Splicing factor TRA2B enhances synthesis of androgen receptor variant AR-V7 in prostate cancer cells

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Abstract

Treatment of locally advanced and metastatic prostate cancer (PC) with androgen receptor–targeting (AR-targeting) therapies has limited durability, with disease eventually progressing to castrate-resistant PC (CRPC). Constitutively active AR splice variants (AR-Vs), such as AR-V7, play a key role in driving treatment resistance and disease progression. Importantly, the failure to attenuate AR-V function represents a major unmet clinical need, and as such, defining how AR-Vs are generated is likely to yield new therapeutic targets. Our knowledge of factors that mediate splicing of AR-V–encoding mRNAs remains limited. Here, we have employed an RNA-targeting CasRx approach to identify selective protein interactors of AR-V7 mRNA in PC. TRA2B and its ortholog, TRA2A, were identified as splicing regulators of AR transcripts that facilitate AR-V synthesis at the expense of full-length AR isoforms. TRA2B expression correlated with AR-V7 transcript in CRPC and attenuation of TRA2-mediated splicing diminished PC cell growth. Exploiting TRA2B function may therefore provide new therapeutic opportunities in advanced disease.

Authors

Nicholas Brittain, Alec Paschalis, Ryan Nelson, Beth Adamson, Laura Walker, Ruaridh Duncan, Graham R. Smith, Suzanne McGill, Richard J.S. Burchmore, Denisa Bogdan, Juan M. Jiménez-Vacas, Jonathan Welti, Wei Yuan, Craig N. Robson, Pasquale Rescigno, Sara Luzzi, Adam Sharp, Johann de Bono, Luke Gaughan