Epithelial-Mesenchymal Transition Induces GSDME Transcriptional Activation for Inflammatory Pyroptosis.
Epithelial-Mesenchymal Transition Induces GSDME Transcriptional Activation for Inflammatory Pyroptosis.
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上皮-间质转化诱导 GSDME 转录激活以治疗炎症性焦亡
DOI：
10.3389/fcell.2021.781365
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发表时间：
2021
影响因子：
5.5
通讯作者：
Zhuang G
中科院分区：
文献类型：
--
作者：
Jia C;Zhang Z;Tang J;Cai MC;Zang J;Shi K;Sun Y;Wu J;Shi H;Shi W;Ma P;Zhao X;Yu Z;Fu Y;Zhuang G
GSDME是一种新发现的细胞性上睑下垂的执行者，最近被认为与肿瘤生长和免疫有关。然而，对GSDME丰度背后的分子调控机制的了解仍然有限。在这里，我们进行了综合的生物信息学分析，发现在人类癌症中，上皮-间充质转化(EMT)基因特征与GSDME水平呈正相关。在多个实验模型中，EMT决定了GSDME可逆上调，这一观察结果支持了因果作用。从机制上讲，GSDME的转录激活是由核心EMT激活转录因子ZEB1/2直接驱动的，ZEB1/2与GSDME启动子区域结合。具有重要功能的是，在抗肿瘤药物作用下，间充质转分化衍生物中升高的GSDME发生蛋白分解，导致嗜酸细胞死亡和随之而来的细胞因子释放。综上所述，我们的发现明确了控制GSDME表达的关键转录机制，并指出了利用GSDME介导炎性下垂治疗间叶性恶性肿瘤的潜在治疗途径。
GSDME is a newly recognized executor of cellular pyroptosis, and has been recently implicated in tumor growth and immunity. However, knowledge about the molecular regulators underlying GSDME abundance remains limited. Here, we performed integrative bioinformatics analyses and identified that epithelial-mesenchymal transition (EMT) gene signatures exhibited positive correlation with GSDME levels across human cancers. A causal role was supported by the observation that EMT dictated GSDME reversible upregulation in multiple experimental models. Mechanistically, transcriptional activation of GSDME was directly driven by core EMT-activating transcription factors ZEB1/2, which bound to the GSDME promoter region. Of functional importance, elevated GSDME in mesenchymally transdifferentiated derivatives underwent proteolytic cleavage upon antineoplastic drug exposure, leading to pyroptotic cell death and consequent cytokine release. Taken together, our findings pinpointed a key transcriptional machinery controlling GSDME expression and indicated potential therapeutic avenues to exploit GSDME-mediated inflammatory pyroptosis for the treatment of mesenchymal malignancies.
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影响因子：
5.2
作者：
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通讯作者：
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Gao D