Transcription factor activating protein 4 is synthetically lethal and a master regulator of MYCN-amplified neuroblastoma
Autor: | Andrea Califano, Jose M. Silva, Darrell J. Yamashiro, Eileen P. Connolly, Jiyang Yu, Presha Rajbhandari, Debarshi Banerjee, Shuobo Boboila, Angela Kadenhe-Chiweshe, Jessica J. Kandel, Gonzalo Lopez |
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Jazyk: | angličtina |
Rok vydání: | 2018 |
Předmět: |
0301 basic medicine
Cancer Research Cellular differentiation Regulator Biology Article Small hairpin RNA 03 medical and health sciences Mice Neuroblastoma Cell Line Tumor Genetics medicine Gene silencing Animals Humans Gene Silencing Molecular Biology Transcription factor neoplasms Cell Proliferation Regulation of gene expression N-Myc Proto-Oncogene Protein Basic Helix-Loop-Helix Leucine Zipper Transcription Factors RNA-Binding Proteins Cell Differentiation medicine.disease 3. Good health DNA-Binding Proteins Gene Expression Regulation Neoplastic 030104 developmental biology Cancer research TFAP4 |
Zdroj: | Oncogene |
ISSN: | 1476-5594 0950-9232 |
Popis: | 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. |
Databáze: | OpenAIRE |
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