The eIF3a/m6A/ENO1 axis orchestrates glycolytic reprogramming and cell growth in cervical cancer

Glycolysis plays a key role in the development of cervical cancer (CC); therefore, investigating its molecular mechanisms is crucial for the development of new therapies targeting CC. In this study, we identified an eukaryotic translation factor 3a (eIF3a)-N6 methyladenosine (m6A)-alpha enolase (ENO1) regulatory axis responsible for glycolysis of CC. Specifically, through bioinformatics analysis, RT-PCR, and western blot assays, eIF3a was identified as a prognosis biomarker in CC. By performing CCK-8 method and flow cytometry technique, we demonstrated that silencing eIF3a in Caski cells decreased proliferation, induced cell cycle arrest at the G0/G1 phase, and increased apoptosis, while overexpression in Hela cells had the opposite effects. eIF3a overexpression also accelerated glycolysis in CC cells, as evidenced by increased glucose uptake, lactate production, and ATP generation. ENO1 was found to be up-regulated at the protein level by eIF3a, and its mRNA was enriched for m6A modifications. Knockdown of YTH domain family, member 3 (YTHDF3) or methyltransferases reduced ENO1 mRNA binding to eIF3a, down-regulating ENO1 protein expression. The functional recovery assays showed that modulating the eIF3a/ENO1 axis altered CC cell growth. Altogether, eIF3a promotes ENO1 translation to accelerate glycolysis in an m6A-dependent manner, thus promoting cell proliferation and cell cycle progression, and inhibiting apoptosis in CC cells.