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Transcription Factor Activating Protein 4 is synthetically lethal and a master regulator of MYCN-amplified neuroblastoma

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 up-regulation of neuronal markers. Taken together, our results demonstrate that TFAP4 is a master regulator of MYCN-amplified neuroblastoma and may represent a valuable novel therapeutic target.

ORGANISM(S): Homo sapiens

PROVIDER: GSE102652 | GEO | 2017/11/15

SECONDARY ACCESSION(S): PRJNA398270

REPOSITORIES: GEO

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| phs000868 | dbGaP

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