MYCN and Its Posttranslational Regulation in Neuroblastoma

High-risk neuroblastoma is frequently associated with amplification of the MYCN oncogene and this genetic aberration correlates strongly with poor prognosis in neuroblastoma patients. However, amplification of MYCN also offers new therapeutic opportunities since tumor cells that become addicted to high levels of N-Myc protein can be selectively targeted. In untransformed neuronal precursor cells, N-Myc is regulated by a series of posttranslational modifications that lead to its proteasomal degradation during mitosis. Neuroblastoma cells harboring amplification of MYCN, however, have developed mechanisms that impede the physiological degradation of N-Myc in order to sustain the high N-Myc activity required for proliferation and survival. Interference with this posttranslational regulation by pharmacologic inhibition of target proteins provides novel therapeutic approaches for neuroblastoma treatment. In this chapter, we will discuss the posttranslational regulation of N-Myc under physiological conditions as well as the mechanisms that MYCN-amplified neuroblastoma cells employ to evade this regulation. We will focus on the posttranslational regulation of N-Myc by PI3K/Akt signaling, Aurora-A, anaplastic lymphoma kinase and histone deacetylases. Furthermore, we will highlight to what extent this knowledge has been translated into new clinical treatment options.