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

Molecular Cancer Research : MCR
Amr M GhalebVincent W Yang

Abstract

The 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 (Klf4(ΔIS)) in a genetic or pharmacological setting of colonic tumorigenesis:Apc(Min/⁺) mutation or carcinogen treatment with azoxymethane (AOM), respectively.Klf4 (ΔIS)/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 (ΔIS)/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 γH2AX, indicating DNA double-strand breaks. InKlf4 (ΔIS)/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 AO...Continue Reading

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Citations

Jun 28, 2017·Journal of Molecular Cell Biology·Hailiang TangY Gong
Dec 5, 2019·Communications Biology·Amr GhalebNatalia Marchenko
Dec 4, 2020·International Journal of Molecular Sciences·Agnieszka Taracha-WisniewskaTomasz Wilanowski
Jan 12, 2020·Communications Biology·Amr GhalebNatalia Marchenko
May 12, 2018·Journal of Proteome Research·Rob M EwingZhenghe Wang

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