MYCN promotes neuroblastoma malignancy by establishing a regulatory circuit with transcription factor AP4
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Chengyuan Xue1,*, Denise M.T. Yu1,*, Samuele Gherardi2, Jessica Koach1, Giorgio Milazzo2, Laura Gamble1, Bing Liu1, Emanuele Valli1, Amanda J. Russell1, Wendy B. London3, Tao Liu1, Belamy B. Cheung1, Glenn M. Marshall1,4, Giovanni Perini2,5, Michelle Haber1,#, Murray D. Norris1,6,#
1Children’s Cancer Institute, Lowy Cancer Research Centre, University of New South Wales, Sydney, Australia
2Department of Pharmacy and Biotechnology, University of Bologna, Bologna, Italy
3Boston Children's Hospital and Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA
4Kids Cancer Centre, Sydney Children’s Hospital, Sydney, Australia
5CIRI Health Sciences and Technologies University of Bologna, Bologna, Italy
6University of New South Wales Centre for Childhood Cancer Research, Sydney, Australia
*Joint first authors
#Joint senior authors
Murray D. Norris, email: [email protected]
Michelle Haber, email: [email protected]
Keywords: neuroblastoma, cancer, MYCN oncogene, TFAP4, cell migration
Received: January 11, 2016 Accepted: June 16, 2016 Published: July 19, 2016
Amplification of the MYCN oncogene, a member of the MYC family of transcriptional regulators, is one of the most powerful prognostic markers identified for poor outcome in neuroblastoma, the most common extracranial solid cancer in childhood. While MYCN has been established as a key driver of malignancy in neuroblastoma, the underlying molecular mechanisms are poorly understood. Transcription factor activating enhancer binding protein-4 (TFAP4) has been reported to be a direct transcriptional target of MYC. We show for the first time that high expression of TFAP4 in primary neuroblastoma patients is associated with poor clinical outcome. siRNA-mediated suppression of TFAP4 in MYCN-expressing neuroblastoma cells led to inhibition of cell proliferation and migration. Chromatin immunoprecipitation assay demonstrated that TFAP4 expression is positively regulated by MYCN. Microarray analysis identified genes regulated by both MYCN and TFAP4 in neuroblastoma cells, including Phosphoribosyl-pyrophosphate synthetase-2 (PRPS2) and Syndecan-1 (SDC1), which are involved in cancer cell proliferation and metastasis. Overall this study suggests a regulatory circuit in which MYCN by elevating TFAP4 expression, cooperates with it to control a specific set of genes involved in tumor progression. These findings highlight the existence of a MYCN-TFAP4 axis in MYCN-driven neuroblastoma as well as identifying potential therapeutic targets for aggressive forms of this disease.
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