# Disruption of androgen receptor-cofactor interactions by the RNA-binding protein FUS/TLS alters androgen signalling in prostate cancer

## TL;DR

This study shows how the protein FUS/TLS affects androgen signaling in prostate cancer by disrupting interactions with the androgen receptor and its cofactors.

## Contribution

The novel contribution is the discovery that FUS/TLS can both regulate and disrupt androgen receptor signaling in prostate cancer.

## Key findings

- FUS/TLS interacts with the androgen receptor and cofactors to repress transcription.
- FUS is down-regulated in primary tumors but up-regulated in advanced prostate cancer stages.
- FUS repression of androgen signaling is linked to disassembly of the transcriptional complex.

## Abstract

Prostate cancer is dependent upon the androgen receptor (AR), the activity of which is modified by cofactors that either enhance or repress its activity, often in a context-dependent manner. FUS/TLS is a multifunctional protein known to be important in multiple cancer types; in prostate cancer, we previously showed that FUS has a potential tumour suppressor role. Here, transcriptomic analysis of the LNCaP prostate cancer cell line shows a significant overlap in genes regulated by FUS and the androgen receptor. We demonstrate that FUS can regulate androgen receptor activity, in either direction, but predominantly represses androgen signalling. Reporter assays and domain-specific analyses of FUS identified mechanisms by which FUS modifies androgen receptor activity. FUS interacts with the androgen receptor and other cofactors to repress transcription; ChIP assays suggest that repression occurs via disassembly of the transcriptional complex. Quantitative proteomics and RNA-Seq were used to investigate FUS expression in patient samples across prostate cancer stages. FUS was found to be down-regulated in primary tumours, but up-regulated in advanced aggressive stages. These findings suggest that in early prostate cancer, FUS represses AR activity and tumour progression, leading to its down-regulation. In contrast, increased FUS expression in advanced disease appears to be linked to a loss of AR regulatory control.