Abstract 4309: DYRK2 regulates cancer invasiveness via Snail/E-cadherin pathway

Abstract

Abstract Epithelial-mesenchymal transition (EMT) is characterized by the loss of cellular adhesion molecule E-cadherin, and plays a fundamental role during early steps of invasion and metastasis. An important regulator of E-cadherin expression is Snail, a zinc-finger transcriptional repressor. Snail is phosphorylated by GSK3-α and then degraded by α-TrCP-mediated ubiquitination. Here we describe another kinase, DYRK2, acts as a priming kinase for snail whose phosphorylation is required for the subsequent GSK3&gamma phosphorylation and proteasomal degradation. Inhibition of DYRK2 expression by siRNA results in up-regulation of Snail and down-regulation of E-cadherin. The expression of fibroblast mrakers, vimentin and fibronectin, emerged in these cells. Furthermore, the invasiveness of MCF7 cells was increased by stable DYRK2 silencing by shRNA. Tumors expressing DYRK2-shRNA robustly formed metastases in nude mice bones, while those expressing control-shRNA little if any. In human breast cancer tissues, DYRK2 exhibits an inverse correlation with the expression of Snail. Conversely, low level expression of DYRK2 is associated with down regulation of E-cadherin. The patiens with tumors expressed low DYRK2 showed significantly poor prognosis and short disease-free survival. These results demonstrate that DYRK2 regulates cancer invasiveness and metastasis via Snail/E-cadherin pathway in human breast cancer. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 4309. doi:1538-7445.AM2012-4309