GATA1 induces epithelial-mesenchymal transition in breast cancer cells through PAK5 oncogenic signaling.

Yang Li,Yanshu Li,Qiang Ke,Feng Li,Feng Jin,Ge Zhu,Nanxi Geng,Yangguang Shao

doi:10.18632/oncotarget.2999

Abstract

Epithelial-mesenchymal transition (EMT) is a key process in tumor metastatic cascade that is characterized by the loss of cell-cell junctions, resulting in the acquisition of migratory and invasive properties. E-cadherin is a major component of intercellular junctions and the reduction or loss of its expression is a hallmark of EMT. Transcription factor GATA1 has a critical anti-apoptotic role in breast cancer, but its function for metastasis has not been investigated. Here, we found that GATA1, as a novel E-cadherin repressor, promotes EMT in breast cancer cells. GATA1 binds to E-cadherin promoter, down-regulates E-cadherin expression, disrupts intercellular junction and promotes metastasis of breast cancer cell in vivo. Moreover, GATA1 is a new substrate of p21-activated kinase 5 (PAK5), which is phosphorylated on serine 161 and 187 (S161 and S187). GATA1 recruits HDAC3/4 to E-cadherin promoter, which is reduced by GATA1 S161A S187A mutant. These data indicate that phosphorylated GATA1 recruits more HDAC3/4 to promote transcriptional repression of E-cadherin, leading to the EMT of breast cancer cells. Our findings provide insights into the novel function of GATA1, contributing to a better understanding of the EMT, indicating that GATA1 and its phosphorylation may play an important role in the metastasis of breast cancer.

Highlights

Occurrence of metastasis due to tumor progression is the primary cause of most cancer-related deaths
It has been reported that GATA1 is overexpressed in aggressive breast cancer [9] and GATA3, another GATA family member, inhibits breast cancer metastasis through increasing E-cadherin expression [19]
The results showed that GATA1 was in high expression while E-cadherin was lost in ZR-75-30 cells

Summary

Introduction

Occurrence of metastasis due to tumor progression is the primary cause of most cancer-related deaths. Which originate from epithelial cells and account for most tumors, acquisition of invasiveness and motility requires them to undergo a dramatic transition to a mesenchymal state (epithelial-mesenchymal transition or EMT) [1, 2]. Dissemination of tumor cells from the primary lesion is the most common event in the metastatic process and leads to the shedding of millions of carcinoma cells into the circulation each day [5]. GATA1 regulates many genes expression depending upon its ability to bind both DNA and various different protein partners [8]. GATA1 is identified as a key feature by enhancing survivin expression [9]. The function of GATA1 in breast cancer metastasis remains unclear

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Conclusion