“Z4” Complex Member Fusions in NUT Carcinoma: Implications for a Novel Oncogenic Mechanism

Nuclear protein in testis (NUT) carcinoma (NC) is a rare, distinctly aggressive subtype of squamous carcinoma defined by the presence of NUT -fusion oncogenes resulting from chromosomal translocation. In most cases, the NUT gene ( NUTM1 ) is fused to bromodomain containing 4 ( BRD4 ) forming the BRD4-NUT oncogene. Here, a novel fusion partner to NUT 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. Visual Overview: http://mcr.aacrjournals.org/content/molcanres/16/12/1826/F1.large.jpg. Mol Cancer Res; 16(12); 1826–33. ©2018 AACR .