Background: Head and neck squamous cell carcinoma (HNSCC) represents a unique and major health concern\nworldwide. Significant increases in glucose uptake and aerobic glycolysis have been observed in HNSCC cells.\nGlucose transporters (GLUTs) represent a major hub in the glycolysis pathway, with GLUT4 having the highest\nglucose affinity. However, GLUT4ââ?¬â?¢s role in HNSCC has not been fully appreciated.\nMethods: An in silico analysis was performed in HNSCC cohorts to identify the most significant glucose transporter\nassociated with HNSCC patient prognosis. An immunohistochemical analysis of a tissue microarray with samples\nfrom 90 HNSCC patients was used to determine the association of GLUT4 with prognosis. Complementary functional\nexpression and knockdown studies of GLUT4 were performed to investigate whether GLUT4 plays a role in HNSCC cell\nmigration and invasion in vitro and in vivo. The detailed molecular mechanism of the function of GLUT4 in inducing\nHNSCC cell metastasis was determined.\nResults: Our clinicopathologic analysis showed that increased GLUT4 expression in oral squamous cell carcinoma\npatients was significantly associated with a poor overall survival (OS, P = 0.035) and recurrence-free survival (RFS, P = 0.\n001). Furthermore, the ectopic overexpression of GLUT4 in cell lines with low endogenous GLUT4 expression resulted\nin a significant increase in migratory ability both in vitro and in vivo, whereas the reverse phenotype was observed in\nGLUT4-silenced cells. Utilizing a GLUT4 overexpression model, we performed gene expression microarray and Ingenuity\nPathway Analysis (IPA) to determine that the transcription factor tripartite motif-containing 24 (TRIM24) was the main\ndownstream regulator of GLUT4. In addition, DDX58 was confirmed to be the downstream target of TRIM24, whose\ndownregulation is essential for the migratory phenotype induced by GLUT4ââ?¬â??TRIM24 activation in HNSCC cells.\nConclusions: Here, we identified altered glucose metabolism in the progression of HNSCC and showed that it could\nbe partially attributed to the novel link between GLUT4 and TRIM24. This novel signaling axis may be used for the\nprognosis and therapeutic treatment of HNSCC in the future
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