Snail Recruits Ring1B to Mediate Transcriptional Repression and Cell Migration in Pancreatic Cancer Cells

被引：64

作者：

Chen, Jiangzhi ^{[1
,2
]}

Xu, Hong ^{[1
]}

Zou, Xiuqun ^{[1
]}

Wang, Jiamin ^{[1
]}

Zhu, Yi ^{[1
]}

Chen, Hao ^{[1
]}

Shen, Baiyong ^{[1
]}

Deng, Xiaxing ^{[1
]}

Zhou, Aiwu ^{[3
]}

Chin, Y. Eugene ^{[3
]}

Rauscher, Frank J., III ^{[4
]}

Peng, Chenghong ^{[1
]}

Hou, Zhaoyuan ^{[1
,3
]}

机构：

[1] Shanghai Jiao Tong Univ, Sch Med, Dept Biochem & Mol Cell Biol, Dept Surg,Ruijin Hosp, Shanghai 200025, Peoples R China

[2] Fujian Med Univ, Union Hosp, Dept Hepatobiliary Surg, Fuzhou, Peoples R China

[3] Shanghai Jiao Tong Univ, Sch Med, Shanghai Key Lab Tumor Microenvironm & Inflammat, Shanghai 200025, Peoples R China

[4] Chinese Acad Sci, Inst Hlth Sci, Shanghai, Peoples R China

来源：

CANCER RESEARCH | 2014年 / 74卷 / 16期

基金：

美国国家科学基金会;

关键词：

E-CADHERIN REPRESSION; HISTONE H2A; POLYCOMB; UBIQUITYLATION; EXPRESSION; DROSOPHILA; MARKS;

D O I：

10.1158/0008-5472.CAN-14-0181

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 [肿瘤学];

摘要：

Transcriptional repressor Snail is a master regulator of epithelial-mesenchymal transition (EMT), yet the epigenetic mechanism governing Snail to induce EMT is not well understood. Here, we report that in pancreatic ductal adenocarcinoma (PDAC), elevated levels of the ubiquitin E3 ligase Ring1B and Snail, along with elevated monoubiquitination of H2A at K119 (H2AK119Ub1), are highly correlated with poor survival. Mechanistic investigations identified Ring1B as a Snail-interacting protein and showed that the carboxyl zinc fingers of Snail recruit Ring1B and its paralog Ring1A to repress its target promoters. Simultaneous depletion of Ring1A and Ring1B in pancreatic cancer cells decreased Snail binding to the target chromatin, abolished H2AK119Ub1 modification, and thereby compromised Snail-mediated transcriptional repression and cell migration. We found that Ring1B and the SNAG-associated chromatin modifier EZH2 formed distinct protein complexes with Snail and that EZH2 was required for Snail-Ring1A/B recruitment to the target promoter. Collectively, our results unravel an epigenetic mechanism underlying transcriptional repression by Snail, suggest Ring1A/B as a candidate therapeutic target, and identify H2AK119Ub1 as a potential biomarker for PDAC diagnosis and prognosis. (C)2014 AACR.

引用

页码：4353 / 4363

页数：11

共 30 条

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