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.

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.

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About

• Item ORO ID
• 59409
• Item Type
• Journal Item
• ISSN
• 1574-7891
• Project Funding Details

• Funded Project Name	Project ID	Funding Body
  Not Set	Not Set	Canadian Institutes of Health Research (CIHR)
  Not Set	Not Set	Prostate Cancer-Canada
  Not Set	Not Set	Terry Fox Research Institute
  Long non-coding RNAs implicated in neuroendocrine prostate cancer initiation and progression: novel therapeutic targets for an incurable disease.	Not Set	Cancer Research UK (CRUK)

• Keywords
• lncRNAs; HORAS; HORAS5; prostate cancer; androgen-independence
• Academic Unit or School
• Faculty of Science, Technology, Engineering and Mathematics (STEM) > Life, Health and Chemical Sciences
  Faculty of Science, Technology, Engineering and Mathematics (STEM)
• Research Group
• Cancer Research Group
• Copyright Holders
• © 2019 The Authors
• Depositing User
• Rebecca Mather