PTBP3-Mediated Regulation of ZEB1 mRNA Stability Promotes Epithelial-Mesenchymal Transition in Breast Cancer.

Pingfu Hou,Junnian Zheng,Yansu Chen,Hui Liu,Jingjing Li,Jin Bai,Fang Chen,Lin Li

doi:10.1158/0008-5472.can-17-0883

Abstract

The RNA polypyrimidine tract-binding protein PTBP3 is a little studied paralog of PTBP1, which has oncogenic properties. In this study, we demonstrate that PTBP3 induces epithelial-mesenchymal transition (EMT) in breast tumor cells and promotes their invasive growth and metastasis. Elevated expression of PTBP3 associated significantly with lymph node metastasis, advanced histology grade, TNM stage, and poor 5-year overall survival of patients. In human mammary epithelial cells, PTBP3 overexpression was sufficient to induce EMT and to enhance cell migration, invasion, and cancer stem-like cell properties. PTBP3 regulated expression of the EMT regulatory transcription factor ZEB1 by binding the 3'UTR of its mRNA, thereby preventing its degradation. Conversely, ZEB1 ablation blocked the ability of PTBP3 to induce EMT. Overall, our findings define PTBP3 as a regulator of EMT that acts by governing expression of ZEB1, and they establish an oncogenic function of PTBP3, suggesting its candidacy as a theranostic target.Significance: These findings define PTBP3 as a regulator of EMT that acts by governing expression of ZEB1, and they establish an oncogenic function of PTBP3, suggesting its candidacy as a theranostic target. Cancer Res; 78(2); 387-98. ©2017 AACR.

Highlights

Breast cancer is the most common cancer among women worldwide
We provide a comprehensive set of data suggesting critical roles for PTBP3 in epithelial-to-mesenchymal transition (EMT) and in breast cancer progression
PTBP3 was shown to support the proper function of the EMT transcription program, acting to downregulate epithelial markers, but upregulating mesenchymal markers

Summary

Introduction

Breast cancer is the most common cancer among women worldwide. Distant metastases are the cause of about 90% of deaths in breast cancer [1]. The epithelial-to-mesenchymal transition (EMT) process, first described in embryogenesis, is characterized by changes in cell morphology, behavior, and plasticity [2, 3]. The activation of EMT program depends on a diverse array of proteins, including transcription factors, cell signaling regulators, and secretory factors, as well as regulation by long noncoding RNAs (lncRNA). EMT is associated with decreased expression of epithelial markers, such as E-cadherin, and increased expression of mesenchymal markers [5]. E-cadherin is repressed at the transcription level by multiple EMT inducers, including Snail, Slug, Twist, ZEB1, Note: Supplementary data for this article are available at Cancer Research Online (http://cancerres.aacrjournals.org/)

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