Abstract
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.
Highlights
Neuroblastoma accounts for almost 15% of all pediatric cancer mortality
To evaluate non-canonical MYCN functions we first tested the hypothesis that MYCN and p53 closely associate when p53 is activated in the presence of high levels of MYCN
We used multiple complementary approaches, including RNA-Seq, ChIP-Seq, metadata analysis, and co-IPs, to define a novel direct interaction between MYCN and p53. This interaction alters the transcriptional activation of critical p53 target genes known to regulate DNA-damage repair and apoptotic responses, opposing p53 functions of apoptosis and promoting cell cycle progression and proliferation
Summary
Neuroblastoma accounts for almost 15% of all pediatric cancer mortality. In approximately 50% of high-risk cases (25% overall), MYCN is amplified with between 10 to 500 additional copies of this oncogene (as double minutes or HSRs) and up to 10,000 copies of MYCN mRNA leading to very high levels of the MYCN protein. Neuroblastoma tumors with low levels of MYCN have better overall responses to chemotherapy, www.oncotarget.com significantly better overall survival, and higher response rates to second line chemotherapy regimens [1, 2]. MYCN amplified tumors tend to relapse earlier and rapidly develop chemotherapy resistance [3]. Patients with relapsed MYCN amplified tumors have less than 5% overall survival. Despite its well-defined negative impact on clinical outcome, the mechanisms distinguishing the clinical behavior of MYCN amplified and non-amplified neuroblastoma remain poorly defined. Most published prognostic gene signatures have little overlap and the primary risk factor for poor outcome remains MYCN expression levels. The primary factor distinguishing high-risk tumors and predicting overall survival remains MYCN amplification itself
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