Abstract
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.
Original language | English (US) |
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Pages (from-to) | 1826-1833 |
Number of pages | 8 |
Journal | Molecular Cancer Research |
Volume | 16 |
Issue number | 12 |
DOIs | |
State | Published - Dec 1 2018 |
Funding
S.A. Gorman and O. Barbash have an ownership interest (including stock, patents, etc.) in GlaxoSmithKline. C.A. French reports receiving commercial research grant from, and is a consultant/advisory board member for, GlaxoSmithKline. No potential conflicts of interest were disclosed by the other authors. The authors thank Tim Martin (Harvard Medical School, Boston, MA) for providing the pAAV-tagBFP U6-gRNA expression vector. This work was supported by the Samuel Waxman Cancer Research Foundation, NIH R01 CA124633, R01CA124633-10S1, R01CA124633-10S2 (to C.A. French), NIH R01 GM101958 (to M.I. Kuroda), and by a GlaxoSmithKline postdoctoral fellowship (to H. Shiota).
ASJC Scopus subject areas
- Molecular Biology
- Oncology
- Cancer Research