Heat Shock Factor 1 (HSF1) Controls Chemoresistance and Autophagy through Transcriptional Regulation of Autophagy-related Protein 7 (ATG7)
Heat Shock Factor 1 (HSF1) Controls Chemoresistance and Autophagy through Transcriptional Regulation of Autophagy-related Protein 7 (ATG7)
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DOI：
10.1074/jbc.m112.422071
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发表时间：
2013-03-29
影响因子：
4.8
通讯作者：
Tan, Ming
中科院分区：
文献类型：
--
作者：
Desai, Shruti;Liu, Zixing;Tan, Ming
热休克因子1（HSF 1）是热休克反应的主要调节因子，在肿瘤发生中起重要作用。在这项研究中，我们证明了HSF 1是化疗药物诱导的细胞保护性自噬所必需的，通过转录上调自噬相关基因ATG 7。有趣的是，这与HSF 1的热休克反应功能无关。用FDA批准的化疗剂卡铂处理癌细胞诱导自噬和生长抑制，其在HSF 1敲低后显著增加。机制研究表明，HSF 1通过直接结合ATG 7启动子并转录上调其表达来调节自噬。值得注意的是，乳腺癌患者样本研究显示，较高的ATG 7表达水平与患者存活率低相关。这一新的发现通过对两个独立的患者数据库的分析得到进一步证实，证明了ATG 7的预后价值。此外，在三阴性乳腺癌患者样本中观察到HSF 1和ATG 7水平之间存在强正相关性，从而验证了我们的体外研究结果。这是第一项确定HSF 1通过调节ATG 7在控制细胞保护性自噬中的关键作用的研究，这与HSF 1在热休克反应中的功能不同。这也是第一项证明ATG 7在乳腺癌患者中的预后价值的研究。这些发现有力地证明，通过抑制HSF 1/ATG 7轴将化疗药物与自噬抑制相结合代表了未来癌症治疗的有希望的策略。
Heat shock factor 1 (HSF1), a master regulator of heat shock responses, plays an important role in tumorigenesis. In this study we demonstrated that HSF1 is required for chemotherapeutic agent-induced cytoprotective autophagy through transcriptional up-regulation of autophagy-related gene ATG7. Interestingly, this is independent of the HSF1 heat shock response function. Treatment of cancer cells with the FDA-approved chemotherapeutic agent carboplatin induced autophagy and growth inhibition, which were significantly increased upon knockdown of HSF1. Mechanistic studies revealed that HSF1 regulates autophagy by directly binding to ATG7 promoter and transcriptionally up-regulating its expression. Significantly, breast cancer patient sample study revealed that a higher ATG7 expression level is associated with poor patient survival. This novel finding was further confirmed by analysis of two independent patient databases, demonstrating a prognostic value of ATG7. Furthermore, a strong positive correlation was observed between levels of HSF1 and ATG7 in triple-negative breast cancer patient samples, thus validating our in vitro findings. This is the first study identifying a critical role for HSF1 in controlling cytoprotective autophagy through regulation of ATG7, which is distinct from the HSF1 function in the heat shock response. This is also the first study demonstrating a prognostic value of ATG7 in breast cancer patients. These findings strongly argue that combining chemotherapeutic agents with autophagy inhibition by repressing HSF1/ATG7 axis represents a promising strategy for future cancer treatment.