Abstract 966: LSD1 functions as a global androgen receptor coactivator and is a therapeutic target in prostate cancer
Bibliographic record
Abstract
Abstract Androgen receptor (AR) plays a pivotal role in prostate cancer (PCa) and remains critical for more aggressive castration-resistant PCa (CRPC) through transactivation of multiple genes. Although CRPC is generally responsive to further CYP17A1 inhibition (abiraterone) or more potent AR antagonist (enzalutamide) treatments, patients treated with these agents still relapse within 1-2 years, and high levels of AR and AR regulated genes in many of these relapsed tumors indicate that AR activity has again been restored. Therefore, there remains a need for further novel AR targeted therapies. Initially identified as a component in the REST complex that functions as a transcriptional suppressor, Lysine Specific Demethylase 1 (LSD1) removes the methyl group from histone 3 lysine 4 (H3K4me1 and 2), and turns off the marks of active transcription. Our recent genome-wide integrated analysis of LSD1 and AR chromatin bindings and gene expression profiles indicates that LSD1 is broadly associated with AR regulated enhancers, and LSD1 functions as a coactivator on AR-stimulated genes through demethylating novel histone or nonhistone substrates in addition to H3K4me. LSD1 is also associated with FOXA1 at AR regulated enhancer sites, and an LSD1-FOXA1 interaction enhances binding of both proteins at these sites. These results clearly demonstrated LSD1 as a therapeutic target in prostate cancer. We then accessed if LSD1 enzymatic activity is required for its global AR coactivator function. AR transcription activity is significantly impaired in cells overexpressing a catalytic-deficient LSD1 mutant. In addition, this mutant also decreased FOXA1 binding on AR-regulated enhancers. We then selected of a panel of LSD1 inhibitors (a few of them have been used in clinical trials for lung cancer and leukemia) to assess the effects on AR activity and PCa cell growth. Inhibition of LSD1 consistently impaired AR activity through abrogating acetylated H3K27 at AR-regulated enhancers. LSD1 inhibitor also decreased FOXA1 binding prior to androgen stimulation. While most of inhibitors showed relatively low efficacy in PCa cells (>50μM), LSD1-C12 is highly potent and specific at μM range to dramatically decrease AR activity and PCa cell growth. Overall, our study suggests that the AR coactivator function of LSD1 depends on its enzymatic activity and targeting LSD1 with more specific and potent inhibitors is a promising therapeutic approach to treat PCa. Furthermore, understanding the mechanism of LSD1 coactivator function will potentially advance PCa therapy by targeting LSD1. Citation Format: Shuai Gao, Yanfei Gao, Hansen He, Myles Brown, Steve Balk, Changmeng Cai. LSD1 functions as a global androgen receptor coactivator and is a therapeutic target in prostate cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 966. doi:10.1158/1538-7445.AM2015-966
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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) | 0.005 | 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".