Table1_Integrated high-throughput analysis identifies super enhancers in metastatic castration-resistant prostate cancer.XLSX

Background: Metastatic castration-resistant prostate cancer (mCRPC) is a highly aggressive stage of prostate cancer, and non-mutational epigenetic reprogramming plays a critical role in its progression. Super enhancers (SE), epigenetic elements, are involved in multiple tumor-promoting signaling pathways. However, the SE-mediated mechanism in mCRPC remains unclear.Methods: SE-associated genes and transcription factors were identified from a cell line (C4-2B) of mCRPC by the CUT&Tag assay. Differentially expressed genes (DEGs) between mCRPC and primary prostate cancer (PCa) samples in the GSE35988 dataset were identified. What’s more, a recurrence risk prediction model was constructed based on the overlapping genes (termed SE-associated DEGs). To confirm the key SE-associated DEGs, BET inhibitor JQ1 was applied to cells to block SE-mediated transcription. Finally, single-cell analysis was performed to visualize cell subpopulations expressing the key SE-associated DEGs.Results: Nine human TFs, 867 SE-associated genes and 5417 DEGs were identified. 142 overlapping SE-associated DEGs showed excellent performance in recurrence prediction. Time-dependent receiver operating characteristic (ROC) curve analysis showed strong predictive power at 1 year (0.80), 3 years (0.85), and 5 years (0.88). The efficacy of his performance has also been validated in external datasets. In addition, FKBP5 activity was significantly inhibited by JQ1.Conclusion: We present a landscape of SE and their associated genes in mCPRC, and discuss the potential clinical implications of these findings in terms of their translation to the clinic.

背景：转移性去势抵抗性前列腺癌（mCRPC）是前列腺癌的高度侵袭性阶段，非突变表观遗传重编程在其进展中扮演着至关重要的角色。超级增强子（SE），作为一种表观遗传元件，参与多种肿瘤促进信号通路。然而，mCRPC中SE介导的机制尚不明确。方法：通过CUT&Tag检测法从mCRPC细胞系（C4-2B）中鉴定了SE相关的基因和转录因子。在GSE35988数据集中，鉴定了mCRPC与原发前列腺癌（PCa）样本之间的差异表达基因（DEGs）。此外，基于重叠基因（称为SE相关DEGs）构建了复发风险预测模型。为了验证关键SE相关DEGs，对细胞施加了BET抑制剂JQ1以阻断SE介导的转录。最终，通过单细胞分析来可视化表达关键SE相关DEGs的细胞亚群。结果：鉴定出九种人类转录因子、867个SE相关基因和5417个DEGs。142个重叠的SE相关DEGs在复发预测中表现出优异的性能。时间依赖性受试者工作特征（ROC）曲线分析显示，在1年（0.80）、3年（0.85）和5年（0.88）时具有强大的预测能力。其效能亦已在外部数据集中得到验证。此外，FKBP5活性被JQ1显著抑制。结论：本研究呈现了mCRPC中SE及其相关基因的图谱，并探讨了这些发现的临床转化潜力，以及其在临床应用中的潜在意义。