Abstract
MYCN, an oncogenic transcription factor of the Myc family, is a major driver of neuroblastoma tumorigenesis. Due to the difficulty in drugging MYCN directly, revealing the molecules in MYCN regulatory networks will help to identify effective therapeutic targets for neuroblastoma therapy. Here we perform ChIP-sequencing and small RNA-sequencing of neuroblastoma cells to determine the MYCN-binding sites and MYCN-associated microRNAs, and integrate various types of genomic data to construct MYCN regulatory networks. The overall analysis indicated that MYCN-regulated genes were involved in a wide range of biological processes and could be used as signatures to identify poor-prognosis MYCN-non-amplified patients. Analysis of the MYCN binding sites showed that MYCN principally served as an activator. Using a computational approach, we identified 32 MYCN co-regulators, and some of these findings are supported by previous studies. Moreover, we investigated the interplay between MYCN transcriptional and microRNA post-transcriptional regulations and identified several microRNAs, such as miR-124-3p and miR-93-5p, which may significantly contribute to neuroblastoma pathogenesis. We also found MYCN and its regulated microRNAs acted together to repress the tumor suppressor genes. This work provides a comprehensive view of MYCN regulations for exploring therapeutic targets in neuroblastoma, as well as insights into the mechanism of neuroblastoma tumorigenesis.
Highlights
Neuroblastoma (NB) is one of the most common extracranial solid tumors in infancy
To study the distribution of MYCN binding around promoter sequences, we aligned the peaks with the annotated transcriptional start sites (TSSs), which were provided by RefSeq
Since transcriptional regulation of TFs is tightly coupled with the post-transcriptional regulation of miRNAs, we investigated the coordination between MYCN and its regulated miRNAs by utilizing threeand four-node feed-forward loops (FFLs; Figure 5A), which are frequently observed network motifs in various regulatory networks [58,59,60]
Summary
Neuroblastoma (NB) is one of the most common extracranial solid tumors in infancy. These tumors occur most frequently in the adrenal medulla, but can originate anywhere along the sympathetic nervous system [1]. Patients with high-risk NB have a five-year survival rate of less than 50%, even with aggressive therapy [3]. Several genetic alterations are commonly found in NB cells, including MYCN amplification, 1p deletion, 11q deletion, and 17q gain, and these are often associated with high-risk tumors and an unfavorable outcome [4,5,6,7]. Understanding the molecular mechanisms underlying these genetic alterations might be helpful for the development of NB risk assessment and therapy
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