Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts.
Division of Genetics, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts.
Mol Cancer Res. 2018 Dec;16(12):1826-1833. doi: 10.1158/1541-7786.MCR-18-0474. Epub 2018 Aug 23.
Nuclear protein in testis (NUT) carcinoma (NC) is a rare, distinctly aggressive subtype of squamous carcinoma defined by the presence of -fusion oncogenes resulting from chromosomal translocation. In most cases, the gene () is fused to bromodomain containing 4 () forming the oncogene. Here, a novel fusion partner to was discovered using next-generation sequencing and FISH from a young patient with an undifferentiated malignant round cell tumor. Interestingly, the NUT fusion identified involved ZNF592, a zinc finger containing protein, which was previously identified as a component of the BRD4-NUT complex. In BRD4-NUT-expressing NC cells, wild-type ZNF592 and other associated "Z4" complex proteins, including ZNF532 and ZMYND8, colocalize with BRD4-NUT in characteristic nuclear foci. Furthermore, ectopic expression of BRD4-NUT in a non-NC cell line induces sequestration of Z4 factors to BRD4-NUT foci. Finally, the data demonstrate the specific dependency of NC cells on Z4 modules, ZNF532 and ZNF592. IMPLICATIONS: This study establishes the oncogenic role of Z4 factors in NC, offering potential new targeted therapeutic strategies in this incurable cancer. http://mcr.aacrjournals.org/content/molcanres/16/12/1826/F1.large.jpg.
睾丸核蛋白（NUT）癌（NC）是一种罕见的、明显侵袭性的鳞状细胞癌亚型，其特征是存在融合癌基因，这些基因是由于染色体易位产生的。在大多数情况下，基因（）与包含溴结构域的 4（）融合，形成 癌基因。在这里，使用下一代测序和 FISH 从一位患有未分化恶性圆形细胞肿瘤的年轻患者中发现了一种新型的 融合伙伴。有趣的是，鉴定出的 NUT 融合涉及 ZNF592，一种含锌指的蛋白质，它以前被鉴定为 BRD4-NUT 复合物的一个组成部分。在 BRD4-NUT 表达的 NC 细胞中，野生型 ZNF592 和其他相关的“Z4”复合物蛋白，包括 ZNF532 和 ZMYND8，与 BRD4-NUT 共定位在特征性的核斑点中。此外，BRD4-NUT 在非-NC 细胞系中的异位表达诱导 Z4 因子被隔离到 BRD4-NUT 斑点中。最后，数据表明 NC 细胞对 Z4 模块、ZNF532 和 ZNF592 的特异性依赖性。意义：这项研究确立了 Z4 因子在 NC 中的致癌作用，为这种无法治愈的癌症提供了潜在的新靶向治疗策略。http://mcr.aacrjournals.org/content/molcanres/16/12/1826/F1.large.jpg。
