Epithelial-Mesenchymal Transition Induces GSDME Transcriptional Activation for Inflammatory Pyroptosis
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 epithel...
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Frontiers Media S.A.
2021
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oai:doaj.org-article:8a9728e0f19446ac8ee076f4facdeab52021-12-01T05:39:02ZEpithelial-Mesenchymal Transition Induces GSDME Transcriptional Activation for Inflammatory Pyroptosis2296-634X10.3389/fcell.2021.781365https://doaj.org/article/8a9728e0f19446ac8ee076f4facdeab52021-11-01T00:00:00Zhttps://www.frontiersin.org/articles/10.3389/fcell.2021.781365/fullhttps://doaj.org/toc/2296-634XGSDME 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.Chenqiang JiaChenqiang JiaZhuqing ZhangZhuqing ZhangJun TangMei-Chun CaiJingyu ZangKaixuan ShiYunheng SunJie WuHailei ShiWeiping ShiPengfei MaXiaojing ZhaoZhuang YuYujie FuGuanglei ZhuangGuanglei ZhuangFrontiers Media S.A.articleepithelial-mesenchymal transitionGSDMEtranscription activationpyroptosisZEB1/2Biology (General)QH301-705.5ENFrontiers in Cell and Developmental Biology, Vol 9 (2021) |
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DOAJ |
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EN |
| topic |
epithelial-mesenchymal transition GSDME transcription activation pyroptosis ZEB1/2 Biology (General) QH301-705.5 |
| spellingShingle |
epithelial-mesenchymal transition GSDME transcription activation pyroptosis ZEB1/2 Biology (General) QH301-705.5 Chenqiang Jia Chenqiang Jia Zhuqing Zhang Zhuqing Zhang Jun Tang Mei-Chun Cai Jingyu Zang Kaixuan Shi Yunheng Sun Jie Wu Hailei Shi Weiping Shi Pengfei Ma Xiaojing Zhao Zhuang Yu Yujie Fu Guanglei Zhuang Guanglei Zhuang Epithelial-Mesenchymal Transition Induces GSDME Transcriptional Activation for Inflammatory Pyroptosis |
| description |
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. |
| format |
article |
| author |
Chenqiang Jia Chenqiang Jia Zhuqing Zhang Zhuqing Zhang Jun Tang Mei-Chun Cai Jingyu Zang Kaixuan Shi Yunheng Sun Jie Wu Hailei Shi Weiping Shi Pengfei Ma Xiaojing Zhao Zhuang Yu Yujie Fu Guanglei Zhuang Guanglei Zhuang |
| author_facet |
Chenqiang Jia Chenqiang Jia Zhuqing Zhang Zhuqing Zhang Jun Tang Mei-Chun Cai Jingyu Zang Kaixuan Shi Yunheng Sun Jie Wu Hailei Shi Weiping Shi Pengfei Ma Xiaojing Zhao Zhuang Yu Yujie Fu Guanglei Zhuang Guanglei Zhuang |
| author_sort |
Chenqiang Jia |
| title |
Epithelial-Mesenchymal Transition Induces GSDME Transcriptional Activation for Inflammatory Pyroptosis |
| title_short |
Epithelial-Mesenchymal Transition Induces GSDME Transcriptional Activation for Inflammatory Pyroptosis |
| title_full |
Epithelial-Mesenchymal Transition Induces GSDME Transcriptional Activation for Inflammatory Pyroptosis |
| title_fullStr |
Epithelial-Mesenchymal Transition Induces GSDME Transcriptional Activation for Inflammatory Pyroptosis |
| title_full_unstemmed |
Epithelial-Mesenchymal Transition Induces GSDME Transcriptional Activation for Inflammatory Pyroptosis |
| title_sort |
epithelial-mesenchymal transition induces gsdme transcriptional activation for inflammatory pyroptosis |
| publisher |
Frontiers Media S.A. |
| publishDate |
2021 |
| url |
https://doaj.org/article/8a9728e0f19446ac8ee076f4facdeab5 |
| work_keys_str_mv |
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