KLF4 Suppresses Tumor Formation in Genetic and Pharmacological Mouse Models of Colonic Tumorigenesis

摘要

The zinc finger transcription factor Kruppel-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 (Klf4(Delta IS)) in a genetic or pharmacological setting of colonic tumorigenesis: Apc(Min/+) mutation or carcinogen treatment with azoxymethane (AOM), respectively. Klf4(Delta IS)/Apc(Min/+) mice developed significantly more colonic adenomas with 100% penetrance as compared with Apc(Min/+) mice with intact Klf4 (Klf4(fl/fl)/Apc(Min/+)). The colonic epithelium of Klf4(Delta IS)/Apc(Min/+) 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 gamma H2AX, indicating DNA double-strand breaks. In Klf4(Delta IS)/Apc(Min/+) 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, Klf4(Delta IS) mice developed significantly more colonic tumors than Klf4(fl/fl) mice, with more Klf4(Delta IS) mice harboring K-Ras mutations than Klf4(fl/fl) mice. Compared with AOM-treated Klf4(fl/fl) mice, adenomas of treated Klf4(Delta IS) 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.