Targeting MYCN: a good BET for improving neuroblastoma therapy?

Abstract

Direct targeting of oncogenic MYC proteins has been an elusive goal of many cancer drug development efforts. In this issue of Cancer Discovery, Stegmaier and colleagues demonstrate that pharmacologically interfering with the bromodomain and extraterminal (BET) class of proteins potently depletes MYCN in neuroblastoma cells, resulting in cellular cytotoxicity and thus providing a novel approach with a potential impact on a previously undruggable major oncogene.

Figure 1

Inhibition of BRD4 complex acetyl-lysine recognition by JQ1. A, BRD4 binds to the MYCN promoter at acetyl-lysine residues, recruiting additional proteins (such as the histone methyltransferase NSD3) that mediate chromatin density and allow for active MYCN transcription. MYCN target genes subsequently increase cellular proliferation by fostering cell-cycle progression as well as inhibiting apoptosis and blocking neuronal differentiation. B, JQ1 displaces BRD4 from the MYCN promoter, thus inhibiting MYCN transcription and leading to cell-cycle arrest, increased apoptosis, and increased neuritogenesis required for terminal differentiation.