Kosibaty Zeinab, Luck Cuyler, Okimoto Ross A
Department of Medicine, University of California, San Francisco, CA, USA.
Helen Diller Comprehensive Cancer Center, University of California, San Francisco, CA, USA.
Oncogene. 2025 Aug 4. doi: 10.1038/s41388-025-03507-9.
Transcription factor (TF) fusion oncoproteins represent cancer-specific alterations that arise from chromosomal rearrangements. Through target gene recognition, TF fusions can disseminate transcriptional responses that collectively work to drive tumorigenesis. Thus, identifying the molecular targets that operate as a disease-driving network can potentially uncover key actionable dependencies. We have taken this strategy to dissect the underlying biological mechanism by which CIC::DUX4, a fusion oncoprotein associated with dismal outcomes, drives sarcomagenesis. We and others have defined a CIC::DUX4 fusion-mediated network that dysregulates cell-cycle and DNA replication checkpoints. Specifically, CIC::DUX4-mediated CCNE1 upregulation compromises the G1/S transition, leading to high DNA replication stress and conferring a dependence on the G2/M checkpoint kinase, WEE1. WEE1 provides a molecular brake to enable effective DNA repair prior to mitotic entry. Importantly, the mechanism by which CIC::DUX4 regulates DNA repair remains unknown. Here we show that the catalytic subunit of DNA polymerase epsilon (POLE) is essential for DNA integrity and cellular division in CIC::DUX4 sarcoma. Mechanistically, POLE loss increases DNA damage and induces p21-mediated cellular senescence to limit CIC::DUX4 tumor growth in vitro and tumor formation in vivo. Collectively, we credential POLE as a CIC::DUX4 target and further characterize a functional network through which CIC::DUX4 operates to drive tumor progression and survival.
转录因子（TF）融合癌蛋白代表了由染色体重排产生的癌症特异性改变。通过靶基因识别，TF融合可以传播转录反应，这些反应共同作用以驱动肿瘤发生。因此，识别作为疾病驱动网络发挥作用的分子靶点可能会揭示关键的可操作依赖性。我们采用了这种策略来剖析与不良预后相关的融合癌蛋白CIC::DUX4驱动肉瘤发生的潜在生物学机制。我们和其他人已经定义了一个CIC::DUX4融合介导的网络，该网络失调细胞周期和DNA复制检查点。具体而言，CIC::DUX4介导的CCNE1上调损害G1/S期转换，导致高DNA复制应激，并赋予对G2/M检查点激酶WEE1的依赖性。WEE1提供一个分子刹车，以便在有丝分裂进入之前进行有效的DNA修复。重要的是，CIC::DUX4调节DNA修复的机制仍然未知。在这里，我们表明DNA聚合酶ε（POLE）的催化亚基对于CIC::DUX4肉瘤中的DNA完整性和细胞分裂至关重要。从机制上讲，POLE缺失会增加DNA损伤并诱导p21介导的细胞衰老，以限制CIC::DUX4在体外的肿瘤生长和体内的肿瘤形成。总的来说，我们证实POLE是CIC::DUX4的一个靶点，并进一步表征了一个功能网络，通过该网络CIC::DUX4发挥作用以驱动肿瘤进展和存活。
