Abstract
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-AS1 and #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 of CRPC-Lnc #6. Thus, our investigation highlights a cluster of lncRNAs which could serve as AR regulators as well as potential biomarkers in CRPC.
Highlights
The molecular and cellular mechanisms of development of castration-resistant prostate cancer (CRPC) remain elusive
To explore the signals involved in prostate cancer progression, we identified transcripts upregulated in CRPC samples compared to both benign prostate and localized prostate cancer tissues and named this category as “Type_A” genes, which are assumed to be abundant in CRPC (Fig. 1b, c)
We found that most of them are upregulated in the metastatic CRPC tissues based on these microarray data, in line with our RNA-seq analysis (Fig. 1d)
Summary
The molecular and cellular mechanisms of development of castration-resistant prostate cancer (CRPC) remain elusive. We discovered AR-regulated lncRNAs, CRPC-Lncs, that are highly expressed in CRPC tissues. Silencing of two lncRNAs (CRPC-Lnc #6: PRKAG2-AS1 and #9: HOXC-AS1) alleviated CRPC tumor growth, showing repression of AR and AR variant expression. The variant AR-V7 was shown to regulate distinct and androgen-independent activation of its downstream signals, which contributes to the development of CRPC5,6. Long non-coding (lnc) RNAs have diverse functions such as epigenetic and gene regulation in cancer cells[7], including prostate cancer cells[8]. Previous reports highlighted lncRNA-mediated association of RNA-binding proteins or transcription factors with specific genomic regions in prostate cancer progression[9]. AS, in the antisense region of carboxyl terminal binding protein 1 (CTBP1) promotes castration-resistant tumor growth[10].
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
