2026/03/31 by Nicholas Brittain, Alec Paschalis, Ryan Nelson +16 · 1 voice
Biochemistry, Genetics and Molecular Biology · Medicine · #Prostate Cancer Diagnosis and Treatment #Prostate Cancer Treatment and Research #RNA Research and Splicing
paper · doi:10.1172/jci198264
openalex publication_date 2026/03/31 · openalex created_date 2026/04/02 · openalex updated_date 2026/07/31
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.