FUS/TLS is a novel mediator of androgen-dependent cell cycle progression and prostate cancer growth.


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Greg Brooke1,Rachel Culley1,Alwyn Dart1,Bradley Spencer-Dene1,Marjorie Walker1,Charlotte Bevan1
1Imperial College London, London, United Kingdom

Background

Progression of prostate cancer is highly dependent upon the androgen receptor pathway and therefore androgen-regulated proteins are important to define pathways involved in disease progression.  Using a proteomic screen, we have found the RNA-binding protein FUS/TLS (Fused in Ewings Sarcoma/Translocated in Liposarcoma) to be down-regulated in response to androgen.  FUS has recently been shown to be recruited by non-coding RNAs to the regulatory regions of target genes such as Cyclin D1, where it represses transcription by disrupting complex formation.

Method

To study the role of FUS in prostate cancer growth, LNCaP cells were stably transfected with the FUS gene under the control of a doxycycline inducible system.  The effects of FUS expression, upon growth was measured in vitro using growth assays and FACS and in vivo using a xenograft model.

Results

We have found that FUS has the characteristics of a tumour suppressor, since over-expression reduces cell growth and promotes apoptosis in vitro and in vivo, whereas knock-down enhances proliferation. FACS analysis has demonstrated that over-expression of FUS causes G1 cell cycle arrest and we have subsequently demonstrated that these effects are as a result of FUS regulation of Cyclin D1 expression.

Using prostate cancer tissue microarrays immunohistochemistry shows FUS expression to be inversely correlated with Gleason grade, suggesting that loss of expression may contribute to cancer progression.

Conclusion

Although it has been previously demonstrated that androgen signalling regulates cell cycle progression, the exact mechanism is not clear. Here we demonstrate that FUS appears to be a key link between androgen receptor signalling and cell cycle progression in prostate cancer.