Obstructing Androgen Receptor Activation in Prostate Cancer Cells Through Post-translational Modification by NEDD8.

摘要

Androgen receptor (AR) mediates the actions of the male sex hormone testosterone and is an important target in the management of prostate cancer. It is known that post-translational modifications of proteins play crucial roles in regulating gene expression; however, whether and how it affects AR activity is largely unknown. The purpose of this study is to understand how AR activity is modified and regulated by an ubiquitin-like protein NEDD8. The scope and major findings from this investigation include: 1. The demonstration that AR is modified by NEDD8 in vitro and in vivo; 2. The revelation that PIASy is the E3 ligase catalyzing AR neddylation; 3. The discovery that Jab1 interacts with AR and enhances its transcriptional activity through de- neddylation. We have further established several Jab1-shRNA expressing cell lines and characterized the effects of Jab1 silencing on prostate cancer cell growth and proliferation. We show that silencing of Jab1 inhibits prostate cancer cell proliferation. These findings are significant to our understanding of the regulation of AR activity.