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Oncogene. 2018 Oct;37(40):5451-5465. doi: 10.1038/s41388-018-0326-9. Epub 2018 Jun 7.

Transcription factor activating protein 4 is synthetically lethal and a master regulator of MYCN-amplified neuroblastoma.

Author information

1
Department of Pediatrics, Columbia University Medical Center, New York, NY, 10032, USA.
2
Department of Pathology and Cell Biology, Columbia University Medical Center, New York, NY, 10032, USA.
3
Department of Radiation Oncology, Columbia University Medical Center, New York, NY, 10032, USA.
4
Department of Systems Biology, Columbia University Medical Center, New York, NY, 10032, USA.
5
Department of Pediatrics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA.
6
Division of Oncology and Center for Childhood Cancer Research, Children's Hospital of Philadelphia, Philadelphia, PA, 19104, USA.
7
Department of Computational Biology, St. Jude Children's Research Hospital Kay Research and Care Center, IA6053, 262 Danny Thomas Place, Mail Stop 1135, Memphis, TN, 38105-3678, USA.
8
Department of Surgery, Columbia University Medical Center, New York, NY, 10032, USA.
9
Department of Surgery, Section of Pediatric Surgery, University of Chicago Medicine & Biological Sciences, Chicago, IL, 60637, USA.
10
Department of Biological Sciences, Columbia University, New York, NY, 10025, USA.
11
Department of Pathology, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA.
12
Department of Systems Biology, Columbia University Medical Center, New York, NY, 10032, USA. ac2248@cumc.columbia.edu.
13
Department of Pediatrics, Columbia University Medical Center, New York, NY, 10032, USA. dy39@cumc.columbia.edu.
14
Department of Pathology and Cell Biology, Columbia University Medical Center, New York, NY, 10032, USA. dy39@cumc.columbia.edu.
15
Department of Surgery, Columbia University Medical Center, New York, NY, 10032, USA. dy39@cumc.columbia.edu.

Abstract

Despite the identification of MYCN amplification as an adverse prognostic marker in neuroblastoma, MYCN inhibitors have yet to be developed. Here, by integrating evidence from a whole-genome shRNA library screen and the computational inference of master regulator proteins, we identify transcription factor activating protein 4 (TFAP4) as a critical effector of MYCN amplification in neuroblastoma, providing a novel synthetic lethal target. We demonstrate that TFAP4 is a direct target of MYCN in neuroblastoma cells, and that its expression and activity strongly negatively correlate with neuroblastoma patient survival. Silencing TFAP4 selectively inhibits MYCN-amplified neuroblastoma cell growth both in vitro and in vivo, in xenograft mouse models. Mechanistically, silencing TFAP4 induces neuroblastoma differentiation, as evidenced by increased neurite outgrowth and upregulation of neuronal markers. Taken together, our results demonstrate that TFAP4 is a key regulator of MYCN-amplified neuroblastoma and may represent a valuable novel therapeutic target.

PMID:
29880876
PMCID:
PMC6172192
DOI:
10.1038/s41388-018-0326-9
[Indexed for MEDLINE]
Free PMC Article

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