Histone deacetylase inhibitor induction of epithelial-mesenchymal transitions via up-regulation of Snail facilitates cancer progression
Histone deacetylase inhibitor induction of epithelial-mesenchymal transitions via up-regulation of Snail facilitates cancer progression
复制标题
组蛋白脱乙酰酶抑制剂通过上调 Snail 诱导上皮间质转化促进癌症进展
DOI：
10.1016/j.bbamcr.2012.12.002
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发表时间：
2013-03-01
影响因子：
5.1
通讯作者：
Du, Jun
中科院分区：
文献类型：
--
作者：
Jiang, Guan-Min;Wang, Hong-Sheng;Du, Jun
组蛋白去乙酰化酶抑制剂（HDACIs）是目前新兴的一类抗肿瘤药物。其中一些已被用于肿瘤的临床治疗，最令人印象深刻的是在血液肿瘤。但它们在上皮来源的肿瘤中的单一药物活性是有限的。HDACIs的这些作用机制尚未完全了解。在这项研究中，首次发现HDACIs能够诱导上皮-间质转化（EMT），这被认为是触发肿瘤细胞侵袭和转移的原因。我们发现HDACIs诱导成纤维细胞样形态，上调Snail和波形蛋白，下调上皮细胞来源的肿瘤细胞系中的E-钙粘蛋白。这表明HDACI处理进一步增强Snail乙酰化并减少其泛素化，并诱导CNE 2细胞中的Snail转录以及Snail核转位。通过siRNA敲除Snail阻止了细胞形态学的变化和波形蛋白响应HDACI的上调。提示Snail在HDACI诱导的EMT中起重要作用。这对于更好地理解HDACIs在上皮细胞源性癌症患者中的临床治疗失败是非常重要的。因此，我们的研究结果表明，应更多地关注使用HDACIs的癌症治疗，因为它会增加癌细胞的扩散风险，促进癌症的进展，并且针对不同的肿瘤选择合适的药物非常重要。(C)2012爱思唯尔有限公司版权所有。
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.