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| Status |
Public on Feb 15, 2013 |
| Title |
The E3 ubiquitin ligase Siah2 contributes to castration-resistant prostate cancer by regulation of androgen receptor transcriptional activity cancer. |
| Organism |
Homo sapiens |
| Experiment type |
Expression profiling by array
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| Summary |
The androgen receptor (AR) plays a central role in the development of castration resistant prostate cancer (CRPC). Here, we demonstrate that the ubiquitin ligase Siah2 targets a select pool of NCOR1-bound, transcriptionally inactive AR for ubiquitination dependent degradation, thereby promoting the expression of ~13% of AR target genes. The Siah2 binding sites located within the AR ligand-binding domain are mutated in PCa, resulting in attenuation of Siah2-mediated regulation. Siah2 is required for growth of PCa cells under androgen-deprivation conditions in vitro and in vivo. Significantly, inhibition of Siah2 promotes PCa regression upon castration and Siah2 expression is markedly increased in human CRPCs. Collectively our findings identify a key role for Siah2 in CRPC through the selective regulation of AR transcriptional activity.
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| Overall design |
Tumor Harvest. When tumor size reached approximately 1.5 cm in diameter (6-8 weeks after injection), and the serum PSA was greater than 50 ng/ml, animals were surgically castrated under methoxyfluorane anesthesia and monitored for PSA levels for several weeks. Animals were sacrificed by carbon dioxide asphyxiation when tumors were harvested at several points along the PSA curve (pre-castrate (11), regressing (6), nadir (10), recurring (6) and castration resistant (12). Tumor segments were placed in RNALater (Qiagen) and frozen immediately at -80°C.weeks. Tumors were harvested at several points along the PSA curve. The epithelial:stromal ratio is consistent within this tumor model and varies 10% between tumors, as assessed by immunohistochemistry of cytokeratin 14 (epithelium) and vimentin (stroma).
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| Contributor(s) |
Qi J, Tripathi M, Sahgal N, Ettinger S, Fazli L, Placzek WJ, Claps G, Chung LW, Bowtell D, Gleave M, Bhowmick N, Ronai ZA |
| Citation missing |
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| |
| Submission date |
Feb 14, 2013 |
| Last update date |
Oct 17, 2018 |
| Contact name |
Shawn Anderson |
| E-mail(s) |
[email protected]
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| Organization name |
Vancouver Prostate Centre
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| Lab |
Laboratory for Advanced Genome Analysis
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| Street address |
2660 Oak Street
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| City |
Vancouver |
| State/province |
BC |
| ZIP/Postal code |
V6H3Z6 |
| Country |
Canada |
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| Platforms (1) |
| GPL16604 |
Agilent-032034 VPC Human 180K v3 (Probe Name version) |
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| Samples (52)
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| Relations |
| BioProject |
PRJNA189455 |
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