CHI-KAT8i5 suppresses ESCC tumor growth by inhibiting KAT8-mediated c-Myc stability

Area of Science:

• Oncology
• Molecular Biology
• Epigenetics

Background:

• Histone modifier enzymes play crucial roles in cancer, but their specific involvement in esophageal squamous cell carcinoma (ESCC) remains understudied.
• Identifying novel prognostic and therapeutic targets is essential for improving ESCC patient outcomes.

Purpose of the Study:

• To investigate the role of histone modifier enzymes in ESCC.
• To identify KAT8 (lysine acetyltransferase 8) as a potential biomarker and therapeutic target for ESCC.

Main Methods:

• Analysis of histone modifier enzyme expression in ESCC tissues.
• In vivo studies using genetically modified mice with esophageal-tissue-specific KAT8 deletion.
• In vitro and in vivo experiments involving KAT8 silencing in cell-line-derived xenograft (CDX) and patient-derived xenograft (PDX) models.
• Investigation of KAT8's mechanism of action on c-Myc protein stability.
• Design and screening of a specific KAT8 inhibitor (CHI-KAT8i5).

Main Results:

• KAT8 was identified as a significant prognostic and therapeutic biomarker in ESCC.
• Esophageal-specific deletion of KAT8 reduced tumor burden in mice.
• KAT8 silencing suppressed tumor growth in CDX and PDX models.
• KAT8 directly binds and regulates c-Myc protein stability.
• The developed KAT8 inhibitor (CHI-KAT8i5) significantly inhibited tumor growth in vitro and in vivo.

Conclusions:

• KAT8 is a potential clinically relevant biomarker and therapeutic target for ESCC.
• Targeting KAT8 with inhibitors like CHI-KAT8i5 presents a promising therapeutic strategy for ESCC patients.