Molecular mechanisms of Kruppel-like Factor 4

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The Wnt/beta-catenin pathway is a key pathway involved in the regulation of proliferation and differentiation within many tissues, including the epithelium of the intestine and of the skin. Wnt signaling is implicated in stem cell renewal. Deregulation of Wnt/beta-catenin signaling is crucial early event in colorectal tumorigenesis. Earlier work in our lab demonstrated that Kruppel-like factor 4 (KLF4) interacts with beta-catenin in vivo, repressing Wnt signaling and inhibiting tumor growth. KLF4 is an anti-proliferative transcription factor expressed in differentiated epithelial cells in the intestine. Previous studies clearly establish KLF4 as a tumor suppressor in colorectal cancer. Expression of KLF4 is downregulated in colorectal tumors, and heterozygous deletion of the Klf4 allele in a mouse model of colorectal cancer results in the formation of approximately 50% more tumors. In addition, KLF4 is important in stem cell programming. KLF4, in combination with three additional transcription factors, is sufficient to reprogram differentiated fibroblasts into embryonic stem cells. This dissertation focuses on the molecular mechanisms of KLF4-mediated transcription, both in the context of KLF4-mediated activation and KLF4-mediated repression. I demonstrate that the N-terminal transactivation domain of KLF4 recruits the co-activator p300/CBP to the promoter of the positively-regulated gene IAP, resulting in increased histone acetylation. On the negatively regulated gene, Cyclin B1, I demonstrate that KLF4 recruits HDAC3, decreasing histone acetylation. In addition, I show that KLF4 is acetylated by p300/CBP, and that acetylation of KLF is important in the activation of target genes as well as its ability to inhibit proliferation. I demonstrate that KLF4 inhibits Wnt/â-catenin signaling by blocking beta-catenin-mediated recruitment of p300/CBP to Wnt-regulated genes. Finally, I show that acetylation of beta-catenin is important in its ability to interact with p300/CBP and that KLF4 inhibits beta-catenin acetylation. These studies provide significant insight into the molecular mechanisms of KLF4-mediated transcription, and will prove useful in the development of targeted therapies for colorectal cancer as well as providing a deeper understanding of the mechanisms behind stem cell reprogramming.

wnt, p300/CBP, KLF4, colon cancer, beta-catenin