Abstract
Although a rare disease, neuroblastoma accounts for the highest proportion of childhood cancer deaths. There is a lack of recurrent somatic mutations in neuroblastoma embryonal tumours, suggesting a possible role for epigenetic alterations in driving this cancer. While an increasing number of reports suggest an association of MYCN with epigenetic machinery, the mechanisms of these interactions are poorly understood in the neuroblastoma setting. Utilising chemo-genomic approaches we revealed global MYCN-epigenetic interactions and identified numerous epigenetic proteins as MYCN targets. The epigenetic regulators HDAC2, CBX8 and CBP (CREBBP) were all MYCN target genes and also putative MYCN interactors. MYCN-related epigenetic genes included SMARCs, HDACs, SMYDs, BRDs and CREBBP. Expression levels of the majority of MYCN-related epigenetic genes showed predictive ability for neuroblastoma patient outcome. Furthermore, a compound library screen targeting epigenetic proteins revealed broad susceptibility of neuroblastoma cells to all classes of epigenetic regulators, belonging to families of bromodomains, HDACs, HATs, histone methyltransferases, DNA methyltransferases and lysin demethylases. Ninety-six percent of the compounds reduced MYCN-amplified neuroblastoma cell viability. We show that the C646 (CBP-bromodomain targeting compound) exhibits switch-like temporal and dose response behaviour and is effective at reducing neuroblastoma viability. Responsiveness correlates with MYCN expression, with MYCN-amplified cells being more susceptible to C646 treatment. Thus, exploiting the broad vulnerability of neuroblastoma cells to epigenetic targeting compounds represents an exciting strategy in neuroblastoma treatment, particularly for high-risk MYCN-amplified tumours.
Highlights
Epigenetics is defined as non-DNA encoded heritable modifications, which result in altered gene expression levels (Jin et al, 2011)
We investigated the MYCN-related epigenetic signalling network, and the potential of epigenetic lead compounds as therapeutic agents for the treatment of high-risk MYCN amplified neuroblastoma
Forty-eight hour 10 μM C646 and 1 μM JQ1 combination treatment reduced cell viability to approximately 25% in both Dox− and Dox+ SY5Y-MYCN cells (Supplementary Figure 3C), whereas differentiated neurons were more tolerant of the combination treatment with approximately 70% remaining viable (Figure 4F). These results demonstrate that the C646 and JQ1 epigenetic targeting compounds are better tolerated by differentiated neurons than their more stem-like neuroblastoma cell counterparts
Summary
Epigenetics is defined as non-DNA encoded heritable modifications, which result in altered gene expression levels (Jin et al, 2011). Neuroblastoma begins in utero and the disease is predominantly diagnosed in the first year of life. Despite being rare, it accounts for 8–10% of all diagnosed childhood cancers (Stack et al, 2007; Dreidax et al, 2014; Henrich et al, 2016). Amplification of the MYCN oncogene, which occurs in approximately 20% of cases (Huang and Weiss, 2013), is one of the clearest markers for identifying high-risk neuroblastoma patients, regardless of disease stage. Is associated with advanced stage disease, an overall poor prognosis, and therapy resistance (Shimada et al, 2001), with MYCN-amplified tumours being resistant to current therapeutic approaches. Deeper understanding of MYCN dependent epigenetic vulnerabilities provides a novel route for targeted therapies in neuroblastoma
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