Unsaturated fatty acid synthesis is associated with poor prognosis and differentially regulated by MYCN and tumor suppressor microRNAs in neuroblastoma

MYCN amplification and disruption of tumor suppressor microRNA (TSmiR) function are central drivers of poor outcomes in neuroblastoma (NB). MYC, MYCN, and TSmiRs regulate glucose metabolism; however, their role in unsaturated fatty acid synthesis (UFAS) remains poorly understood. Here we show that de novo and UFAS pathway genes FASN , ELOVL6 , SCD , FADS2 , and FADS1 are upregulated in high-risk NB and are associated with poor prognosis. RNA-Seq analysis of eight human NB cell lines revealed parallel UFAS gene expression patterns. Consistent with this, we found that NB-related TSmiRs were predicted to extensively target these genes. In addition, we observed that both MYC and MYCN upregulated UFAS pathway genes while suppressing TSmiR host gene expression, thereby creating a possible UFAS regulatory network between MYCN and TSmiRs in NB. Furthermore, NB cells are high in omega 9 (ω9) unsaturated fatty acids that can be synthesized de novo and low in both ω6 and ω3, providing a plausible means for NB to limit cell-autonomous immune stimulation and reactive oxygen species (ROS)-driven apoptosis from ω6 and ω3 unsaturated fatty acid derivatives, respectively. We propose a model in which the UFAS pathway, through novel regulation by MYCN and TSmiRs, plays a key role in neuroblastoma pathology with implications for other MYC -driven cancers. ### Competing Interest Statement The authors have declared no competing interest. * ALA : alpha-linolenic acid (18:3ω3) AR : omega-6 arachidonic acid (20:4ω6) DH : omega-3 docosahexaenoic acid (22:6ω3) DTr : omega-9 docosatrienoic acid (22:3ω9) EFAD : essential fatty acid deficiency F : fatty acid(s) FAS : de novo fatty acid synthesis (pathway) FAS-core : genes, ( FASN, ELOVL6, SCD, FADS2, FADS1 ) FPKM : fragments per kilobase of exon per million mapped fragments HUF : highly unsaturated fatty acids; 3 or more double bonds L : linoleic acid (18:2ω6) Mead : Mead acid (20:3ω9 NB : neuroblastoma NHF : normal human fibroblasts O : omega-9 oleic acid (18:1ω9) TSmiRs : tumor suppressor microRNAs UFAS : unsaturated fatty acid synthesis (pathways) U/FAS : unsaturated and de novo fatty acid synthesis (pathways) ω3 : omega-3 ω6 : omega-6 ω9 : omega-9