HIF2α negatively regulates MYCN protein levels and promotes a low-risk noradrenergic phenotype in neuroblastoma

The role of HIF2α, encoded by <i>EPAS1</i>, in neuroblastoma remains controversial. Here, we demonstrate that induction of high levels of HIF2α in MYCN-amplified neuroblastoma cells results in a rapid and profound reduction of the oncoprotein MYCN. This is followed by an upregulation of genes characteristic of noradrenergic cells in the adrenal medulla. Additionally, upon induction of HIF2α, the proliferation rate drops substantially, and cells develop elongated neurite-like protrusions, indicative of differentiation. In vivo HIF2α induction in established xenografts significantly attenuates tumor growth. Notably, analysis of sequenced neuroblastoma patient samples, revealed a negative correlation between <i>EPAS1</i> and <i>MYCN</i> expression and a strong positive correlation between <i>EPAS1</i> expression, high expression levels of noradrenergic markers, and improved patient outcome. This was paralleled by analysis of human developing adrenal medulla datasets wherein <i>EPAS1</i> expression was prominent in populations with high expression levels of genes characteristic of noradrenergic chromaffin cells. Our findings show that high levels of HIF2α in neuroblastoma, leads to drastically reduced MYCN protein levels, cell cycle exit, and noradrenergic cell differentiation. Taken together, our results challenge the dogma that HIF2α acts as an oncogene in neuroblastoma.