METTL14 promotes neuroblastoma by inhibiting YWHAH via an m6A-YTHDF1-dependent mechanism

Abstract Neuroblastoma (NB) is a widely recognized childhood tumor with high global incidence. The regulatory role of RNA N6-methyladenosine (m6A) in gene expression has gained significant attention, and the impact of methyltransferase-like 14 (METTL14) on tumor progression has been extensively investigated in various cancer types. Nevertheless, the precise influence of METTL14 on NB remains unexplored. Based on the data obtained from the Target database, our study revealed a significant upregulation of METTL14 expression in high-risk patients, which exhibited a strong correlation with a poor prognosis. Additionally, we identified ETS1 and YY1 as upstream regulators of METTL14, exerting control over its expression. In vitro experiments involving the knockdown of METTL14 in NB cells demonstrated a substantial inhibition of cell proliferation, migration, and invasion. Moreover, the suppression of METTL14 also resulted in the inhibition of NB tumorigenesis in nude mouse models. Through MeRIP-seq and RNA-seq analyses, we further discovered that YWHAH is a downstream gene of METTL14. Mechanistically, we observed that methylated YWHAH transcripts, particularly in the 5'UTR region, were specifically recognized by the m6A "reader" protein, YTHDF1, which promoted the degradation of YWHAH mRNA. Furthermore, the downregulation of YWHAH led to the activation of the PI3K/AKT signaling pathway, thereby facilitating the activity of neuroblastoma cells. Collectively, The findings of our study have provided valuable insights into the oncogenic effects of METTL14 in NB cells, highlighting its role in the inhibition of YWHAH expression through an m6A-YTHDF1-dependent mechanism. These results also indicate the potential utility of a biomarker panel for prognostic prediction in neuroblastoma.