A G316A Polymorphism in the Ornithine Decarboxylase Gene Promoter Modulates MYCN-Driven Childhood Neuroblastoma

Ornithine decarboxylase (ODC1), a critical regulatory enzyme in polyamine biosynthesis, is a direct transcriptional target of MYCN, amplification of which is a powerful marker of aggressive neuroblastoma. A single nucleotide polymorphism (SNP), G316A, within the first intron of , results in genotype...

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Bibliographic Details
Published in:Cancers 2021-04, Vol.13 (8), p.1807
Main Authors: Gamble, Laura D, Purgato, Stefania, Henderson, Michelle J, Di Giacomo, Simone, Russell, Amanda J, Pigini, Paolo, Murray, Jayne, Valli, Emanuele, Milazzo, Giorgio, Giorgi, Federico M, Cowley, Mark, Ashton, Lesley J, Bhalshankar, Jaydutt, Schleiermacher, Gudrun, Rihani, Ali, Van Maerken, Tom, Vandesompele, Jo, Speleman, Frank, Versteeg, Rogier, Koster, Jan, Eggert, Angelika, Noguera, Rosa, Stallings, Raymond L, Tonini, Gian Paolo, Fong, Kwun, Vaksman, Zalman, Diskin, Sharon J, Maris, John M, London, Wendy B, Marshall, Glenn M, Ziegler, David S, Hogarty, Michael D, Perini, Giovanni, Norris, Murray D, Haber, Michelle
Format: Article
Language:English
Subjects:
Acetylation
Alleles
C cells
Cancer
Cell growth
Children
Cloning
Colorectal cancer
CRISPR
Enzymes
Gene polymorphism
Genetic diversity
Genotype & phenotype
Growth rate
Histones
Influence
Medical prognosis
Neuroblastoma
Neuroblastoma cells
Ornithine decarboxylase
Patients
Polyamines
Polymorphism
Single-nucleotide polymorphism
Transcription
Transcription factors
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Summary:Ornithine decarboxylase (ODC1), a critical regulatory enzyme in polyamine biosynthesis, is a direct transcriptional target of MYCN, amplification of which is a powerful marker of aggressive neuroblastoma. A single nucleotide polymorphism (SNP), G316A, within the first intron of , results in genotypes wildtype GG, and variants AG/AA. CRISPR-cas9 technology was used to investigate the effects of AG clones from wildtype -amplified SK-N-BE(2)-C cells and the effect of the SNP on MYCN binding, and promoter activity was investigated using EMSA and luciferase assays. AG clones exhibited decreased expression, growth rates, and histone acetylation and increased sensitivity to ODC1 inhibition. MYCN was a stronger transcriptional regulator of the promoter containing the G allele, and preferentially bound the G allele over the A. Two neuroblastoma cohorts were used to investigate the clinical impact of the SNP. In the study cohort, the minor AA genotype was associated with improved survival, while poor prognosis was associated with the GG genotype and AG/GG genotypes in -amplified and non-amplified patients, respectively. These effects were lost in the GWAS cohort. We have demonstrated that the G316A polymorphism has functional significance in neuroblastoma and is subject to allele-specific regulation by the MYCN oncoprotein.
ISSN:2072-6694
2072-6694
DOI:10.3390/cancers13081807