MYCN acts as a direct co-regulator of p53 in MYCN amplified neuroblastoma
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Saurabh Agarwal1,*, Giorgio Milazzo2,*, Kimal Rajapakshe3,*, Ronald Bernardi1, Zaowen Chen1, Eveline Barberi1, Jan Koster4, Giovanni Perini2,**, Cristian Coarfa3,** and Jason M. Shohet1,**
1Division of Hematology-Oncology, Department of Pediatrics, Baylor College of Medicine, Houston, Texas, USA
2Department of Pharmacy and Biotechnology, University of Bologna, Bologna, Italy
3Dan L Duncan Cancer Center, Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas, USA
4Department of Oncogenomics, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands
*These authors are considered as co-first authors
**These authors are considered as co-last authors
Jason M. Shohet, email: firstname.lastname@example.org
Cristian Coarfa, email: email@example.com
Giovanni Perini, email: Giovanni.firstname.lastname@example.org
Keywords: neuroblastoma; MYCN; p53; p53 C-terminal domain; DNA damage resposone
Received: January 19, 2018 Accepted: March 06, 2018 Published: April 17, 2018
The MYC oncogenes and p53 have opposing yet interrelated roles in normal development and tumorigenesis. How MYCN expression alters the biology and clinical responsiveness of pediatric neuroblastoma remains poorly defined. Neuroblastoma is p53 wild type at diagnosis and repression of p53 signaling is required for tumorigenesis. Here, we tested the hypothesis that MYCN amplification alters p53 transcriptional activity in neuroblastoma. Interestingly, we found that MYCN directly binds to the tetrameric form of p53 at its C-terminal domain, and this interaction is independent of MYCN/MAX heterodimer formation. Chromatin analysis of MYCN and p53 targets reveals dramatic changes in binding, as well as co-localization of the MYCN-p53 complex at p53-REs and E-boxes of genes critical to DNA damage responses and cell cycle progression. RNA sequencing studies show that MYCN-p53 co-localization significantly modulated the expression of p53 target genes. Furthermore, MYCN-p53 interaction leads to regulation of alternative p53 targets not regulated in the presence of low MYCN levels. These novel targets include a number of genes involved in lipid metabolism, DNA repair, and apoptosis. Taken together, our findings demonstrate a novel oncogenic role of MYCN as a transcriptional co-regulator of p53 in high-risk MYCN amplified neuroblastoma. Targeting this novel oncogenic function of MYCN may enhance p53-mediated responses and sensitize MYCN amplified tumors to chemotherapy.
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