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

被引：46

作者：

Lu, H. ^{[1
,2
]}

Sun, J. ^{[1
]}

Wang, F. ^{[1
]}

Feng, L. ^{[1
]}

Ma, Y. ^{[1
]}

Shen, Q. ^{[1
,2
]}

Jiang, Z. ^{[3
]}

Sun, X. ^{[4
]}

Wang, X. ^{[1
,2
]}

Jin, H. ^{[1
]}

机构：

[1] Zhejiang Univ, Sch Med, Sir Runrun Shaw Hosp, Lab Canc Biol,Biomed Res Ctr, Hangzhou 310016, Zhejiang, Peoples R China

[2] Zhejiang Univ, Sch Med, Sir Runrun Shaw Hosp, Dept Med Oncol, Hangzhou 310016, Zhejiang, Peoples R China

[3] Zhejiang Univ, Sch Med, Sir Runrun Shaw Hosp, Deaprtment Pathol, Hangzhou 310016, Zhejiang, Peoples R China

[4] Zhejiang Univ, Sir Runrun Shaw Hosp, Dept Radiat Oncol, Hangzhou 310016, Zhejiang, Peoples R China

来源：

CELL DEATH & DISEASE | 2013年 / 4卷

关键词：

EZH2; Wnt/beta-catenin signaling; CXXC4; gastric cancer; FREQUENT EPIGENETIC INACTIVATION; FAMILY GENES; POLYCOMB; CANCER; EZH2; EXPRESSION; PATHWAY; REPRESSION; PROMOTES; TRANSFORMATION;

D O I：

10.1038/cddis.2013.293

中图分类号：

Q2 [细胞生物学];

学科分类号：

071009 ; 090102 ;

摘要：

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 beta-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.

引用

页码：e776 / e776

页数：9

共 44 条

[1] Genome-Wide Analysis of Allelic Imbalances Reveals 4q Deletions as a Poor Prognostic Factor and MDM4 Amplification at 1q32.1 in Hepatoblastoma [J].

Arai, Yasuhito ;

Honda, Shohei ;

Haruta, Masayuki ;

Kasai, Fumio ;

Fujiwara, Yuiko ;

Ohshima, Junjiro ;

Sasaki, Fumiaki ;

Nakagawara, Akira ;

Horie, Hiroshi ;

Yamaoka, Hiroyuki ;

Hiyama, Eiso ;

Kaneko, Yasuhiko .

GENES CHROMOSOMES & CANCER, 2010, 49 (07) :596-609

[2] Mining the Wnt pathway for cancer therapeutics [J].

Barker, Nick ;

Clevers, Hans .

NATURE REVIEWS DRUG DISCOVERY, 2006, 5 (12) :997-1014

[3] The gene encoding the prostatic tumor suppressor PSP94 is a target for repression by the Polycomb group protein EZH2 [J].

Beke, L. ;

Nuytten, M. ;

Van Eynde, A. ;

Beullens, M. ;

Bollen, M. .

ONCOGENE, 2007, 26 (31) :4590-4595

[4] Deletion of chromosome 4q predicts outcome in Stage II colon cancer patients [J].

Brosens, R. P. M. ;

Belt, E. J. T. H. ;

Haan, J. C. ;

Buffart, T. E. ;

Carvalho, B. ;

Grabsch, H. ;

Quirke, P. ;

Cuesta, M. A. ;

Engel, A. F. ;

Ylstra, B. ;

Meijer, G. A. .

CELLULAR ONCOLOGY, 2011, 34 (03) :215-223

[5] Repression of E-cadherin by the polycomb group protein EZH2 in cancer [J].

Cao, Q. ;

Yu, J. ;

Dhanasekaran, S. M. ;

Kim, J. H. ;

Mani, R-S ;

Tomlins, S. A. ;

Mehra, R. ;

Laxman, B. ;

Cao, X. ;

Yu, J. ;

Kleer, C. G. ;

Varambally, S. ;

Chinnaiyan, A. M. .

ONCOGENE, 2008, 27 (58) :7274-7284

[6] Down-regulation of human DAB2IP gene expression mediated by polycomb Ezh2 complex and histone deacetylase in prostate cancer [J].

Chen, H ;

Tu, SW ;

Hsieh, JT .

JOURNAL OF BIOLOGICAL CHEMISTRY, 2005, 280 (23) :22437-22444

[7] EZH2-Mediated Concordant Repression of Wnt Antagonists Promotes β-Catenin-Dependent Hepatocarcinogenesis [J].

Cheng, Alfred S. L. ;

Lau, Suki S. ;

Chen, Yangchao ;

Kondo, Yutaka ;

Li, May S. ;

Feng, Hai ;

Ching, Arthur K. ;

Cheung, Kin F. ;

Wong, Hoi K. ;

Tong, Joanna H. ;

Jin, Hongchuan ;

Choy, Kwong W. ;

Yu, Jun ;

To, Ka F. ;

Wong, Nathalie ;

Huang, Tim H. -M. ;

Sung, Joseph J. Y. .

CANCER RESEARCH, 2011, 71 (11) :4028-4039

[8] Wnt/β-catenin signaling in development and disease [J].

Clevers, Hans .

CELL, 2006, 127 (03) :469-480

[9]

Correa P, 2003, CANCER EPIDEM BIOMAR, V12, p238S

[10] RACK1 Suppresses Gastric Tumorigenesis by Stabilizing the β-Catenin Destruction Complex [J].

Deng, Yue-Zhen ;

Yao, Fan ;

Li, Jing-Jing ;

Mao, Zheng-Fa ;

Hu, Ping-Ting ;

Long, Ling-Yun ;

Li, Guo ;

Ji, Xiao-Dan ;

Shi, Shuo ;

Guan, Dong-Xian ;

Feng, Yuan-Yuan ;

Cui, Lei ;

Li, Dang-Sheng ;

Liu, Yong ;

Du, Xiang ;

Guo, Ming-Zhou ;

Xu, Li-Yan ;

Li, En-Min ;

Wang, Hong-Yang ;

Xie, Dong .

GASTROENTEROLOGY, 2012, 142 (04) :812-U246

← 1 2 3 4 5 →