Enhancer of zeste homolog 2 activates wnt signaling through downregulating CXXC finger protein 4

H Lu,X Wang,X Sun,F Wang,Z Jiang,L Feng,Q Shen,J Sun,Y Ma,H Jin

doi:10.1038/cddis.2013.293

Abstract

Through silencing tumor suppressor genes, epigenetic changes can activate signaling pathways important to cancer development. In this report, we found an epigenetic contribution to the aberrant activation of wnt signaling in human gastric cancer. CXXC4 (CXXC finger protein 4) was identified as a novel target of EZH2 (enhancer of zeste homolog 2), and EZH2 promotes the activation of wnt singaling by downregulating CXXC4 expression. CXXC4 inhibits the growth of gastric cancer cells both in vitro and in vivo through inactivating wnt signaling. In contrast, depletion of CXXC4 activates wnt signaling and promotes the anchorage-independent growth of nontumor gastric epithelial cells. CXXC4 is downregulated in gastric carcinoma tissues and its downregulation is associated with poor outcome of gastric cancer patients (hazard ratio: 5.053, P<0.05). Through its binding to dishevelled (Dvl), CXXC4 stabilizes the destruction complex of β-catenin to inhibit wnt signaling. Two critical amino acid residues in CXXC4, K161 and T162 were found to be important to its binding to Dvl and the growth inhibitory effect of CXXC4. In summary, EZH2 promotes the activation of wnt signaling in gastric carcinogenesis through the downregulation of CXXC4 expression. CXXC4 is a novel potential tumor suppressor directly regulated by EZH2, and its expression is a significant prognosis factor for patients with early stages of gastric cancer.

Highlights

Wnt/b-catenin signaling has key roles in embryonic development.[3]
Mutations in adenomatous polyposis coli (APC) and CTNNB1 mutations are relatively infrequent in gastric cancer,[20,21] indicating that other mechanisms may be responsible for the activation of Wnt signaling in gastric carcinogenesis
We uncover that enhancer of zeste homolog 2 (EZH2) promotes the activation of Wnt signaling through downregulating CXXC finger protein 4 (CXXC4) expression, representing an epigenetic mechanism of wnt signaling activation in gastric cancer cells (Figure 6h)

Summary

Introduction

Wnt/b-catenin signaling has key roles in embryonic development.[3]. In the absence of Wnt sigals, cytoplasmic b-catenin can be degraded by a destruction complex consisting of Axin, adenomatous polyposis coli (APC), casein kinase 1 (CK1) and glycogen synthase kinase-3 (GSK-3). Wnt signaling is implicated in human diseases, including cancers.[3,6,7,8] For example, APC dysfunction could promote intestinal tumorigenesis both in human and animal models Germline mutations in this gene cause familial adenomatous polyposis, an autosomal dominant pre-malignant disease that usually progresses to malignancy, mainly colorectal cancer. Aberrant activation of wnt signaling was frequently observed in other cancers, such as gastric cancer, genetic changes of APC are relatively rare It remains unclear how Wnt signaling is deregulated in the development of gastric cancer.

Methods

Results

Conclusion