Simultaneous inhibition of TRIM24 and TRIM28 sensitises prostate cancer cells to antiandrogen therapy, decreasing VEGF signalling and angiogenesis.

Castrate-resistant prostate cancer (CRPC) is a likely outcome of hormone treatment for advanced prostate cancer. Although no longer dependent on androgen levels, CRPC remains driven by the androgen receptor (AR). One proposed progression mechanism is altered repertoires of coregulator proteins possessing the ability to alter AR activity. Increased expression of tripartite motif-containing 24 (TRIM24) and TRIM28-two members of a distinct bromodomain-containing subfamily of Tripartite motif (TRIM) coregulators-occurs in CRPC. Endogenous TRIM24 and TRIM28 interact with each other and AR, bind to chromatin and regulate genes such as the angiogenic factor vascular endothelial growth factor A (VEGFA) and oncogene MYC. Silencing of TRIM24 and TRIM28 simultaneously, but not either alone, sensitised CRPC model cell lines to the antiandrogen enzalutamide and bicalutamide. This re-sensitisation to antiandrogen therapeutics could then be reversed by addition of VEGF. Furthermore, both TRIM24 and TRIM28 expression associated with angiogenesis signatures in tumour samples, and conditioned media from TRIM24 and TRIM28-silenced cancer cells inhibited endothelial cell proliferation and formation of vascular tube structures. Our data suggest that TRIM24 and TRIM28 proteins interact, in gene-specific manners, to regulate AR activity, increase VEGF signalling and angiogenesis, and that targeting these coregulators may increase the effectiveness of antiandrogen therapy.