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

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.

5-Hydroxymethylcytosine: An epigenetic mark frequently deregulated in cancer

“…CXXC5 is overexpressed in a number of solid cancers (breast cancer, melanoma, thyroid cancer) and correlated with poor prognosis in breast cancer [84]. Furthermore, CXXC4 overexpression has been described in adenomas of the colon [85], whereas CXXC4 downregulation has been described in gastric carcinoma, where it associated with poor prognosis [86]. Future studies should examine whether overexpression or downregulation of CXXC4/5 proteins influences 5hmC levels in these types of cancer.…”

Role of the Wnt/β-catenin pathway in gastric cancer: An in-depth literature review

“…The upregulation of Fzd-3, Wnt palmitoyltransferase porcupine (PPN), and CDH17 has been found to be critical for cell proliferation and activation of the Wnt/ b-catenin signaling pathway in gastric cancer [78][79][80] . Moreover, Lu et al [81] have provided evidence indicating that EZH2 (histone methyl-transferase, enhancer of zeste homolog 2) activates Wnt signaling in gastric cancer mainly by downregulating the expression of CXXC4 (CXXC finger protein 4) without involving DNA methylation. It was also confirmed that overexpression of CXXC4 disrupts the association of Dvl with AxinGSK3b by directly interacting with Dvl, thus functioning as a tumor suppressor [81] .…”

“…Moreover, Lu et al [81] have provided evidence indicating that EZH2 (histone methyl-transferase, enhancer of zeste homolog 2) activates Wnt signaling in gastric cancer mainly by downregulating the expression of CXXC4 (CXXC finger protein 4) without involving DNA methylation. It was also confirmed that overexpression of CXXC4 disrupts the association of Dvl with AxinGSK3b by directly interacting with Dvl, thus functioning as a tumor suppressor [81] . Upregulation of Actin-binding protein anillin (ANLN), a protein involved in the cytokinesis and known to be dysregulated in many cancers, was found responding to the activity of Wnt/b-catenin pathway in gastric cancer [82] .…”

“…Homeostasis of the gastrointestinal epithelium is 87 [47,[69][70][71][72][73][74][75]232] Fzd-3 [78] CTNNB1 [9,[88][89][90][91][92][93]96,97] LRP6 [228] TCF7L2 [98][99][100] PPN [79] CDH17 [80] EZH2 [81] HMGA1, HMGA2 [210,211] YY1 [86] TC1 (C8orf4) [201,202] miR-17-92 [161] mir-10a [168] has-miR-335 [166] hsa-miR-375 [163] Downregulation or function inhibition in gastric cancer Downregulation by hypermethylation Inactivation by miRNAs APC [145,146] APC [175] sFRP1, sFRP2, sFRP4, sFRP5 [78,96,149] AXIN2 [159] WIF-1 [144,149] EZF1 [78] Dkk-1, Dkk-2, Dkk-3 [59,144,148,…”

Interaction between Wnt/β-catenin pathway and microRNAs regulates epithelial-mesenchymal transition in gastric cancer (Review)

“…Of note, according to a study from Korea, RNF43 gene might harbor mutational regional intratumoral heterogeneity (ITH), which could be accountable for tumorigenesis of GC (72). Lu et al (73) discussed that enhancer of zeste homolog 2 (EZH2) has ectopic expression in gastric cancer tissues. In a mechanistic manner, repressing CXXC finger protein 4 (CXXC4), a protein stabilize the degradation complex of β-catenin, was necessary for the contribution of EZH2 to GC.…”