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

Shuobo Boboila1,2,3, Gonzalo Lopez4,5,6, Jiyang Yu4,7

  • 1Department of Pediatrics, Columbia University Medical Center, New York, NY, 10032, USA.

Oncogene
|June 9, 2018
PubMed

Insights

Transcription factor activating protein 4 (TFAP4) is a critical effector of MYCN amplification in neuroblastoma. Silencing TFAP4 inhibits neuroblastoma growth and induces differentiation, offering a novel therapeutic target.

Area of Science:

  • Oncology
  • Molecular Biology
  • Genetics

Background:

  • MYCN amplification is a poor prognostic marker in neuroblastoma.
  • Effective MYCN inhibitors are currently lacking for neuroblastoma treatment.

Purpose of the Study:

  • To identify novel therapeutic targets for MYCN-amplified neuroblastoma.
  • To investigate the role of transcription factor activating protein 4 (TFAP4) in neuroblastoma.

Main Methods:

  • Whole-genome shRNA library screen to identify key effectors.
  • Computational inference of master regulator proteins.
  • In vitro and in vivo studies including xenograft mouse models.

Main Results:

  • TFAP4 identified as a critical effector of MYCN amplification.
  • TFAP4 is a direct MYCN target, negatively correlating with patient survival.
  • TFAP4 silencing selectively inhibits MYCN-amplified neuroblastoma growth and induces differentiation.

Conclusions:

  • TFAP4 is a key regulator in MYCN-amplified neuroblastoma.
  • TFAP4 represents a promising synthetic lethal target for neuroblastoma therapy.

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