Transcription factor Sp1 transcriptionally enhances GSDME expression for pyroptosis

Area of Science:

• Molecular Biology
• Cell Biology
• Immunology

Background:

• Gasdermin-E (GSDME) is essential for pyroptosis, a programmed cell death pathway critical in tumor defense and chemotherapy response.
• Mechanisms regulating GSDME expression during cell death remain largely unknown.

Purpose of the Study:

• To identify and characterize novel regulators of GSDME gene expression.
• To elucidate the role of transcription factors in controlling GSDME-mediated pyroptosis.

Main Methods:

• Luciferase reporter assays to assess promoter activity.
• Chromatin immunoprecipitation to confirm Sp1 binding to the GSDME promoter.
• Western blotting and quantitative PCR to measure GSDME expression levels.
• Cell viability assays and pyroptosis assessment following drug treatment and Sp1 manipulation.

Main Results:

• Specificity protein 1 (Sp1) was identified as a positive regulator of GSDME expression.
• Sp1 directly binds to the GSDME promoter region (-36 to -28) and enhances its transcription.
• Sp1 knockdown or inhibition significantly reduced GSDME expression and chemotherapy-induced pyroptosis.
• This regulation synergizes with STAT3 activity and is antagonized by DNA methylation.

Conclusions:

• Sp1 is a novel positive regulator of GSDME-mediated pyroptosis.
• Understanding Sp1-GSDME interaction provides insights into GSDME regulation during cell death.
• This pathway represents a potential therapeutic target for GSDME-dependent inflammatory diseases and cancer therapy.