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The long non-coding RNA HORAS5 mediates castration-resistant prostate cancer survival by activating the androgen receptor transcriptional program

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). The long non-coding RNA HORAS5 mediates castration-resistant prostate cancer survival by activating the androgen receptor transcriptional program. Molecular Oncology, 13(5) pp. 1121–1136.

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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.

Item Type: Journal Item
Copyright Holders: 2019 The Authors
ISSN: 1574-7891
Project Funding Details:
Funded Project NameProject IDFunding Body
Not SetNot SetCanadian Institutes of Health Research (CIHR)
Not SetNot SetProstate Cancer-Canada
Not SetNot SetTerry Fox Research Institute
Long non-coding RNAs implicated in neuroendocrine prostate cancer initiation and progression: novel therapeutic targets for an incurable disease.C58076/A22592Cancer Research UK (CRUK)
Keywords: lncRNAs; HORAS; HORAS5; prostate cancer; androgen-independence
Academic Unit/School: Faculty of Science, Technology, Engineering and Mathematics (STEM) > Life, Health and Chemical Sciences
Faculty of Science, Technology, Engineering and Mathematics (STEM)
Item ID: 59409
Depositing User: Rebecca Mather
Date Deposited: 01 Mar 2019 14:45
Last Modified: 22 Jan 2020 19:25
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