SETD8 Inhibition Activates p53 in High-Risk Neuroblastoma

MYCN amplification reduces p53 activity in a subset of neuroblastomas, but in patients with MYCN–wild-type high-risk neuroblastoma the mechanisms by which p53 activity is attenuated are not clear. Few druggable recurrent mutations have been identified in patients with high-risk neuroblastoma, suggesting the possibility that epigenetic dysregulation may promote neuroblastoma initiation and progression. Veschi and colleagues performed a high-throughput siRNA screen to find epigenetic regulators whose depletion reduced cell proliferation and induced differentiation, identifying 53 genes whose loss of function inhibited the growth of neuroblastoma cells, including 16 that also induced differentiation. These results together with a chemical screen of 21 compounds that target epigenetic regulators pointed to an essential role for the histone methyltransferase SETD8, which catalyzes monomethylation of lysine 20 on histone H4 (H4K20me1). SETD8 and H4K20me1 levels were increased in neuroblastoma cells compared to nontransformed cells, and, in MYCN–wild-type primary neuroblastomas, elevated SETD8 expression was associated with a poor prognosis. RNA sequencing of SETD8-depleted cells revealed an upregulation of genes associated with p53 signaling and neuronal differentiation, suggesting that loss of SETD8 promotes differentiation and p53 activation. Moreover, SETD8 depletion in neuroblastoma cells resulted in decreased levels of H4K20me1 and reduced p53 monomethylation (p53K382me1), which resulted in increased activation of the canonical p53 pathway, reduced cell growth, and increased apoptosis. Similarly, a small-molecule SETD8 inhibitor, UNC0379, activated p53 to induce p53-dependent cell death in neuroblastoma cells. In vivo, UNC0379-treated neuroblastoma cells grew more slowly than control cells, thereby extending the survival of tumor bearing mice. Collectively, these findings indicate that SETD8 monomethylates p53 to suppress its activity and promote tumor growth, and suggest that targeting SETD8 may be a potential therapeutic strategy to activate p53 in patients with high-risk neuroblastoma.

Veschi V, Liu Z, Voss TC, Ozbun L, Gryder B, Yan C, et al. Epigenetic siRNA and chemical screens identify SETD8 inhibition as a therapeutic strategy for p53 activation in high-risk neuroblastoma. Cancer Cell 2017;31:50–63.