Work

KLF13-mediated CES2 upregulation via p300-dependent acetylation sensitizes gastric cancer cells to irinotecan

Year: 2025

Type: article

Abstract: Irinotecan (CPT-11) is a key chemotherapeutic agent for gastric cancer (GC), but its efficacy is limited by variable patient responses. The activation of CPT-11 to its active form, SN-38, depends on the enzyme carboxylesterase 2 (CES2), yet the regulation of CES2 in GC is poorly understood. Here, we identify Krüppel-like factor 13 (KLF13) as a direct transcriptional activator of CES2. We show that KLF13 expression correlates with CES2 levels and treatment response in GC patients. Mechanistically, KLF13 binds to specific elements in the CES2 promoter to drive its expression. This function of KLF13 is critically dependent on its acetylation by the co-activator p300, as demonstrated by site-directed mutagenesis and p300 inhibition. Functionally, the KLF13-CES2 axis dictates cellular sensitivity to CPT-11. Our findings unveil a p300-KLF13-CES2 signaling pathway that governs irinotecan sensitivity, providing potential predictive biomarkers and therapeutic targets for GC.

Source: iScience

DOI: 10.1016/j.isci.2025.114199

Authors: Hai-bin Zhang, Ren-hao Hu, Ke-hui Zhang, Xi-mao Cui, Shun Zhang

Institutions: Tongji University, Shanghai East Hospital

Language: English

Topic: Kruppel-like factors research

Subfield: Molecular Biology

Field: Biochemistry, Genetics and Molecular Biology

Domain: Life Sciences

SDG: Good health and well-being

Open Access status: gold

Estimated APC paid: $3,240