Identification of long non-coding RNAs in advanced prostate cancer associated with androgen receptor splicing factors

By RNA sequencing of prostate cancer samples, Takayama et al identify a cluster of lncRNAs that are enriched in castration-resistant prostate cancer. This cluster is regulated by androgen receptor (AR) and associate with factors involved in AR splicing, suggesting a role for these lncRNAs in AR signalling and tumorigenesis. The molecular and cellular mechanisms of development of castration-resistant prostate cancer (CRPC) remain elusive. Here, we analyzed the comprehensive and unbiased expression profiles of both protein-coding and long non-coding RNAs (lncRNAs) using RNA-sequencing to reveal the clinically relevant molecular signatures in CRPC tissues. For protein-coding genes upregulated in CRPC, we found that mitochondria-associated pathway, androgen receptor (AR), and spliceosome associated genes were enriched. Moreover, we discovered AR-regulated lncRNAs,CRPC-Lncs, that are highly expressed in CRPC tissues. Notably, silencing of two lncRNAs (CRPC-Lnc #6:PRKAG2-AS1and#9:HOXC-AS1) alleviated CRPC tumor growth, showing repression of AR and AR variant expression. Mechanistically, subcellular localization of the splicing factor, U2AF2, with an essential role in AR splicing machinery was modulated dependent on the expression level ofCRPC-Lnc #6. Thus, our investigation highlights a cluster of lncRNAs which could serve as AR regulators as well as potential biomarkers in CRPC.