Downregulation of MYCN oncogene by retinoic acid in neuroblastoma

Abstract

Neuroblastoma is the most common extracranial solid tumor for children. Up to 30% of neuroblastoma tumors show the gene amplification of MYCN oncogene. Because MYCN plays a critical role, MYCN gene amplification is considered an important risk factor of neuroblastoma. Retinoic acid (RA) is one of the few agents which can improve the survival rate of patients in the high risk group. RA induces the growth arrest and cell differentiation of neuroblastoma cells. RA represses MYCN expression in neuroblastoma and it is the first molecular event which occurs prior to the cell differentiation. Therefore, it is believed that the downregulation of MYCN is the key step for cell differentiation of neuroblastoma by RA and its clinical benefit. However, the molecular mechanism of how RA downregulates MYCN is still unknown. A recent study revealed that the binding site of E2F transcription factor within the MYCN promoter is the key element for the repression of MYCN by RA in neuroblastoma. In this study, we figured out that MYCN downregulation starts before or around 6 hours after RA treatment, and the bindings of E2F proteins and Rb family proteins onto the MYCN promoter did not change during RA treatment. However, reporter assays with RNA interference revealed that Rb is essential for the repression of MYCN by RA, even though its binding onto the MYCN promoter does not change. Our findings indicate that Rb is involved in MYCN repression, acting as the connector for the real repressor, and RA treatment activates the real repressor at the MYCN promoter.