15417786mcr150410-sup-156380_2_supp_3328632_j1mj39.png (533.24 kB)
Supplementary Figure 1 from KLF4 Suppresses Tumor Formation in Genetic and Pharmacological Mouse Models of Colonic Tumorigenesis
figureposted on 2023-04-03, 17:10 authored by Amr M. Ghaleb, Enas A. Elkarim, Agnieszka B. Bialkowska, Vincent W. Yang
Klf4Î”IS/ApcMin/+ mice develop significantly more small intestinal adenomas than Klf4fl/fl/ApcMin/+ mice.
ARTICLE ABSTRACTThe zinc finger transcription factor Krüppel-like factor 4 (KLF4) is frequently downregulated in colorectal cancer. Previous studies showed that KLF4 is a tumor suppressor in the intestinal tract and plays an important role in DNA damage-repair mechanisms. Here, the in vivo effects of Klf4 deletion were examined from the mouse intestinal epithelium (Klf4ΔIS) in a genetic or pharmacological setting of colonic tumorigenesis: ApcMin/+ mutation or carcinogen treatment with azoxymethane (AOM), respectively. Klf4ΔIS/ApcMin/+ mice developed significantly more colonic adenomas with 100% penetrance as compared with ApcMin/+ mice with intact Klf4 (Klf4fl/fl/ApcMin/+). The colonic epithelium of Klf4ΔIS/ApcMin/+ mice showed increased mTOR pathway activity, together with dysregulated epigenetic mechanism as indicated by altered expression of HDAC1 and p300. Colonic adenomas from both genotypes stained positive for γH2AX, indicating DNA double-strand breaks. In Klf4ΔIS/ApcMin/+ mice, this was associated with reduced nonhomologous end joining (NHEJ) repair and homologous recombination repair (HRR) mechanisms as indicated by reduced Ku70 and Rad51 staining, respectively. In a separate model, following treatment with AOM, Klf4ΔIS mice developed significantly more colonic tumors than Klf4fl/fl mice, with more Klf4ΔIS mice harboring K-Ras mutations than Klf4fl/fl mice. Compared with AOM-treated Klf4fl/fl mice, adenomas of treated Klf4ΔIS mice had suppressed NHEJ and HRR mechanisms, as indicated by reduced Ku70 and Rad51 staining. This study highlights the important role of KLF4 in suppressing the development of colonic neoplasia under different tumor-promoting conditions.Implications: The study demonstrates that KLF4 plays a significant role in the pathogenesis of colorectal neoplasia. Mol Cancer Res; 14(4); 385–96. ©2016 AACR.
CarcinogenesisAnimal models of carcinogenesisDNA damage and repairPremalignancyTumor initiation and promotionCell CycleCell cycle checkpointsGastrointestinal CancersColorectal cancerGene RegulationMechanisms of transcriptionOncogenes & Tumor SuppressorsAPCTumor suppressor genesPreclinical ModelsAnimal models of cancerProgression, Invasion & MetastasisTumor progression