The lncRNAs PART1 and ADAMTS9-AS2 act in an antithetic manner on AR signaling and induction of cellular senescence in prostate cancer cells.

BACKGROUND

Prostate cancer (PCa) is initially a hormone-dependent disease and the development and spread of PCa are tightly linked to the androgen receptor (AR) signaling activity. Therapy that targets the AR pathway is a standard approach for treating PCa including AR antagonists and supraphysiological androgen levels (SAL) used in bipolar androgen therapy. Here, we identified that the two lncRNAs PART1 and ADAMTS9-AS2 mediate in part androgen signaling in PCa cells by examining PCa specimen and response to AR antagonists or SAL as well as functionally by knockdown.

METHODS

This study utilized expression analysis of tumor tissues (TT) samples in comparison to their corresponding normal tissue adjacent to the tumor (NTAT) counterparts of 50 patients. RNA-seq and treatment of patient prostatectomy samples ex-vivo confirmed regulation of lncRNAs by SAL. Knockdown of both lncRNAs were used to analyze androgen signaling of AR target genes by qRT-PCR and in PCa senescence pathway by analyzing senescence markers. Correlation analyses of patient tumor samples confirmed co-expression. RNA immunoprecipitation (RIP) used in both LNCaP and C4-2 cells detect AR-lncRNA interaction. Bioinformatic analyses were employed to identify ligand-specific lncRNAs and miRNA interactions with PART1 and ADAMTS9-AS2 and confirmed by treatment of patient prostatectomy samples ex-vivo .

RESULTS

PART1 and ERVH48-1 were significantly overexpressed in TT samples, ADAMTS9-AS2 expression is lower in TT samples compared to NTAT samples. SAL treatment indicates opposite regulation in two human PCa cell lines and patient tumor samples. While ADAMTS9-AS2 is upregulated, PART1 is repressed by SAL. Furthermore, the obtained data suggest that ADAMTS9-AS2 may act as a co-activator and PART1 as a co-repressor of AR signaling. Interestingly, the knockdown indicates that both lncRNAs ADAMTS9-AS2 and PART1 regulate AR activity and protein level as well as SAL-mediated induction of cellular senescence. Thus, the data suggest that ADAMTS9-AS2 and PART1 control AR signaling at SAL.

CONCLUSION

In summary, we identified novel AR signaling pathways that involve lncRNAs oppositely regulated by SAL and in PCa tumorigenesis.