Ablation of the oncogenic transcription factor ERG by deubiquitinase inhibition in prostate cancer

Significance The transcription factor E-twenty-six related gene (ERG) is a major driver of prostate cancer, which makes this protein an interesting target for drug development. In this study, we report the discovery of an enzyme, ubiquitin-specific peptidase 9, X-linked (USP9X), which stabilizes ERG. We demonstrate that inhibition of USP9X with the small molecule WP1130 causes rapid degradation of ERG and blocked the growth of cultured prostate cancer cells and prostate tumors that express ERG. These findings suggest that inhibition of USP9X with small molecules should be explored for the development of a prostate cancer therapy that targets ERG. The transcription factor E-twenty-six related gene (ERG), which is overexpressed through gene fusion with the androgen-responsive gene transmembrane protease, serine 2 (TMPRSS2) in ∼40% of prostate tumors, is a key driver of prostate carcinogenesis. Ablation of ERG would disrupt a key oncogenic transcriptional circuit and could be a promising therapeutic strategy for prostate cancer treatment. Here, we show that ubiquitin-specific peptidase 9, X-linked (USP9X), a deubiquitinase enzyme, binds ERG in VCaP prostate cancer cells expressing TMPRSS2-ERG and deubiquitinates ERG in vitro. USP9X knockdown resulted in increased levels of ubiquitinated ERG and was coupled with depletion of ERG. Treatment with the USP9X inhibitor WP1130 resulted in ERG degradation both in vivo and in vitro, impaired the expression of genes enriched in ERG and prostate cancer relevant gene signatures in microarray analyses, and inhibited growth of ERG-positive tumors in three mouse xenograft models. Thus, we identified USP9X as a potential therapeutic target in prostate cancer cells and established WP1130 as a lead compound for the development of ERG-depleting drugs.