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E-GEOD-44319 - The E3 ubiquitin ligase Siah2 contributes to castration-resistant prostate cancer by regulation of androgen receptor transcriptional activity cancer

Status
Released on 15 February 2013, last updated on 24 February 2013
Organism
Homo sapiens
Samples (52)
Array (1)
Protocols (7)
Description
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. 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).
Experiment type
transcription profiling by array 
Contacts
Shawn Anderson <Sanderson@prostatecentre.com>, David Bowtell, Giuseppina Claps, Jianfei Qi, Ladan Fazli, Leland W Chung, Manisha Tripathi, Martin Gleave, Natasha Sahgal, Neil Bhowmick, Susan Ettinger, William J Placzek, Ze’ev A Ronai
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