Polyamine synthesis as a target of MYC oncogenes

Abstract

This paper is in recognition of the 100th birthday of Dr. Herbert Tabor, a true pioneer in the polyamine field for over 70 years, who served as the editor-in-chief of the Journal of Biological Chemistry from 1971 to 2010. We review current knowledge of MYC proteins (c-MYC, MYCN, and MYCL) and focus on ornithine decarboxylase 1 (ODC1), an important bona fide gene target of MYC, which encodes the sentinel, rate-limiting enzyme in polyamine biosynthesis. Although notable advances have been made in designing inhibitors against the "undruggable" MYCs, their downstream targets and pathways are currently the main avenue for therapeutic anticancer interventions. To this end, the MYC-ODC axis presents an attractive target for managing cancers such as neuroblastoma, a pediatric malignancy in which MYCN gene amplification correlates with poor prognosis and high-risk disease. ODC and polyamine levels are often up-regulated and contribute to tumor hyperproliferation, especially of MYC-driven cancers. We therefore had proposed to repurpose α-difluoromethylornithine (DFMO), an FDA-approved, orally available ODC inhibitor, for management of neuroblastoma, and this intervention is now being pursued in several clinical trials. We discuss the regulation of ODC and polyamines, which besides their well-known interactions with DNA and tRNA/rRNA, are involved in regulating RNA transcription and translation, ribosome function, proteasomal degradation, the circadian clock, and immunity, events that are also controlled by MYC proteins.

Keywords: DFMO; MYC; Myc (c-Myc); Neuroblastoma clinical trials; ODC; cancer; circadian clock; glycolysis; neuroblastoma; polyamine; polyamines; proteasome; translation; translation initiation factor.

Figure 1.

Human MYC proteins. Shown is a schematic alignment of human c-MYC, MYCN, and MYCL. I–IV, MYC homology boxes I–IV; TAD, transactivation domain; NLS, nuclear localization signal; BR, basic region; HLH–LZ, helix-loop-helix–leucine zipper domain; aa, amino acid. Depicted are the longest RefSeq isoforms at NCBI_gene (https://www.ncbi.nlm.nih.gov/gene): NP_002458.2 (c-MYC IF1), NP_005369.2 (MYCN IF1), and NP_001028254.2 (MYCL IF3). Domains are assigned based on Ref. for c-MYC, and combined NCBI_gene annotation and BlastP alignment (https://blast.ncbi.nlm.nih.gov/Blast.cgi) for the other MYC proteins.

Figure 2.

Hypusine–polyamine pathway in human neuroblastoma. Shown is a graphical overview of the genes involved in eIF5A hypusination and polyamine metabolism with their protein activities and metabolites. Spermidine is the sole substrate and is mandatory for the synthesis of hypusine in eIF5A. Also shown are the action sites of the inhibitors used in neuroblastoma (NB) studies. References for additional inhibitor studies in neuroblastoma not named in the main text are as follows: DENSPM (164) and PG11047 (165). Genes are highlighted in green or red according to their prognostic value in Zhang-498, the largest publicly available RNA-Seq dataset for human neuroblastoma (166). Green or red indicates that high mRNA expression is significantly prognostic for poor or good patient survival in Kaplan-Meier analysis, respectively. In addition, gene mRNA expression was analyzed for correlation with MYCN gene amplification and MYCN mRNA expression using the R2 website (http://r2.amc.nl). (Please note that the JBC is not responsible for the long-term archiving and maintenance of this site or any other third party hosted site.) With the exception of DOHH and MAT1B, all other pathway genes that are prognostic for neuroblastoma also appear to be regulated by MYCN in this tumor. For more details on the analysis see Refs. , , . Data from Zhang-498 are available at the Gene Expression Omnibus database under accession number GSE62564. Reproduced with permission from Ref. . This research was originally published in Biochemical Journal. C. R. Schultz, D. Geerts, M. Mooney, R. El-Khawaja, J. Koster, and A. S. Bachmann. Synergistic drug combination GC7/DFMO suppresses hypusine/spermidine-dependent eIF5A activation and induces apoptotic cell death in neuroblastoma.. Biochem. J.2018; 475, 531–545. © Portland Press Ltd.