Abstract 4082: Mechanisms of androgen receptor splicing in prostate cancer cells.
Bibliographic record
Abstract
Abstract Prostate tumors develop resistance to androgen deprivation therapy (ADT) involving multiple mechanisms, one of which is expression of the constitutively active androgen receptor (AR) splice variants, which lack the ligand-binding domain. AR-V7 is the most abundantly expressed of the constitutively active AR-splice variants. In the VCaP human prostate cancer cell line as well as several human prostate cancer xenografts that do not have intragenic AR gene rearrangements, AR-V7 is expressed in response to ADT, suggesting that AR-splicing may occur in association with AR gene transcription initiation and elongation rate. Inhibition of transcription in VCaP cells was examined using actinomycin D (ActD), benzimidazole (DRB) or trichostatin A (TSA). ActD and DRB eliminated, while TSA weakened, ADT's capability in inducing AR full-length (ARfl) and AR-V7 mRNA, indicating association of AR-splicing with AR gene transcription initiation and elongation rate. The decision as to which splicing site is excised is determined by both the regulatory RNA sequences (cis-elements) and their associated RNA splicing proteins (trans-elements). Using chromatin immunoprecipitation (ChIP) assays with primers amplifying pre-mRNA regions that correspond to the 5’ and 3’ splice regions for ARfl and AR-V7 we identified trans-splicing elements recruited by ADT as well as ADT induced recruitment of U1A, U2AF, ASF/SF2 and p54nrb to intron splice sites for generation of AR-V7. Similar recruitment of these splicing factors to the splice sites was not seen in LNCaP cells in which ADT does not increase AR-V7. To locate potential RNA sequences (cis-elements) that are responsible for AR-V7 splicing, we screened exon 3B and its flanking region using the Splicing Rainbow and ESEfinder 3.0 programs. One intronic splicing enhancer (ISE) and one exonic splicing enhancer (ESE) near the 3’ss of exon 3B were identified. Pull-down assays with oligos for the ISE demonstrated binding to hnRNP I and U2AF65, while the ESE bound ASF/SF2. The activity of these two motifs was confirmed using an AR-V7 minigene. When the various splicing motifs were mutated, AR-V7 was not generated. These RNA-protein interactions are also regulated by ADT. siRNA knock-down of hnRNP I, U2AF65, and ASF/SF2 suppressed AR-V7 expression in VCaP cells in response to ADT. These data indicate that ADT-induced AR gene transcription rate and splicing factor recruitment to AR pre-mRNA contribute to the enhanced AR-7 levels detected in prostate cancer cells. Pacific Northwest Prostate Cancer SPORE, National Cancer Institute (XD and SRP); Canadian Institute of Health Research (XD, MOP-97934); Department of Defense plus Veterans Administration Grants (SRP). Citation Format: Xeusen Dong, Liangliang Liu, Ning Xie, Shihua Sun, Stephen R. Plymate. Mechanisms of androgen receptor splicing in prostate cancer cells. [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 4082. doi:10.1158/1538-7445.AM2013-4082
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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 | 0.000 |
| Insufficient payload (model declined to judge) | 0.003 | 0.002 |
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".