ERK2-Dependent Phosphorylation of CSN6 Is Critical in Colorectal Cancer Development

被引：70

作者：

Fang, Lekun ^{[1
,2
,3
]}

Lu, Weisi ^{[4
,5
,11
]}

Choi, Hyun Ho ^{[3
]}

Yeung, Sai-Ching J. ^{[6
]}

Tung, Jung-Yu ^{[7
]}

Hsiao, Chwan-Deng ^{[7
]}

Fuentes-Mattei, Enrique ^{[3
]}

Menter, David ^{[8
]}

Chen, Chuangqi ^{[9
]}

Wang, Lei ^{[1
,2
]}

Wang, Jianping ^{[1
,2
]}

Lee, Mong-Hong ^{[2
,3
,10
,11
]}

机构：

[1] Sun Yat Sen Univ, Affiliated Hosp 6, Dept Colorectal Surg, Guangzhou 510655, Guangdong, Peoples R China

[2] Sun Yat Sen Univ, Affiliated Hosp 6, Guangdong Prov Key Lab Colorectal & Pelv Floor Di, Guangzhou 510655, Guangdong, Peoples R China

[3] Univ Texas MD Anderson Canc Ctr, Dept Mol & Cellular Oncol, Houston, TX 77030 USA

[4] Sun Yat Sen Univ, Zhongshan Ophthalm Ctr, State Key Lab Ophthalmol, Guangzhou 510060, Guangdong, Peoples R China

[5] Sun Yat Sen Univ, Sch Life Sci, Minist Educ, Key Lab Gene Engn, Guangzhou 510275, Guangdong, Peoples R China

[6] Univ Texas MD Anderson Canc Ctr, Dept Endocrine Neoplasia & Hormonal Disorders, Houston, TX 77030 USA

[7] Acad Sinica, Inst Mol Biol, Taipei 11529, Taiwan

[8] Univ Texas MD Anderson Canc Ctr, Dept Gastrointestinal Med Oncol, Houston, TX 77030 USA

[9] Sun Yat Sen Univ, Affiliated Hosp 1, Dept Surg, Guangzhou 510080, Guangdong, Peoples R China

[10] Univ Texas Houston, Grad Sch Biomed Sci Houston, Program Canc Biol, Houston, TX 77030 USA

[11] Univ Texas Houston, Grad Sch Biomed Sci Houston, Program Genes & Dev, Houston, TX 77030 USA

来源：

CANCER CELL | 2015年 / 28卷 / 02期

关键词：

CDK INHIBITOR P57(KIP2); COP9; SIGNALOSOME; BETA-CATENIN; UBIQUITIN LIGASE; CELL-PROLIFERATION; RAS MUTATIONS; MAP KINASES; KRAS; DEGRADATION; PANITUMUMAB;

D O I：

10.1016/j.ccell.2015.07.004

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

Biomarkers for predicting prognosis are critical to treating colorectal cancer (CRC) patients. We found that CSN6, a subunit of COP9 signalosome, is overexpressed in CRC samples and that CSN6 overexpression is correlated with poor patient survival. Mechanistic studies revealed that CSN6 is deregulated by epidermal growth factor receptor (EGFR) signaling, in which ERK2 binds directly to CSN6 Leu163/Val165 and phosphorylates CSN6 at Ser148. Furthermore, CSN6 regulated beta-Trcp and stabilized beta-catenin expression by blocking the ubiquitin-proteasome pathway, thereby promoting CRC development. High CSN6 expression was positively correlated with ERK2 activation and beta-catenin overexpression in CRC samples, and inhibiting CSN6 stability with cetuxinnab reduced colon cancer growth. Taken together, our study's findings indicate that the deregulation of beta-catenin by ERK2-activated CSN6 is important for CRC development.

引用

页码：183 / 197

页数：15

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