Abstract 4729: LSD1 activates oncogenic super-enhancers in castration-resistant prostate cancer by forming nuclear condensates with BRD4
Bibliographic record
Abstract
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.
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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) | 0.002 | 0.000 |
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".