Transcription factor Sp1 transcriptionally enhances GSDME expression for pyroptosis

作者：Jiasong Pan, Yuanyuan Li, Wenqing Gao, Qizhou Jiang, Lu Geng, Jin Ding, Suhua Li, Jixi Li · 发表于：Cell Death and Disease · 年份：2024 · DOI：10.1038/s41419-024-06455-6 · 被引用次数：42 · 研究领域：Inflammasome and immune disorders、interferon and immune responses、Toxoplasma gondii Research Studies

Gasdermin-E (GSDME), the executioner of pyroptosis when cleaved by caspase 3, plays a crucial role in tumor defense and the response to chemotherapy drugs in cells. So far, there are poorly known mechanisms for the expression regulation of GSDME during cell death. Here, we identify the transcription factor Sp1 (Specificity protein 1) as a positive regulator of GSDME-mediated pyroptosis. Sp1 directly interacts with the GSDME promoter at -36 ~ -28 site and promotes GSDME gene transcription. Further, Sp1 knockdown or inhibition suppresses GSDME expression, thus reducing chemotherapy drugs (topotecan, etoposide, doxorubicin, sorafinib and cisplatin) induced cell pyroptosis. The regulation process synergizes with STAT3 (Signal transducer and activator of transcription 3) activity and antagonizes with DNA methylation but barely affects GSDMD-mediated pyroptosis or TNF-induced necroptosis. Our current finding reveals a new regulating mechanism of GSDME expression, which may be a viable target for the intervention of GSDME-dependent inflammatory diseases and cancer therapy.