TY - JOUR
T1 - Enhancer of zeste homolog 2 activates wnt signaling through downregulating CXXC finger protein 4
AU - Lu, H.
AU - Sun, J.
AU - Wang, F.
AU - Feng, L.
AU - Ma, Y.
AU - Shen, Q.
AU - Jiang, Z.
AU - Sun, X.
AU - Wang, X.
AU - Jin, H.
N1 - Funding Information:
Acknowledgements. This work was supported by the Qianjiang Scholar Program of Zhejiang province to XW (number 2011R10073) and Natural Science foundation of Zhejiang Province (number LR12H16001) to HJ.
PY - 2013/8
Y1 - 2013/8
N2 - 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.
AB - 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.
KW - CXXC4
KW - EZH2
KW - Gastric cancer
KW - Wnt/β-catenin signaling
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U2 - 10.1038/cddis.2013.293
DO - 10.1038/cddis.2013.293
M3 - Article
C2 - 23949225
AN - SCOPUS:84882702709
SN - 2041-4889
VL - 4
JO - Cell Death and Disease
JF - Cell Death and Disease
IS - 8
M1 - e776
ER -