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.
Keyphrases
- transcription factor
- poor prognosis
- cell death
- dna methylation
- nlrp inflammasome
- binding protein
- cancer therapy
- induced apoptosis
- cell cycle arrest
- rheumatoid arthritis
- randomized controlled trial
- genome wide
- long non coding rna
- cell proliferation
- oxidative stress
- signaling pathway
- single cell
- locally advanced
- radiation therapy
- squamous cell carcinoma
- stem cells
- genome wide identification
- copy number
- immune response
- toll like receptor
- endoplasmic reticulum stress