miR-214 alters glucose metabolism and mitochondrial functions in melanoma

Metabolic reprogramming is a hallmark of cancer, that allows malignant cells to energetically sustain their activities, including proliferation and metastasis formation, and to survive in harsh microenvironment and upon stress conditions. microRNAs (miRNAs) are small non-coding RNAs that negatively modulate their mRNA targets at the post-transcriptional level. Some miRNAs are known metabolic regulators, able to affect cell behaviour in health and disease. In the present study, we assessed the metabolic impact of the pro-metastatic miR-214 on melanoma cells. We observed that it promoted aerobic glycolysis, which, in turn, affected cell metastatic traits. Indeed, upon glycolysis inhibition, miR-214-mediated improved migration and adhesion were abolished. Moreover, we found out that miR-214 induced mitochondrial dysfunction, reflected by a decreased mitochondrial activity and an enhanced mitochondrial damage. In addition, it downregulated key proteins involved in mitochondrial dynamics. Among them, we identified Mitofusin 2 (MFN2), a previously demonstrated miR-214 direct target, as potential player mediating miR-214-regulation of melanoma metabolism. Furthermore, we explored miR-214 effects on some signaling pathways controlling cell metabolism. We observed that miR-214 activated AMPK, while it inhibited AKT. In our hypothesis, MFN2 targeting by miR-214 could be responsible for mitochondrial dysfunction, which, in turn, could lead to glycolysis upregulation via AMPK activation.