Regulation of the Potential Marker for Intestinal Cells, Bmi1, by β-Catenin and the Zinc Finger Protein KLF4

Tianxin Yu,Xi Chen,Wen Zhang,Deannon Colon,Jiandang Shi,Dana Napier,Piotr Rychahou,Wange Lu,Eun Y Lee,Heidi L Weiss,B Mark Evers,Chunming Liu

doi:10.1074/jbc.m111.316349

Abstract

B lymphoma Mo-MLV insertion region 1 (Bmi1) is a Polycomb Group (PcG) protein important in gene silencing. It is a component of Polycomb Repressive Complex 1 (PRC1), which is required to maintain the transcriptionally repressive state of many genes. Bmi1 was initially identified as an oncogene that regulates cell proliferation and transformation, and is important in hematopoiesis and the development of nervous systems. Recently, it was reported that Bmi1 is a potential marker for intestinal stem cells. Because Wnt signaling plays a key role in intestinal stem cells, we analyzed the effects of Wnt signaling on Bmi1 expression. We found that Wnt signaling indeed regulates the expression of Bmi1 in colon cancer cells. In addition, the expression of Bmi1 in human colon cancers is significantly associated with nuclear β-catenin, a hallmark for the activated Wnt signaling. Krüppel-like factor 4 (KLF4) is a zinc finger protein highly expressed in the gut and skin. We recently found that KLF4 cross-talks with Wnt/β-catenin in regulating intestinal homeostasis. We demonstrated that KLF4 directly inhibits the expression of Bmi1 in colon cancer cells. We also found that Bmi1 regulates histone ubiquitination and is required for colon cancer proliferation in vitro and in vivo. Our findings further suggest that Bmi1 is an attractive target for cancer therapeutics.

Highlights

B lymphoma Mo-MLV insertion region 1 (Bmi1) is a potential marker for the intestinal stem cells
We found that Bmi1-mediated increase in cell proliferation was sequestered by Krüppel-like factor 4 (KLF4); and KLF4-induced inhibition on cell proliferation was not rescued by Bmi1 expression (Fig. 4D)
Activation of Wnt/␤-catenin signaling is a hallmark of colorectal cancer; it interacts with many other signaling pathways in regulating both normal intestinal stem cells and cancer stem cells

Summary

Background

Bmi is a potential marker for the intestinal stem cells. Results: Wnt regulates Bmi indirectly, while KLF4 directly inhibits Bmi, as well as Bmi1-mediated histone ubiquitination in colon cancer cells. Krüppel-like factor 4 (KLF4), a zinc finger protein highly expressed in the gut and skin, was recently found to interact with the ␤-catenin/TCF complex to repress Wnt signaling and inhibit tumor growth [4, 5]. In Wnt signalinginduced adenomas, the expression of Lgr5-EGFP was restricted to a small population of cells, suggesting that stem cells or progenitor cells are maintained in these tumors, supporting the cancer stem cell concept in colorectal tumorigenesis [14] Another potential stem cell marker, B lymphoma Mo-MLV insertion region 1 (Bmi1), belongs to the polycomb group (PcG) gene family, which functions in gene silencing through chromatin modifications. The role of Bmi in controlling cell proliferation and self-renewal might be through its function as a polycomb group (PcG) protein, which facilitates histone modification and regulates gene silencing [22,23,24]. The mechanisms of Bmi function and regulation in colon cancer were examined in this study

EXPERIMENTAL PROCEDURES

RESULTS

DISCUSSION