Androgen enhances the activity of ETS-1 and promotes the proliferation of HCC cells.

Hui Ren,Jia Li,Zhijie Li,Bo Ren,Xiaofeng Zhang,Lixin Li,Xuemei Ma,Yinjie Gao,Jiabin Zhang,Lingzhan Meng

doi:10.18632/oncotarget.22669

Abstract

The expression of androgen receptor (AR) has been detected in hepatocellular cancer (HCC). However, there is no universal model detailing AR’s function and mechanism in HCC. This study’s results show that treatment with dihydrotestosterone (DHT), an endogenous androgen, promoted HCC cells’ proliferation and up-regulated the transcription factor activity of ETS-1 (E26 transformation specific sequence 1), which mediates the migration and invasion of cancer cells via protein-protein interaction between AR and ETS-1. Results from luciferase assays showed that ETS-1’s activity was significantly up-regulated following androgen treatment. AR mediated ETS-1’s DHT-induced transcription factor activity. A potential protein-protein interaction between ETS-1 and AR was identified via glutathione S-transferase (GST) pull-down and co-immunoprecipitation assays. The mechanisms’ data indicated that enhancing AR activity increases ETS-1’s activity by modulating its cytoplasmic/nuclear translocation and recruiting ETS-1 to its target genes’ promoter. Moreover, while overexpression of AR significantly increased the proliferation or in vitro migration or invasion of HepG2 cells in the presence of androgen, inhibiting AR’s activity reduced these abilities. Thus, AR’s function as a novel ETS-1 co-activator or potentially therapeutic target of HCC has been demonstrated.

Highlights

In mammalian cells, androgen responds to androgen receptor (AR), which plays a central role in male health and the maintenance or progress of prostatic carcinoma [1]
To discover whether androgen modulates the transcription factor activity of ETS-1, luciferase assays were performed in HepG2 cells, which were cotransfected with ETS-1 binding site EBS-Luc reporters
And 1D, while hepatocyte growth factor (HGF) induced the EBS-Luc reporter activity in a dose-dependent manner (EC50 value = 7.55 ± 1.02 ng/ml), ARQ-197 inhibited this activity (IC50 value = 20.44 ± 2.95 nM). These results indicate that enhancing AR activity increased ETS-1transcriptional activity

Summary

Introduction

Androgen responds to androgen receptor (AR), which plays a central role in male health and the maintenance or progress of prostatic carcinoma [1]. Researchers have identified that androgen/AR plays a key role in prostatic carcinoma’s maintenance and development [1,2,3]. It may be involved in other types of human cancer. Multiple studies have shown that AR is involved in HCC’s progression [6,7,8,9,10], the function and detailed mechanisms of how AR regulates HCC’s cell proliferation remain unclear. A deeper understanding of how AR regulates the proliferation, migration, and invasion of HCC cells will be helpful for developing further treatments

Methods

Results

Conclusion