Genetic amplification ofMYCNand disruption of tumor suppressor (TS) microRNA (miRNA) function are central indicators of poor outcome in neuroblastoma (NB). While both MYC family activity and TS miRNAs (TSmiRs) have been broadly implicated in glucose metabolism, their role in unsaturated fatty acid synthesis (UFAS) is poorly understood. We show here that UFAS pathway genesFASN, ELOVL6, SCD, FADS2, andFADS1are overexpressed in human NB cell lines. Based on these data, we show that UFAS are associated with poor prognosis in high-risk NB patients, and that these genes contain extensive target sites for TSmiRsmiR-1, let-7, miR-22, miR-26, miR-34, miR-142, andmiR-204, all of which are known NB-associated TSmiR families. Several lines of evidence including KEGG pathway analysis indicate that increased MYC/N expression downregulates TSmiR which then attenuates inhibition of UFAS genes, causing increased synthesis of HUFA. Human NB cells grown under standard culture conditions are rich in ω9 Mead acid, and low in ω3 docosahexaenoic acid (DHA) and ω6 arachidonic acid (ARA) and adrenic acid (AdrA), consistent with dramatic upregulation of UFAS genes in NB. With this profile, immune stimulating ω6 fatty acid metabolites and reactive oxygen species (ROS)-driven apoptosis from ω3 fatty acids would both be low. Collectively, these observations establish a model in which the UFAS pathway plays a key role in NB patient outcomes, identifying novel roles forMYCNtranscriptional regulation of FAS and UFAS genes, as well as TSmiR post-transcriptional regulation of the UFAS pathway in NB, and MYC family driven cancers in general.

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