells can gain a migratory and invasive phenotype, allowing them to disseminate from the primary tumour and enter the circulation.
EMT is regulated by a core cassette of transcription factors including Zeb1, Snail, Slug, Twist and Zeb2. Their expression is regulated by several different growth factors, most notably TGF-beta. Once activated, this set of transcription factors repress epithelial cell marker expression, such as E-cadherin, and induce the expression of mesenchymal genes. While post-translational regulatory mechanisms of Snail, Slug, Twist and Zeb2 have been described; the regulation of Zeb1 protein is currently unknown.
Here, we show that Siah ubiquitin ligases regulate Zeb1 protein levels. The induction of EMT in MCF-7 and NMuMG cells results in the down-regulation of Siah protein, while the knockdown of Siah in MCF-7 cells results in the expression of a mesenchymal gene signature. In addition, the genetic knockout of Siah2 in murine epithelial breast cancer cells induces a mesenchymal phenotype. In breast cancer patients, Siah2 gene expression is inversely correlated with mesenchymal gene expression in breast cancer patients, and Zeb1 and Siah2 protein distribution is mutually exclusive in breast cancer tissues. These data demonstrate that Siah is a novel regulator of EMT by controlling Zeb1 protein levels.