Disrupting the interaction between androgen receptor and its coregulator WDR77 delays the growth of treatment-resistant prostate cancer
Continued reliance on androgen receptor (AR) after androgen deprivation therapy (ADT) has failed causes 35,000 American prostate cancer (CaP) deaths annually. AR's transcriptional activity is an attractive target to overcome this acquired resistance but has been challenging to pursue. We demonstrate the therapeutic potential of disrupting interactions between AR and its coregulator WDR77. WDR77 stimulated growth of CaP cells and xenografts and its overexpression associated with worse patient survival. AR and WDR77 cistromes overlapped considerably, AR- and WDR77-bound genes correlated with aggressive CaP features, and the AR cistrome was reduced after WDR77 loss. We delineated direct interaction between WDR77 and AR, which when disrupted prevented AR-WDR77 complex formation, reduced AR DNA-binding and AR-dependent gene expression. Such disruption decreased cell proliferation to the same extent as ADT, and inhibited cell growth when ADT-resistant AR action was modelled and after ADT-resistance without impacting AR-negative CaP cells or benign cells. Blocking AR-WDR77 cooperation also delayed growth of organoids generated from patient-derived xenografts and fresh CaP specimens. Disrupting coregulator control over AR action may thus improve survival from ADT-resistant CaP. Overall design: In a first study, LNCaP cells were transfected with an expression construct encoding WDR77-peptide 3 or empty vector.  The next day, medium was changed to androgen-deprived medium. One day later, androgen-deprived medium was refreshed and cells were treated with 5nM of the synthetic androgen R1881 or vehicle (ethanol).  48h later, cells were harvested in Trizol, RNA was extracted and column-purified.  Biological triplicates were generated for each treament group.  300,000 cells were seeded per well of a 6 well plate. In a second study, LNCaP cells were transfected with siRNAs targeting WDR77 or non-targeting control siRNA.  The next day, medium was changed to androgen-deprived medium. One day later, androgen-deprived medium was refreshed and cells were treated with 5nM of the synthetic androgen R1881 or vehicle (ethanol).  48h later, cells were harvested in Trizol, RNA was extracted and column-purified. Biological triplicates were generated for each treatment group. 300,000 cells were seeded per well of a 6 well plate.