PLX099035

GSE102652: Transcription Factor Activating Protein 4 is synthetically lethal and a master regulator of MYCN-amplified neuroblastoma

• Organsim human
• Type RNASEQ
• Target gene
• Project ARCHS4

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. SOURCE: Gonzalo LopezMaris Lab Children's Hospital of Philadelphia