Abstract 1976: Androgen receptor activity is reprogrammed by lysine-specific demethylase 1 in prostate cancer
Bibliographic record
Abstract
Abstract In the recurrent PCa treated with CYP17A1 inhibitor (abiraterone) and more potent AR antagonist (enzalutamide), high levels of AR and AR regulated genes indicate that AR activity has been restored. One major mechanism that contributes to the disease recurrence is reprogramming of AR cistrome by collaborations of other key transcriptional factors and chromatin modifiers. In this process, AR will be recruited to a subset of newly opened enhancers that can drive the expression of genes promoting tumor cell proliferation. Lysine Specific Demethylase 1 (LSD1) is well known for repressing transcription by removing the methyl group from histone 3 lysine 4 (H3K4me1/2). However, our genome-wide integrated analysis in prostate cancer cells reveals that LSD1 is broadly associated with AR regulated enhancers that are marked by high levels of H3K4me2 and functions as a coactivator of AR. Significantly, LSD1 also tightly associates with pioneer factor FOXA1, and LSD1-FOXA1 interaction enhances binding of both proteins at AR-mediated enhancers. As increased demethylase activity of LSD1 has been reported in several types of cancers including prostate cancer, we hypothesize that LSD1 can reprogram AR cistrome via the interaction with FOXA1 to regulate the availability of enhancers. To test this hypothesis, we performed ChIP-qPCR analyses of LSD1, FOXA1, AR, and histone marks for active enhancers such as H3K4me1,2 and acetylated H3K27 in prostate cancer cells stably expressing wild type LSD1 versus catalytic-deficient mutant, and in cells treated with LSD1 inhibitors. FOXA1 binding on AR-regulated enhancers was significantly decreased by LSD1 inhibition. Importantly, the active histone marks were also decreased at those sites, indicating inactivation of enhancers. These results clearly demonstrated that the availability of AR-mediated enhancers could be dynamically tuned by LSD1-FOXA1 to facilitate prostate cancer development. We are currently carrying out the whole genome ChIP-seq analyses on FOXA1 and enhancer marks to examine the global impact on enhancer availability by inhibiting LSD1. Mechanistically, by immunoprecipitation of methyl-lysine antibody we further showed that methylated FOXA1 is a direct substrate of LSD1 and the demethylase activity of LSD1 is absolutely required for regulating the FOXA1 binding to chromatin. By liquid chromatography-tandem mass spectrometry (LC/MS/MS), we are currently trying to identify and characterize the methylated-lysine sites on FOXA1 in cells treated with LSD1 inhibitor and cells overexpressing the catalytic-deficient LSD1 mutant. Overall, our study suggests that the LSD1-FOXA1 interaction plays important function in determination of active enhancer prior to AR recruitment and targeting LSD1 in conjunction with AR antagonists may be a promising therapeutic approach to treat PCa. Citation Format: Shuai Gao, Dong Han, Yanfei Gao, Hansen He, Wanting Han, Steve Balk, Changmeng Cai. Androgen receptor activity is reprogrammed by lysine-specific demethylase 1 in prostate cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1976.
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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 | 0.001 |
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".