The expression of ELOVL4, repressed by MYCN, defines neuroblastoma patients with good outcome
- 31 July 2021
- journal article
- research article
- Published by Springer Science and Business Media LLC in Oncogene
- Vol. 40 (38), 5741-5751
- https://doi.org/10.1038/s41388-021-01959-3
Abstract
Cancer cells exhibit dysregulation of critical genes including those involved in lipid biosynthesis, with subsequent defects in metabolism. Here, we show that ELOngation of Very Long chain fatty acids protein 4 (ELOVL4), a rate-limiting enzyme in the biosynthesis of very-long polyunsaturated fatty acids (n-3, ≥28 C), is expressed and transcriptionally repressed by the oncogene MYCN in neuroblastoma cells. In keeping, ELOVL4 positively regulates neuronal differentiation and lipids droplets accumulation in neuroblastoma cells. At the molecular level we found that MYCN binds to the promoter of ELOVL4 in close proximity to the histone deacetylases HDAC1, HDAC2, and the transcription factor Sp1 that can cooperate in the repression of ELOVL4 expression. Accordingly, in vitro differentiation results in an increase of fatty acid with 34 carbons with 6 double bonds (FA34:6); and when MYCN is silenced, FA34:6 metabolite is increased compared with the scrambled. In addition, analysis of large neuroblastoma datasets revealed that ELOVL4 expression is highly expressed in localized clinical stages 1 and 2, and low in high-risk stages 3 and 4. More importantly, high expression of ELOVL4 stratifies a subsets of neuroblastoma patients with good prognosis. Indeed, ELOVL4 expression is a marker of better overall clinical survival also in MYCN not amplified patients and in those with neuroblastoma-associated mutations. In summary, our findings indicate that MYCN, by repressing the expression of ELOVL4 and lipid metabolism, contributes to the progression of neuroblastoma.This publication has 51 references indexed in Scilit:
- Cooperative Synthesis of Ultra Long-Chain Fatty Acid and Ceramide during Keratinocyte DifferentiationPLOS ONE, 2013
- MYC inhibition induces metabolic changes leading to accumulation of lipid droplets in tumor cellsProceedings of the National Academy of Sciences of the United States of America, 2013
- A SP1/MIZ1/MYCN Repression Complex Recruits HDAC1 at the TRKA and p75NTR Promoters and Affects Neuroblastoma Malignancy by Inhibiting the Cell Response to NGFCancer Research, 2011
- Coordination of Lipid Metabolism in Membrane BiogenesisAnnual Review of Cell and Developmental Biology, 2009
- Role of Stargardt-3 macular dystrophy protein (ELOVL4) in the biosynthesis of very long chain fatty acidsProceedings of the National Academy of Sciences of the United States of America, 2008
- Statins Increase p21 through Inhibition of Histone Deacetylase Activity and Release of Promoter-Associated HDAC1/2Cancer Research, 2008
- Combined analysis of oligonucleotide microarray data from transgenic and knockout mice identifies direct SREBP target genesProceedings of the National Academy of Sciences of the United States of America, 2003
- Arachidonic acid synthesis and lipid metabolism in retinoic acid-differentiated neuroblastoma cellsJournal of Lipid Mediators and Cell Signalling, 1996
- Phenotype-specific “tissue” transglutaminase regulation in human neuroblastoma cells in response to retinoic acid: Correlation with cell death by apoptosisInternational Journal of Cancer, 1992
- Biology of pediatric peripheral neuroectodermal tumorsCancer and Metastasis Reviews, 1991