TY - JOUR
T1 - "Z4" complex member fusions in nut carcinoma
T2 - Implications for a novel oncogenic mechanism
AU - Shiota, Hitoshi
AU - Elya, Janine E.
AU - Alekseyenko, Artyom A.
AU - Chou, Pauline M
AU - Gorman, Shelby A.
AU - Barbash, Olena
AU - Becht, Kelly
AU - Danga, Kristina
AU - Kuroda, Mitzi I.
AU - Nardi, Valentina
AU - French, Christopher A.
N1 - Funding Information:
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.
Funding Information:
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).
Publisher Copyright:
© 2018 American Association for Cancer Research.
PY - 2018/12/1
Y1 - 2018/12/1
N2 - 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.
AB - 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.
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U2 - 10.1158/1541-7786.MCR-18-0474
DO - 10.1158/1541-7786.MCR-18-0474
M3 - Article
C2 - 30139738
AN - SCOPUS:85055717251
SN - 1541-7786
VL - 16
SP - 1826
EP - 1833
JO - Molecular Cancer Research
JF - Molecular Cancer Research
IS - 12
ER -
