MYCN Amplifications and Metabolic Rewiring in Neuroblastoma

Abstract

Cancer is a disease caused by (epi)genomic and gene expression abnormalities and characterized by metabolic phenotypes that are substantially different from the normal phenotypes of the tissues of origin. Metabolic reprogramming is one of the key features of tumors, including those established in the human nervous system. In this work, we emphasize a well-known cancerous genomic alteration: the amplification of MYCN and its downstream effects in neuroblastoma phenotype evolution. Herein, we extend our previous computational biology investigations by conducting an integrative workflow applied to published genomics datasets and comprehensively assess the impact of MYCN amplification in the upregulation of metabolism-related transcription factor (TF)-encoding genes in neuroblastoma cells. The results obtained first emphasized overexpressed TFs, and subsequently those committed in metabolic cellular processes, as validated by gene ontology analyses (GOs) and literature curation. Several genes encoding for those TFs were investigated at the mechanistic and regulatory levels by conducting further omics-based computational biology assessments applied on published ChIP-seq datasets retrieved from MYCN-amplified- and MYCN-enforced-overexpression within in vivo systems of study. Hence, we approached the mechanistic interrelationship between amplified MYCN and overexpression of metabolism-related TFs in neuroblastoma and showed that many are direct targets of MYCN in an amplification-inducible fashion. These results illuminate how MYCN executes its regulatory underpinnings on metabolic processes in neuroblastoma.