METTL14 Promotes Lipid Metabolism Reprogramming and Sustains Nasopharyngeal Carcinoma Progression via Enhancing m6A Modification of ANKRD22 mRNA

Abstract

Abstract N6-methyladenosine (m6A) modification, a prevalent post-transcriptional RNA modification, plays a crucial role in regulating RNA processing and expression, particularly in the context of malignant tumor progression. However, the exploration of m6A modification in nasopharyngeal carcinoma (NPC) remains very limited. In this study, we revealed a significant upregulation of the core m6A methyltransferase, methyltransferase-like 14 (METTL14), in NPC, correlating with poor patient prognosis. In vitro and in vivo experiments demonstrated that METTL14 actively promoted the proliferation and metastasis of NPC cells. Significantly, we identified ANKRD22 as a pivotal downstream target regulated by METTL14. METTL14 catalyzed m6A modification on ANKRD22 mRNA, recognized by the reader IGF2BP2, leading to increased mRNA stability and higher translational efficiency. Moreover, ANKRD22, a metabolism-related protein on mitochondria, interacted with SLC25A1 to enhance citrate transport, elevating intracellular acetyl-CoA content. This dual impact of ANKRD22 promoted lipid metabolism reprogramming and cellular lipid synthesis while upregulating the expression of cell cycle-related genes (GINS3 and POLE2) and cytoskeleton-related genes (PLEK2 and FERMT1) through heightened epigenetic histone acetylation levels in the nucleus. This intricate network facilitated NPC growth and metastasis. Intriguingly, our findings highlighted elevated ANKRD22-mediated histone H3 lysine 27 acetylation (H3K27AC) signals near the METTL14 promoter, contributing to a positive feedback loop that perpetuated the malignant progression of NPC. The identified METTL14-ANKRD22-SLC25A1 axis emerges as a promising therapeutic target for NPC, and also these molecules may serve as novel diagnostic biomarkers.