Activation of KIT signaling promotes early tumorigenesis through the AP-1 pathway in APC/TP53 double-knockout human colon organoidsDownload PDF Download PDF ArticleOpen accessPublished: 04 July 2026Younghee Choi ORCID: orcid.org/0009-0002-8806-88451,2,Eunju Kim1,2,Soo-Yeon Cho2,Jihyun Park1,2,Youngwon Cho1,2,Sungho Kim3,Sang-Hyun Song2 &…Tae-You Kim ORCID: orcid.org/0009-0006-6039-63361,2,4 Cell Death & Disease (2026) Cite this article We are providing an unedited version of this manuscript to give early access to its findings. Before final publication, the manuscript will undergo further editing. Please note there may be errors present which affect the content, and all legal disclaimers apply.SubjectsChromatin remodellingColon cancerAbstractColorectal 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.AcknowledgementsThe authors are grateful to all members of our group for their helpful advice.FundingMinistry of Science and ICT grant 2016R1D1A1B03930736. Ministry of Science and ICT grant 2017M3A9A7050610.Author informationAuthors and AffiliationsDepartment of Molecular Medicine and Biopharmaceutical Sciences, Graduate School of Convergence Science and Technology, Seoul National University, Seoul, Republic of KoreaYounghee Choi, Eunju Kim, Jihyun Park, Youngwon Cho & Tae-You KimCancer Genomics Research Laboratory, Cancer Research Institute, Seoul National University, Seoul, Republic of KoreaYounghee Choi, Eunju Kim, Soo-Yeon Cho, Jihyun Park, Youngwon Cho, Sang-Hyun Song & Tae-You KimState University of New York Upstate Medical University, Syracuse, NY, USASungho KimDepartment of Internal Medicine, Seoul National University Hospital, Seoul, Republic of KoreaTae-You KimAuthorsYounghee ChoiView author publicationsSearch author on:PubMed Google ScholarEunju KimView author publicationsSearch author on:PubMed Google ScholarSoo-Yeon ChoView author publicationsSearch author on:PubMed Google ScholarJihyun ParkView author publicationsSearch author on:PubMed Google ScholarYoungwon ChoView author publicationsSearch author on:PubMed Google ScholarSungho KimView author publicationsSearch author on:PubMed Google ScholarSang-Hyun SongView author publicationsSearch author on:PubMed Google ScholarTae-You KimView author publicationsSearch author on:PubMed Google ScholarCorresponding authorCorrespondence to Tae-You Kim.Ethics declarationsCompeting interestsThe authors declare no competing interests.Additional informationPublisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.Edited by Professor Giorgio StassiSupplementary informationoriginal data (download PDF )supplementary figures (download DOCX )Rights and permissionsOpen Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.Reprints and permissionsAbout this articleDownload PDF