Activation of KIT signaling promotes early tumorigenesis through the AP-1 pathway in APC/TP53 double-knockout human colon organoids.

Authors

Younghee Choi, Eunju Kim, Soo-Yeon Cho, Jihyun Park, Youngwon Cho, Sungho Kim, Sang-Hyun Song, Tae-You Kim

Published in

Cell death & disease. Jul 04, 2026. Epub Jul 04, 2026.

Abstract

Colorectal cancer (CRC) develops through a series of progressive genetic mutations, with alterations in APC and TP53 being the most frequently observed in the early stages. Although the loss of APC is recognized as a significant initiating event, the epigenetic processes through which the simultaneous inactivation of APC and TP53 facilitates the onset of colorectal tumorigenesis remain poorly characterized. To address this gap, we developed a human colon organoid model using CRISPR-Cas9 to achieve a double knockout of APC and TP53. Through extensive multi-omics profiling, we characterized the epigenetic landscape distinctive of early-stage CRC. We identified KIT, a receptor tyrosine kinase, as a critical oncogenic driver that is significantly upregulated in ΔDKO (APC and TP53 double knockout) organoids, thereby activating the MAPK and Wnt signaling pathways to augment proliferation and tumorigenesis. Furthermore, AP-1 transcription factors (FOS/JUN) regulate KIT expression via chromatin remodeling. Functional analyses indicated that KIT is integral to sustaining the elevated proliferation rates observed in ΔDKO organoids. These findings reveal a novel AP-1/KIT signaling axis that is central to the early progression of CRC, thereby presenting a promising avenue for therapeutic intervention.

PMID:
42401564
Bibliographic data and abstract were imported from PubMed on 05 Jul 2026.

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