Histone deacetylase inhibitor induction of epithelial-mesenchymal transitions via up-regulation of Snail facilitates cancer progression

Histone deacetylase inhibitors (HDACIs) are now emerging as a new class of anticancer drugs. Some of them have been used in clinical treatment for tumors, most impressively in the hematological tumors. But their single-agent activities in epithelial-derived tumors are limited. The mechanisms of these actions of HDACIs are not yet well understood. In this study, it was found for the first time that HDACIs were able to induce epithelial-mesenchymal transitions (EMT) which is believed to trigger tumor cell invasion and metastasis. We show that HDACIs induce fibroblast-like morphology, up-regulate Snail and Vimentin and down-regulate E-cadherin in epithelial cell-derived tumor cell lines. It demonstrates that HDACI treatment enhances further Snail acetylation and reduces its ubiquitylation, and induces Snail transcription as well as Snail nuclear translocation in CNE2 cells. Snail knockdown by siRNAs prevents the change in cell morphology and Vimentin up-regulation in response to HDACIs. The results suggested that Snail plays an important role in the HDACI-induced EMT. It is very crucial for a better understanding of clinical therapeutical failure of HDACIs in the patients with epithelial cell-derived cancers. Therefore, our results indicate that more attention should be paid to the cancer treatment using HDACIs due to the fact that it will enhance the spread risks of cancer cells to facilitate cancer progression and it is very important to select appropriate drugs for different tumors. (C) 2012 Elsevier B.V. All rights reserved.