Novel Cross Talk of Krüppel-Like Factor 4 and β-Catenin Regulates Normal Intestinal Homeostasis and Tumor Repression

Abstract

Epithelial cells of the intestinal mucosa undergo a continual process of proliferation, differentiation, and apoptosis which is regulated by multiple signaling pathways. The Wnt/β-catenin pathway plays a critical role in this process. Mutations in the Wnt pathway, however, are associated with colorectal cancers. Krüppel-like factor 4 (KLF4) is an epithelial transcriptional factor that is down-regulated in many colorectal cancers. Here, we show that KLF4 interacts with β-catenin and represses β-catenin-mediated gene expression. Moreover, KLF4 inhibits the axis formation of Xenopus embryos and inhibits xenograft tumor growth in athymic nude mice. Our findings suggest that the cross talk of KLF4 and β-catenin plays a critical role in homeostasis of the normal intestine as well as in tumorigenesis of colorectal cancers.

Supplemental material for this article may be found at http://mcb.asm.org/.

We thank Hans Clevers, Mark van de Wetering, Scott L. Friedman, and Bert Vogelstein for stable cell lines and plasmids; Mark Hellmich and Qingding Wang for helpful discussions; and Xiaofu Wang, Zhaoyong (Daniel) Hu, and Hui-Qun Wang for technical assistance.

The tandem affinity purification of β-catenin complex was initiated by C.L. in the laboratory of X.H., who is supported by R01 GM057603 and R01 GM074241 from the National Institutes of Health (NIH); X.H. is a W. M. Keck Foundation Distinguished Young Scholar. V.W.Y. is supported by R01 DK52230 and R01 CA84197 from NIH. B.M.E. is supported by R01 DK48498, R01 CA104748, and P01 DK35608 from the NIH. C.L. is supported by a John Sealy Memorial Fund Recruitment Award and by R21 CA112007 from the NIH.