Huang Furong, Li Kexin, Chen Zhong, Cui Zhifen, Hankey William, Fang Kun, Yan Jingyue, Wang Hongyan, Jin Victor X, Dong Yizhou, Wang Qianben
Department of Pathology, Duke University School of Medicine, Durham, NC, USA.
Data Science Institute, MCW Cancer Center and Mellowes Center for Genome Science and Precision Medicine, Medical College of Wisconsin, Milwaukee, WI, USA.
Oncogene. 2025 Mar;44(8):481-493. doi: 10.1038/s41388-024-03239-2. Epub 2024 Nov 29.
Acquired resistance to androgen receptor (AR)-targeted therapies underscores the need to identify alternative therapeutic targets for treating lethal prostate cancer. In this study, we evaluated the prognostic significance of 1635 human transcription factors (TFs) by analyzing castration-resistant prostate cancer (CRPC) datasets from the West and East Stand Up to Cancer (SU2C) cohorts. Through this screening approach, we identified E2F8, a putative transcriptional repressor, as a TF consistently associated with poorer patient outcomes in both cohorts. Notably, E2F8 is highly expressed and active in AR-negative CRPC compared to AR-positive CRPC. Integrative profiling of E2F8 cistromes and transcriptomes in AR-negative CRPC cells revealed that E2F8 directly and non-canonically activates target oncogenes involved in cancer-associated pathways. To target E2F8 in CRPC, we employed the CRISPR/CasRx system to knockdown E2F8 mRNA, resulting in effective and specific downregulation of E2F8 and its target oncogenes, as well as significant growth inhibition in AR-negative CRPC in both cultured cells and xenograft models. Our findings identify and characterize E2F8 as a targetable transcriptional activator driving CRPC, particularly the growth of AR-negative CRPC.
对雄激素受体（AR）靶向治疗产生的获得性耐药突出了识别治疗致命性前列腺癌替代治疗靶点的必要性。在本研究中，我们通过分析来自东西方“抗击癌症”（SU2C）队列的去势抵抗性前列腺癌（CRPC）数据集，评估了1635种人类转录因子（TFs）的预后意义。通过这种筛选方法，我们确定了一种假定的转录抑制因子E2F8，它是两个队列中均与较差患者预后持续相关的转录因子。值得注意的是，与AR阳性CRPC相比，E2F8在AR阴性CRPC中高度表达且具有活性。对AR阴性CRPC细胞中E2F8顺式作用元件组和转录组的综合分析表明，E2F8直接且非经典地激活参与癌症相关通路的靶癌基因。为了在CRPC中靶向E2F8，我们采用CRISPR/CasRx系统敲低E2F8 mRNA，导致E2F8及其靶癌基因有效且特异性地下调，以及在培养细胞和异种移植模型中对AR阴性CRPC产生显著的生长抑制。我们的研究结果确定并表征了E2F8是驱动CRPC尤其是AR阴性CRPC生长的可靶向转录激活因子。
