TPX2 Enhanced the Activation of the HGF/ETS-1 Pathway and Increased the Invasion of Endocrine-Independent Prostate Carcinoma Cells.

Hongqing Zhou,Qiong Miao,Jiaxi Peng,Shaojie Zhu,Peng Zhang,Wei Wang,Mingsheng Liu,Tao Shao,Pingbo Xie

doi:10.3389/fonc.2021.618540

Abstract

The prognosis for endocrine-independent prostate carcinoma is still poor due to its highly metastatic feature. In the present work, TPX2 (the targeting protein for Xklp2), which is known as a micro-tubulin interacted protein, was identified as a novel coactivator of ETS-1, a transcription factor that plays a central role in mediating the metastasis of human malignancies. TPX2 enhanced the transcription factor activation of ETS-1 and increased the expression of ETS-1’s downstream metastasis-related genes, such as mmp3 or mmp9, induced by HGF (hepatocyte growth factor), a typical agonist of the HGF/c-MET/ETS-1 pathway. The protein-interaction between TPX2 and ETS-1 was examined using immunoprecipitation (IP). TPX2 enhanced the accumulation of ETS-1 in the nuclear and the recruitment of its binding element (EST binding site, EBS) located in the promoter region of its downstream gene, mmp9. Moreover, TPX2 enhanced the in vitro or in vivo invasion of a typical endocrine-independent prostate carcinoma cell line, PC-3. Therefore, TPX2 enhanced the activation of the HGF/ETS-1 pathway to enhance the invasion of endocrine-independent prostate carcinoma cells and thus it would be a promising target for prostate carcinoma treatment.

Highlights

The prognosis for endocrine-independent prostate carcinoma (PC) is still poor due to its insensitivity to androgen deprivation therapy (ADT) or its highly metastatic feature [1]
It is valuable to explore the detailed mechanisms of resistance and progression in endocrine-independent PC cells, with specific focus on the molecular alterations that participate in the activation of androgen receptor (AR)-independent pathways [2, 3]
Our results revealed a novel mechanism of TPX2 in its ability to promote the invasion of PC-3 cells, a typical ARdeficiency PC cells, by interacting with ETS-1 and enhancing its transcription factor activation

Summary

Introduction

The prognosis for endocrine-independent prostate carcinoma (PC) is still poor due to its insensitivity to androgen deprivation therapy (ADT) or its highly metastatic feature [1]. It is valuable to explore the detailed mechanisms of resistance and progression in endocrine-independent PC cells, with specific focus on the molecular alterations that participate in the activation of androgen receptor (AR)-independent pathways [2, 3]. TPX2/ETS1 in PC cells transformation specific sequence 1), which belongs to the ETS protein family, is a kind of transcription factor containing the ETS domain (transcription activation domain) and the helix DNA-binding domains (DBD) [5]. The activated ETS-1could promote the invasion of cancerous cells by mediating the transcription of mmps [6]. Based on the important role of ETS-1in mediating the invasion of cancerous cells, it is valuable to reveal the roles of ETS-1 and its co-factors in endocrine-independent PC cells

Methods

Results

Conclusion