Suberoylanilide hydroxamic acid (SAHA) promotes the epithelial mesenchymal transition of triple negative breast cancer cells via HDAC8/FOXA1 signals
Suberoylanilide hydroxamic acid (SAHA) promotes the epithelial mesenchymal transition of triple negative breast cancer cells via HDAC8/FOXA1 signals
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辛二酰苯胺异羟肟酸 (SAHA) 通过 HDAC8/FOXA1 信号促进三阴性乳腺癌细胞的上皮间质转化
DOI：
10.1515/hsz-2015-0215
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发表时间：
2016-01-01
影响因子：
3.7
通讯作者：
He, Yu-Wen
中科院分区：
文献类型：
--
作者：
Wu, Shao;Luo, Zhi;He, Yu-Wen
摘要组蛋白去乙酰化酶抑制剂（HDACIs）对三阴性乳腺癌（TNBC）患者具有重要的治疗价值。有趣的是，我们目前的研究表明，辛二酰苯胺异羟肟酸（SAHA），最先进的泛HDAC抑制剂之一，可以明显促进MDA-MB-231和BT-549细胞的体外运动，通过诱导上皮间质转化（EMT）。SAHA处理显著下调上皮标志物E-钙粘蛋白（E-Cad）的表达，而上调间充质标志物N-钙粘蛋白（N-Cad）、波形蛋白（Vim）和纤连蛋白（FN）的表达。SAHA对EMT相关转录因子Snail、Slug、Twist和ZEB的表达和核转位无影响。而SAHA处理则下调FOXA 1蛋白和mRNA的表达，进而减少其核转位。F0 XA 1的过表达显著减弱SAHA诱导的TNBC细胞的EMT。此外，HDAC 8的沉默而不是HDAC 6的沉默证实了用SAHA处理的MDA-MB-231细胞中FOXA 1的下调和N-Cad和Vim的上调。总之，SAHA可以通过HDAC 8/FOXA 1信号通路促进TNBC细胞的EMT，提示SAHA作为抗癌药物用于肿瘤治疗时应引起更多的关注。
Abstract Inhibitor of histone deacetylases (HDACIs) have great therapeutic value for triple negative breast cancer (TNBC) patients. Interestingly, our present study reveals that suberoyl anilide hydroxamic acid (SAHA), one of the most advanced pan-HDAC inhibitor, can obviously promote in vitro motility of MDA-MB-231 and BT-549 cells via induction of epithelial-mesenchymal transition (EMT). SAHA treatment significantly down-regulates the expression of epithelial markers E-cadherin (E-Cad) while up-regulates the mesenchymal markers N-cadherin (N-Cad), vimentin (Vim) and fibronectin (FN). However, SAHA has no effect on the expression and nuclear translocation of EMT related transcription factors including Snail, Slug, Twist and ZEB. While SAHA treatment down-regulates the protein and mRNA expression of FOXA1 and then decreases its nuclear translocation. Over-expression of FOXA1 markedly attenuates SAHA induced EMT of TNBC cells. Further, silence of HDAC8, while not HDAC6, alleviates the down-regulation of FOXA1 and up-regulation of N-Cad and Vim in MDA-MB-231 cells treated with SAHA. Collectively, our present study reveals that SAHA can promote EMT of TNBC cells via HDAC8/FOXA1 signals, which suggests that more attention should be paid when SAHA is used as anti-cancer agent for cancer treatment.