The positive feedback between Snail and DAB2IP regulates EMT, invasion and metastasis in colorectal cancer.

Jianmei Wang,Yanqing Ding,Xiaoli Ren,Xiaohui Zhu,Jinlong Hu,Pingxiang Wu,Feifei Wang,Li Liang,Guoyang He,Xiaomei Li,Wenting Liao

doi:10.18632/oncotarget.4861

Abstract

DAB2IP has been identified as a tumor suppressor in several cancers but its oncogenic role and transcriptionally regulatory mechanisms in the progression of colorectal carcinoma (CRC) remain unknown. In this study, DAB2IP was down-regulated in CRC tissues and a valuable prognostic marker for survival of CRC patients, especially in the late stage. Moreover, DAB2IP was sufficient to suppress proliferation, epithelial-mesenchymal transition (EMT), invasion and metastasis in CRC. Mechanically, the linear complex of EZH2/HDAC1/Snail contributed to DAB2IP silencing in CRC cells. The study further proved that the positive feedback loop between Snail and DAB2IP existed in CRC cells and DAB2IP was required for Snail-induced aggressive cell behaviors. Finally, DAB2IP correlated negatively with Snail and EZH2 expressions in CRC tissues. Our findings reveal the suppressive role and a novel regulatory mechanism of DAB2IP expression in the progression of CRC. DAB2IP may be a potential, novel therapeutic and prognostic target for clinical CRC patients.

Highlights

Colorectal carcinoma (CRC) is a major cause of cancer-related morbidity and mortality
We unveil the suppressive role of DAB2IP in the progression of CRC, in which we identify the novel mechanism of the positive feedback between Snail and DAB2IP regulating epithelial-mesenchymal transition (EMT), invasion and metastasis in CRC cells
To characterize the oncogenic functions of DAB2IP in the progression of CRC, we investigated the effect of DAB2IP knockdown (KD) on CRC cell behaviors

Summary

Introduction

Colorectal carcinoma (CRC) is a major cause of cancer-related morbidity and mortality. DAB2IP via its Ras-GAP activity, inhibits Ras-mediated cell survival signaling, causing cell growth inhibition [4]. DAB2IP functions as a positive regulator in cell apoptosis by mediating activation of the apoptotic kinase ASK1 [4, 5]. Consistent with its role as an inhibitor of cell survival and growth, DAB2IP expression is often down-regulated in several human cancers [6,7,8,9], which is frequently associated with the promoter hypermethylation [8,9,10,11,12,13] or enhancer of zeste homolog 2 (EZH2)-mediated transcriptional silencing [14, 15]

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Results

Conclusion