PLX246411

GSE100568: Combined epigenetic and differentiation-based treatment inhibits neuroblastoma tumor growth and links HIF2 to tumor suppression

• Organsim human
• Type RNASEQ
• Target gene
• Project ARCHS4

Neuroblastoma is a pediatric cancer characterized by variable outcomes ranging from spontaneous regression to life-threatening progression. High-risk neuroblastoma patients receive myeloablative chemotherapy with hematopoietic stem-cell transplant followed by adjuvant retinoid differentiation treatment. However, the overall survival remains low; hence, there is an urgent need for alternative therapeutic approaches. One feature of high-risk neuroblastoma is the high level of DNA methylation of putative tumor suppressors. Combining the reversibility of DNA methylation with the differentiation-promoting activity of retinoic acid (RA) could provide an alternative strategy to treat high-risk neuroblastoma. Here we show that treatment with the DNA demethylating drug 5-Aza-deoxycytidine (AZA) restores high-risk neuroblastoma sensitivity to RA. Combined systemic distribution of AZA and RA impedes tumor growth and prolongs survival. Genomewide analysis of treated tumors reveals that this combined treatment rapidly induces a HIF2-associated hypoxia-like transcriptional response followed by an increase in neuronal gene expression and a decrease in cell-cycle gene expression. A small-molecule inhibitor of HIF2 activity diminishes the tumor response to AZA+RA treatment, indicating that the increase in HIF2 levels is a key component in tumor response to AZA+RA. The link between increased HIF2 levels and inhibited tumor growth is reflected in large neuroblastoma patient datasets. Therein, high levels of HIF2, but not HIF1, significantly correlate with expression of neuronal differentiation genes and better prognosis but negatively correlate with key features of high-risk tumors, such as MYCN amplification. Thus, contrary to previous studies, our findings indicate an unanticipated tumor-suppressive role for HIF2 in neuroblastoma. SOURCE: Johan Holmberg (johan.holmberg@ki.se) - Karolinska Institute