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| Status |
Public on Jul 20, 2018 |
| Title |
The miR-96 and RARG signaling axis governs androgen signaling and prostate cancer progression IV |
| Organism |
Homo sapiens |
| Experiment type |
Expression profiling by array
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| Summary |
Expression levels of retinoic acid receptor gamma (NR1B3/RARG, encodes RARG), are commonly reduced in prostate cancer (PCa). Therefore we sought to establish the cellular and gene regulatory consequences of reduced RARG expression, and determine RARG regulatory mechanisms. RARG shRNA approaches in non-malignant (RWPE-1 and HPr1-AR) and malignant (LNCaP) prostate models revealed that reducing RARG levels, rather than adding exogenous retinoid ligand, had the greatest impact on prostate cell viability and gene expression. ChIP-Seq defined the RARG cistrome which was significantly enriched at active enhancers associated with AR binding sites. Reflecting a significant genomic role for RARG to regulate androgen signaling, RARG knockdown in HPr1-AR cells significantly regulated the magnitude of the AR transcriptome. RARG down-regulation was explained by increased miR-96 in PCa cell and mouse models, and TCGA PCa cohorts. Biochemical approaches confirmed that miR-96 directly regulated RARG expression and function. Capture of the miR-96 targetome by biotin-miR96 identified that RARG and a number of RARG interacting co-factors including TACC1 were all targeted by miR-96, and expression of these genes were prominently altered, positively and negatively, in the TCGA-PRAD cohort. Differential gene expression analyses between tumors in the TCGA-PRAD cohort with lower quartile expression levels of RARG and TACC1 and upper quartile miR-96, compared to the reverse, identified a gene network including several RARG target genes (e.g. SOX15) that significantly associated with worse disease free survival (hazard ratio 2.23, 95% CI 1.58 to 2.88, p=0.015). In summary, miR-96 targets a RARG network to govern AR signaling, PCa progression and disease outcome.
RWPE1 non-malignant, immortalized cell line +/- shRARG, +/- 10nM CD437 for 24 hours
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| Overall design |
12 sample total, 4 experimental conditions (each in triplicate); shCTL-DMSO, shCTL_CD437, shRARG-DMSO, shRARG-CD437
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| Contributor(s) |
Long MD, Smiraglia DJ, Campbell MJ |
| Citation(s) |
30120411 |
| |
| Submission date |
Jul 13, 2018 |
| Last update date |
Oct 17, 2018 |
| Contact name |
Mark D Long |
| E-mail(s) |
mark.long@roswellpark.org
|
| Organization name |
Roswell Park Comprehensive Cancer Center
|
| Department |
Bioinformatics & Biostatistics
|
| Street address |
Elm & Carlton Streets
|
| City |
Buffalo |
| State/province |
NY |
| ZIP/Postal code |
14263 |
| Country |
USA |
| |
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| Platforms (1) |
| GPL10558 |
Illumina HumanHT-12 V4.0 expression beadchip |
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| Samples (12)
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| This SubSeries is part of SuperSeries: |
| GSE117182 |
The miR-96 and RARG signaling axis governs androgen signaling and prostate cancer progression |
|
| Relations |
| BioProject |
PRJNA481052 |
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