"Z4" complex member fusions in nut carcinoma: Implications for a novel oncogenic mechanism

Hitoshi Shiota, Janine E. Elya, Artyom A. Alekseyenko, Pauline M Chou, Shelby A. Gorman, Olena Barbash, Kelly Becht, Kristina Danga, Mitzi I. Kuroda, Valentina Nardi, Christopher A. French*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

7 Scopus citations

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 languageEnglish (US)
Pages (from-to)1826-1833
Number of pages8
JournalMolecular Cancer Research
Volume16
Issue number12
DOIs
StatePublished - Dec 1 2018

ASJC Scopus subject areas

  • Molecular Biology
  • Oncology
  • Cancer Research

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