HSF1 upregulates ATG4B expression and enhances epirubicin-induced protective autophagy in hepatocellular carcinoma cells
HSF1 upregulates ATG4B expression and enhances epirubicin-induced protective autophagy in hepatocellular carcinoma cells
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HSF1上调ATG4B表达并增强表阿霉素诱导的肝细胞癌细胞保护性自噬
DOI：
10.1016/j.canlet.2017.08.039
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发表时间：
2017-11-28
期刊：
影响因子：
9.7
通讯作者：
He, Fengtian
中科院分区：
文献类型：
--
作者：
Zhang, Nan;Wu, Yaran;He, Fengtian
大量研究表明，热休克转录因子1（HSF 1）和自噬均能降低肝癌细胞对化疗药物的敏感性。然而，HSF 1是否与自噬在调节肝癌细胞化疗敏感性方面相关仍然知之甚少。本研究首次证明HSF 1通过增强表阿霉素（epirrhosis，EPI）诱导的保护性自噬，显著减弱EPI对肝癌细胞的杀伤作用。HSF 1上调HCC细胞中自噬相关的4 B（ATG 4 B），这增强了EPI触发的保护性自噬。报告基因分析表明，HSF 1能增强ATG 4 B基因启动子的转录活性，染色质免疫沉淀分析证实HSF 1与ATG 4 B基因启动子区的-1429 ~-1417位点结合。裸鼠体内实验表明，HSF 1或ATG 4 B基因的敲除可增强EPI的体内抗肝癌作用。综上所述，HSF 1通过促进ATG 4 B的转录而提高其表达水平，从而通过增强保护性自噬而增强EPI对肝癌细胞的敏感性，提示“HSF 1/ATG 4 B/保护性自噬”通路可能成为肝癌化疗增敏策略的新靶点。(C)2017爱思唯尔B. V.保留所有权利。
Considerable evidences have shown that both heat shock transcription factor 1 (HSF1) and autophagy can attenuate the sensitivity of hepatocellular carcinoma (HCC) cells to chemotherapeutic reagents. However, it is still little known whether HSF1 is associated with autophagy in regulating the chemosensitivity of HCC cells. In this study, we for the first time demonstrated that HSF1 markedly attenuated the killing effect of epirubicin (EPI) to HCC cells via enhancing the EPI-induced protective autophagy. Mechanistically, HSF1 upregulated autophagy related 4B (ATG4B) in HCC cells, which enhanced the EPI-triggered protective autophagy. Reporter assay showed that HSF1 increased the transcriptional activity of ATG4B gene promoter, and chromatin immunoprecipitation assay verified that HSF1 bound to the site (-1429 to -1417) in ATG4B gene promoter region. The experiments in nude mice showed that knockdown of HSF1 or ATG4B strengthened the anti-HCC effect of EPI in vivo. Collectively, these results revealed that HSF1 elevates ATG4B via promoting its transcription, which alleviates the sensitivity of EPI in HCC cells through enhancing protective autophagy, suggesting that the "HSF1/ATG4B/protective autophagy" pathway may be a novel target for developing sensitizing strategy to HCC chemotherapy. (C) 2017 Elsevier B.V. All rights reserved.