Abstract 4729: LSD1 activates oncogenic super-enhancers in castration-resistant prostate cancer by forming nuclear condensates with BRD4
Notice bibliographique
Résumé
Abstract Lysine-specific demethylase (LSD1) was initially identified as a transcriptional repressor through demethylation of mono/di-methylated histone 3 lysine 4 (H3K4me1/2). Subsequent work suggests that LSD1 may trigger gene activation via demethylating H3K9me1/2 in the context of steroid receptors. Our previous studies have confirmed that LSD1 functions broadly as a coactivator of androgen receptor (AR)-regulated enhancers but retains its H3K4 demethylation function at these sites. Importantly, our recent work revealed that LSD1 regulates the accessibility of active enhancers through the interaction with FOXA1, which functions as a pioneer transcription factor by facilitating AR access to chromatin LSD1 inhibition disrupts the global binding of FOXA1 by blocking the demethylation of K270 of FOXA1, leading to inhibition of AR binding and transcriptional activity. However, in addition to AR signaling, it remains largely unknown whether LSD1 regulates other critical oncogenic programs during prostate cancer (PCa) progression. In this study, we aimed to fully understand the functional targets of LSD1 in castration-resistant PCa (CRPC) models. We performed a large transcriptomic profiling of CRPC patient-derived xenograft (PDX) models that are sensitive to LSD1 inhibitors. Our analyses indicated that LSD1 inhibition targeted multiples oncogenic programs, including previously known pathways such as AR, FOXA1, and E2F, and a previously undefined pathway, MYC signaling. Through single-cell RNA-seq analysis in a CRPC PDX model, we confirmed that MYC signaling was decreased in the responsive tumor cells and identified a previously unknown molecular subtype, AR+/FOXA1+/LSD1low/RB1−, which was resistant to LSD1 inhibition. It is well known that MYC is driven by super-enhancers (SEs), which are regulated by BRD4 (bromodomain and extraterminal (BET) protein). We further evaluated LSD1, FOXA1 and BRD4 ChIP-seq and defined SEs by using H3K27ac ChIP-seq followed by ROSE analysis. We found that LSD1, FOXA1, and BRD4 co-occupied at MYC SEs and BRD4 was recruited by unmethylated FOXA1 but not K270-methylated FOXA1. In addition, we observed the puncta-like formation of LSD1/BRD4 marked nuclear condensates under confocal immunofluorescence microscopy. By examining the public datasets of H3K27ac ChIP-seq of samples with different stages of PCa development, we identified a subset of SEs which were distinctly activated in CRPC. Using multiple CRPC PDXs, we revealed that combining LSD1 inhibitors with BET inhibitors exhibited strong synergy possibly via disrupting the CRPC-specific SEs. In summary, this study reveals a novel oncogenic function of LSD1 in driving PCa progression by activating SE-driven oncogenic programs, such as MYC signaling. These results provide a strong therapeutic potential of combining inhibitors of LSD1 and BRD4 in treating CRPC. Citation Format: Mingyu Liu, Muqing Li, Dong Han, Zifeng Wang, Wanting Han, Housheng Hansen He, Shuai Gao, Changmeng Cai. LSD1 activates oncogenic super-enhancers in castration-resistant prostate cancer by forming nuclear condensates with BRD4. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4729.
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) | 0,002 | 0,000 |
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 ».