50 patients' tumor tissue samples showed significant overexpression of PART1 and ERVH48-1 compared to normal adjacent tissues.
Two , PART1 and ADAMTS9-AS2, have been identified as regulators of androgen signaling in prostate cancer cells.
signaling appears to be oppositely regulated by supraphysiological androgen levels, with ADAMTS9-AS2 being upregulated and PART1 repressed.
Knockdown experiments indicate that both lncRNAs influence androgen receptor activity and protein levels, affecting .
ADAMTS9-AS2 may function as a co-activator while PART1 may act as a co-repressor in the context of androgen receptor signaling.
The findings suggest novel pathways of androgen receptor signaling that involve these lncRNAs and their roles in prostate cancer development.
Simplified
BACKGROUND: Prostate cancer (PCa) is initially a hormone-dependent disease and the development and spread of PCa are tightly linked to the (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 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 . 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.
Key numbers
13.1
Expression Ratio of
Expression ratio of in tumor tissues vs. non-tumor adjacent tissues.
3.6
Expression Ratio of
Expression ratio of in tumor tissues vs. non-tumor adjacent tissues.
0.726
Correlation Coefficient with PSA Levels
Correlation coefficient between expression and PSA levels in patient samples.
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