YY1 Suppresses Tumor Growth by Negatively Regulating the Expression and Translation Activity of eIF4E in Nasopharyngeal Carcinoma

Background: Nasopharyngeal carcinoma (NPC) is a complex malignancy, and the molecular mechanisms that drive its progression have not yet been fully elucidated. Eukaryotic translation initiation factor 4E (eIF4E), a pivotal regulator of protein synthesis, is frequently dysregulated in cancers. We previously identified eIF4E as a direct transcriptional target of Yin Yang 1 (YY1) in an axis where YY1 suppressed NPC invasion and metastasis. Methods: Here, we investigated the function of eIF4E in NPC growth and its regulatory relationship with YY1. The CCK-8 assay, clonogenic survival assay, Annexin V/propidium iodide assay, and xenograft models were used to determine the role of YY1/eIF4E in NPC growth; Western blotting and Co-IP were performed to examine protein expression and protein–protein interactions, respectively. Results: Our findings demonstrate that eIF4E potently promoted NPC cell proliferation, accelerated cell cycle progression, and inhibited apoptosis. Moreover, these effects were critically dependent on its phosphorylation at serine 209 (S209). Furthermore, we uncovered a novel regulatory mechanism whereby YY1 enhances the association between 4E-BP1 and eIF4E, downregulates eIF4G expression, and is associated with reduced interaction between eIF4E and eIF4G, thereby potentially limiting eIF4F complex formation. Conclusions: This study establishes eIF4E phosphorylation as an oncogenic driver of NPC cell growth and survival and identifies YY1 as a tumor suppressor that negatively regulates this axis. These insights position eIF4E as a promising and precise therapeutic target for NPC intervention.