"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

doi:10.1158/1541-7786.MCR-18-0474

"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

Pathology

Research output: Contribution to journal › Article › peer-review

53 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 language	English (US)
Pages (from-to)	1826-1833
Number of pages	8
Journal	Molecular Cancer Research
Volume	16
Issue number	12
DOIs	https://doi.org/10.1158/1541-7786.MCR-18-0474
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

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1158/1541-7786.MCR-18-0474

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title = "{"}Z4{"} complex member fusions in nut carcinoma: Implications for a novel oncogenic mechanism",

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.",

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

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doi = "10.1158/1541-7786.MCR-18-0474",

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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.

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

Abstract

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