Transcription factor KLF4 suppresses the malignant progression of colorectal cancer by activating ETFDH transcription.

Abstract

Colorectal cancer (CRC) is a common cause of cancer-related deaths worldwide. Electron transfer flavoprotein dehydrogenase (ETFDH) is a novel prognostic biomarker for human CRC. However, the role and molecular mechanism of ETFDH in CRC are still unclear. DEGs in CRC development were identified using mRNA microarray datasets GSE23011, GSE44076, and GSE113513. Gene expression was determined using RT-qPCR and Western blot. Cell proliferation, migration, and invasion were detected by EdU, Colony formation, Transwell, and wound healing. Effects of CRC cells on CD8+ T cell apoptosis were analyzed using flow cytometry. Effects of ETFDH on CRC cell growth in vivo was analyzed using xenograft model. After JASPAR prediction, the binding between Transcription factor Kruppel-like factor 4 (KLF4) and ETFDH promoter was verified using ChIP and dual-luciferase reporter. ETFDH and KLF4 were decreased in CRC tissues and cells. ETFDH upregulation blocked CRC cell proliferation, migration, invasion, and repress the apoptosis of CD8+ T cells in vitro. ETFDH overexpression hindered CRC tumor growth in vivo. Mechanistically, KLF4 enhanced the transcriptional activity of ETFDH via binding to its promoter region. KLF4-activated ETFDH transcription suppresses CRC cell malignant behavior and decreases the apoptosis of CD8+T cells, which provides a promising therapeutic target for CRC.