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"Z4" Complex Member Fusions in NUT Carcinoma: Implications for a Novel Oncogenic Mechanism
Hitoshi Shiota1, Janine E Elya1, Artyom A Alekseyenko2,3
1Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts.
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.Visual Overview: http://mcr.aacrjournals.org/content/molcanres/16/12/1826/F1.large.jpg.
Insights
Researchers discovered a new fusion partner, ZNF592, for the NUT gene in Nuclear protein in testis (NUT) carcinoma. This finding highlights the oncogenic role of Z4 factors, offering potential new therapeutic targets for this aggressive cancer.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Nuclear protein in testis (NUT) carcinoma (NC) is a rare, aggressive squamous carcinoma.
- NC is characterized by NUT-fusion oncogenes, most commonly BRD4-NUT, resulting from chromosomal translocations.
Purpose of the Study:
- To identify novel NUT fusion partners in NC.
- To investigate the role of Z4 complex proteins in NC pathogenesis.
- To explore Z4 factors as potential therapeutic targets.
Main Methods:
- Next-generation sequencing and Fluorescence In Situ Hybridization (FISH) were used to identify gene fusions.
- Immunofluorescence microscopy was employed to study protein localization.
- Ectopic expression studies were performed in cell lines.
Main Results:
- A novel NUT fusion involving ZNF592 was identified in a patient with NC.
- Wild-type ZNF592 and other Z4 complex proteins (ZNF532, ZMYND8) colocalize with BRD4-NUT in nuclear foci.
- Ectopic BRD4-NUT expression induced Z4 factor sequestration.
- NC cells demonstrated a specific dependency on ZNF532 and ZNF592.
Conclusions:
- ZNF592 is a novel oncogenic fusion partner for NUT in NC.
- Z4 factors play a critical oncogenic role in NC.
- Targeting Z4 factors presents a potential therapeutic strategy for NC.