Neuroblastoma is a tumor that poses important challenges to establishing more effective and less toxic therapies, and industry is hardly engaged in developing new specific drugs. Reasons are the marked heterogeneity of the tumor, a substantial lack of deep understanding of its molecular basis, the paucity of targetable driving mutations.
The ascertained role of segmental chromosomal aberrations and, therefore, gene expression imbalances in guiding aggressiveness and the embryonic derivation of neuroblastoma initiating cells could suggest an involvement of post-transcriptional control of gene expression in the phenotypic derangement of this tumor.
The importance of mRNA methylation has remained a mystery for decades until rapid advances in the field of epitranscriptomics and RNA sequencing have raised the exciting hypothesis that reversible N6-methyl-adenosine (m6A) modification of mRNA may constitute an essential mechanism of post-transcriptional regulation. Currently, the function of mRNA methylation and the signaling pathways controlling mRNA methylation are still in the route of being uncovered, but m6A-mediated gene expression control has already proved to be an indispensable process guiding self-renewal and differentiation of embryonic stem cells.
We found that the expression of the methyltransferase METTL14 is specifically higher in neuroblastoma compared to other solid-tumor cell types. We also found that increased levels of the METTL14 methyltransferase, along with that of the m6A-binding protein YTHDF1, are associated with worse clinical features and poor prognoses. When overexpressed, METTL14 increases the growth rate of neuroblastoma cells, while its depletion reduces proliferation and tumor-spheroid formation. Further data will be required to substantiate the hypothesis that modulation of mRNA methylation might have a direct impact on gene expression during neuroblastoma progression although the possibility of reversing m6A modifications through enzymatic inhibitors may open the way to conceive new prospects for therapeutic intervention.