Abstract 5456: The E3 ubiquitin ligase Siah2 regulates the androgen receptor activity and contributes to castration-resistant prostate cancer.
Bibliographic record
Abstract
Abstract The androgen receptor (AR) plays a central role in the development of castration-resistant prostate cancer (CRPC), which is a major challenge for hormone therapy of advanced/metastatic prostate cancer (PCa). Here, we demonstrate that the ubiquitin ligase Siah2 targets a select pool of NCOR1-bound, transcriptionally inactive AR for ubiquitination-dependent degradation, and this promotes the subsequent recruitment of p300-bound, transcriptionally active AR to a select group of AR target gene promoters/enhancers. Consequently, Siah2 promotes the expression of ∼13% of androgen-responsive genes involved in lipid metabolism, cell motility and proliferation. 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 the androgen-deprivation condition 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. Citation Format: Jianfei Qi, Manisha Tripathi, Natasha Sahgal, Ladan Fazil, Susan Ettinger, William J. Placzek, Giuseppina Claps, Leland W.K. Chung, David Bowtell, Martin Gleave, Neil Bhowmick, Ze'ev Ronai. The E3 ubiquitin ligase Siah2 regulates the androgen receptor activity and contributes to castration-resistant prostate cancer. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 5456. doi:10.1158/1538-7445.AM2013-5456 Note: This abstract was not presented at the AACR Annual Meeting 2013 because the presenter was unable to attend.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.001 |
| Insufficient payload (model declined to judge) | 0.010 | 0.003 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".