| Summary: | The multi-functional RNA binding protein FUS was identified as an androgen down-regulated target in a 2D proteomic screen in the LNCaP cell line. This screen was designed to identify novel markers and therapeutic targets for prostate cancer. Cell cycle analysis and growth assays revealed that increased FUS levels in LNCaP cells resulted in inhibition of the androgen-dependent G1-S cell cycle transition and induced apoptosis. This is brought about, in part, via the FUS-dependent modulation of the expression of G1- S check-point regulatory proteins, including decreased expression of Cyclin D1. Therefore, we have identified FUS as a key link between androgen signalling and cell cycle regulation. FUS also modulates androgen signalling by repressing Androgen Receptor (AR) activity. FUS is known to interact with the DNA binding domain of some nuclear receptors, and a mammalian 2-hybrid interaction assay revealed a ligand-dependent interaction between FUS and the AR that required the FUS RNA recognition motif. Transcription assays demonstrated that FUS is a novel co-repressor of AR activity, and quantitative real time PCR showed that increasing FUS levels down-regulated androgen-regulated gene expression in LNCaP cells, whilst reducing FUS levels resulted in an increase of the androgen-regulated gene TMPRSS2. Investigation into the mechanism(s) by which FUS represses AR activity revealed that FUS contains an NH2-terminal activation domain (amino acids 1-366) that is consistent with the AR transcriptional repression domain. Furthermore, the FUS NH2- terminal interacts with co-activators, including SRC-1, suggesting FUS may repress AR activity by competition with co-activator activity. Recent studies in Dr Charlotte Bevan’s laboratory demonstrated an inverse correlation between FUS expression and Gleason grade in human prostate tumours. This, combined with these findings that FUS is an inhibitor of androgen-dependent growth which is, in part, via repression of the AR, suggests that FUS is a key regulator in AR signalling and prostate cancer progression, and may be a novel tumour suppressor.
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