Poly (A) Binding Protein Cytoplasmic 1 Is a Novel Co-Regulator of the Androgen Receptor

Kurtis Eisermann,Khalid Z Masoodi,Javid A Dar,Zhou Wang,Jun Dong,Dan Wang,Mohammad Saleem

doi:10.1371/journal.pone.0128495

Abstract

The androgen receptor (AR) is a member of the steroid receptor superfamily that regulates gene expression in a ligand-dependent manner. The NTD of the AR plays a key role in AR transactivation including androgen-independent activation of the AR in castration-resistant prostate cancer (CRPC) cells. We recently reported that amino acids (a.a.) 50-250 of the NTD are capable of modulating AR nucleocytoplasmic trafficking. To further explore the mechanism associated with a.a. 50-250, GFP pull-down assays were performed in C4-2 CRPC cells transfected with GFP tagged a.a. 50-250 of the AR. Mass spectrometry analysis of the pulled down proteins identified poly (A) binding protein cytoplasmic 1 (PABPC1) interaction with this region of the AR. In silico analysis of gene expression data revealed PABPC1 up-regulation in prostate cancer tissue specimens and this up-regulation correlates to increased disease recurrence. Co-immunoprecipitation assays confirmed the association of PABPC1 with a.a. 50-250 of the NTD of the AR. Knockdown of PABPC1 decreased nuclear AR protein levels and inhibited androgen activation of the AR target PSA in LNCaP and C4-2 cells. Additionally, knockdown of PABPC1 inhibited transactivation of the PSA promoter by NAR (AR lacking the LBD) and attenuated proliferation of AR-positive prostate cancer cells. These findings suggest that PABPC1 is a novel co-regulator of the AR and may be a potential target for blocking activation of the AR in CRPC.

Highlights

Prostate cancer is the second leading cause of cancer death in the United States killing almost 30,000 men annually [1]
The N-terminal domain (NTD) of the androgen receptor (AR) plays a key role in AR transactivation including androgen-independent activation of the AR in castration-resistant prostate cancer (CRPC) cells
The AR plays a major role in all stages of prostate cancer development and progression, including CRPC, it is important to determine the mechanisms involved including the impact of AR co-regulators

Summary

Introduction

Prostate cancer is the second leading cause of cancer death in the United States killing almost 30,000 men annually [1]. PABPC1 Is a Co-Regulator of the AR progression of prostate cancer, the first line of therapy for patients with metastatic prostate cancer is usually androgen deprivation therapy (ADT). Most patients eventually relapse and the cancer becomes resistant to hormone therapy, a condition known as castration-resistant or–recurrent prostate cancer (CRPC). Abiraterone and enzalutamide are newly approved drugs for CRPC patients; patients will still eventually relapse and the overall survival is prolonged only ~4–5 months after treatment with the AR signaling becoming active in most of these relapsed tumors [7,8]. A detailed understanding of the mechanisms regulating AR function may lead to novel approaches targeting the AR in CRPC as well as in CRPC relapsed after treatment with abiraterone and enzalutamide

Methods

Results

Conclusion