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 noncoding RNA (lncRNA) represent an uncharted region of the transcriptome. Several lncRNA have been recently described to mediate oncogenic functions, suggesting that these molecules can be potential therapeutic targets. Here, we identified CRPC‐associated lncRNA by analyzing patient‐derived xenografts (PDXs) and clinical data. Subsequently, we characterized one of the CRPC‐promoting lncRNA,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 lncRNA function in cancer progression.
Highlights
Prostate cancer (PCa) proliferation is fueled by activation of the androgen receptor (AR)-signaling pathway (Culig and Santer, 2014)
To identify Long noncoding RNA (lncRNA) that are up-regulated upon progression of primary PCa to castration-resistant PCa (CRPC), we analyzed our unique collection of PCa patient-derived xenograft (PDX) models (Lin et al, 2014a)
We decided to focus on the intergenic subclass of lncRNA that are coded on distinct chromosomal loci and are easier to functionally characterize
Summary
Prostate cancer (PCa) proliferation is fueled by activation of the androgen receptor (AR)-signaling pathway (Culig and Santer, 2014). Androgens directly bind to the AR and trigger this process. Hormone-deprivation therapy (aka surgical or medical ‘castration’) is an effective therapeutic strategy for localized and metastatic PCa. a substantial fraction of prostatic neoplasms (~ 25%) develop resistance to castration, mainly via genetic and/or epigenetic alterations that enable aberrant ligand-independent activation of AR-signaling (Feldman and Feldman, 2001; Scher and Sawyers, 2005) and cell survival pathways (Gao et al, 2013; Karantanos et al, 2013). Despite the development of new therapies that delay disease progression, castration-resistant PCa (CRPC) is still an incurable disease (Chandrasekar et al, 2015).
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