Background: MYCN amplification is a prognostic biomarker associated with poor prognosis of
neuroblastoma in children. The overall survival of children with MYCN-amplified neuroblastoma has only
marginally improved within the last 20 years. The Bromodomain and Extra-Terminal motif (BET) inhibitor,
JQ1, has been shown to downregulate MYCN in neuroblastoma cells.
Objective: To determine if JQ1 downregulation of MYCN in neuroblastomas can offer a target- specific therapy
for this, difficult to treat, pediatric cancer.
Methods: Since MYCN-amplified neuroblastoma accounts for as much as 40 to 50 percent of all high-risk
cases, we compared the effect of JQ1 on both MYCN-amplified and non-MYCN-amplified neuroblastoma cell
lines and investigated its mechanism of action.
Results: In this study, we show that JQ1 can specifically target MYCN for downregulation, though this effect is
not specific to only MYCN-amplified cells. And although we can confirm that the loss of MYCN alone can
induce apoptosis, the exogenous rescue of MYCN expression can abrogate much of this cytotoxicity. More
fascinating, however, was the discovery that the JQ1-induced knockdown of MYCN, which led to the loss of the
human double minute 2 homolog (HDM2) protein, also led to the accumulation of tumor protein 53 (also known
as TP53 or p53), which ultimately induced apoptosis. Likewise, the knockdown of p53 also blunted the cytotoxic
effects of JQ1.
Conclusion: These data suggest a mechanism of action for JQ1 cytotoxicity in neuroblastomas and offer a possible
prognostic target for determining its efficacy as a therapeutic.