Abstract 1976: Androgen receptor activity is reprogrammed by lysine-specific demethylase 1 in prostate cancer
Notice bibliographique
Résumé
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.
Récupéré en direct depuis OpenAlex et désinversé. Les résumés ne sont pas conservés dans cette base de données : les index inversés représentent 8,6 Go des 9,3 Go de texte de la base, et le serveur dispose de 13 Go libres.
Comment cette classification a été obtenuedéplier
Prédiction machine sur la base complète
Imitation des enseignantsNi prévalence calibrée, ni vérité terrain. Validation humaine à venir. Le volet Gemma est une étiquette directe du modèle pour chaque travail de la base, lue sur la notice réduite au titre. Le volet Codex est un classifieur appris des 10 348 étiquettes directes de Codex et calibré sur les taux pondérés de l'échantillon; les champs sans appui suffisant ne portent aucun appel Codex. Le mode candidate est l'union des deux volets; le consensus est leur intersection. Ces sorties portent le statut machine_predicted_unvalidated et ne sont pas des étiquettes humaines.
Scores du classifieur distillé par catégorie (deux têtes)
| Catégorie | Codex | Gemma |
|---|---|---|
| Métarecherche | 0,000 | 0,000 |
| Méta-épidémiologie (sens strict) | 0,000 | 0,000 |
| Méta-épidémiologie (sens large) | 0,000 | 0,000 |
| Bibliométrie | 0,000 | 0,000 |
| Études des sciences et des technologies | 0,000 | 0,000 |
| Communication savante | 0,000 | 0,000 |
| Science ouverte | 0,000 | 0,000 |
| Intégrité de la recherche | 0,000 | 0,000 |
| Charge utile insuffisante (le modèle a refusé de juger) | 0,003 | 0,001 |
Scores machine (provisoires)
Les deux têtes enseignantes du modèle étudiant, lues sur ce travail. Un score ordonne la base pour la relecture; il n'affirme jamais une catégorie, et le statut de validation accompagne chaque rangée tel quel.
Scores de référence d'un modèle non mature (critères de maturité non atteints, 7 itérations). Un score ordonne; il n'affirme jamais une catégorie.
score_only:v0-immature-baseline · tel quel depuis la passe de notation : score_only signifie que le nombre peut ordonner les travaux, et qu'aucune étiquette de catégorie n'en découleClassification
machine, non validéePrédiction automatique; un appel candidat d’une seule source (Gemma direct ou Codex distillé), pas un consensus.
Le détail, modèle par modèle et score par score, se trouve en fin de page sous « Comment cette classification a été obtenue ».