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Parolia, Abhijit; Venalainen, Erik; Xue, Hui; Mather, Rebecca; Lin, Dong; Wu, Rebecca; Pucci, Perla; Rogalski, Jason; Evans, Joseph; Feng, Felix; Collins, Colin; Wang, Yuzhuo and Crea, Francesco
(2019).
DOI: https://doi.org/10.1002/1878-0261.12471
Abstract
Prostate Cancer (PCa) is driven by the androgen receptor (AR)-signaling axis. Hormonal therapy often mitigates PCa progression, but a notable number of cases progress to castration-resistant PCa (CRPC). CRPC retains AR-activity and is incurable. Long non-coding RNAs (lncRNAs) represent an uncharted region of the transcriptome. Several lncRNAs have been recently described to mediate oncogenic functions, suggesting that these molecules can be potential therapeutic targets. Here, we identified CRPC-associated lncRNAs by analyzing patient-derived xenografts (PDXs) and clinical data. Subsequently, we characterized one of the CRPC-promoting lncRNAs, HORAS5, in vitro and in vivo. We demonstrated that HORAS5 is a stable, cytoplasmic lncRNA that promotes CRPC proliferation and survival by maintaining AR activity under androgen-depleted conditions. Most strikingly, knockdown of HORAS5 causes a significant reduction in the expression of AR itself and oncogenic AR targets such as KIAA0101. Elevated expression of HORAS5 is also associated with worse clinical outcomes in patients. Our results from HORAS5 inhibition in in vivo models further confirm that HORAS5 is a viable therapeutic target for CRPC. Thus, we posit that HORAS5 is a novel, targetable mediator of CRPC through its essential role in the maintenance of oncogenic AR activity. Overall, this study adds to our mechanistic understanding of how lncRNAs function in cancer progression.
CORE (COnnecting REpositories)
CORE (COnnecting REpositories)
