title: Glucose transporter 4 promotes head and neck squamous cell carcinoma metastasis through the TRIM24-DDX58 axis.
abstract: Head and neck squamous cell carcinoma (HNSCC) represents a unique and major health concern worldwide. Significant increases in glucose uptake and aerobic glycolysis have been observed in HNSCC cells. Glucose transporters (GLUTs) represent a major hub in the glycolysis pathway, with GLUT4 having the highest glucose affinity. However, GLUT4's role in HNSCC has not been fully appreciated.
  
  
  
  An in silico analysis was performed in HNSCC cohorts to identify the most significant glucose transporter associated with HNSCC patient prognosis. An immunohistochemical analysis of a tissue microarray with samples from 90 HNSCC patients was used to determine the association of GLUT4 with prognosis. Complementary functional expression and knockdown studies of GLUT4 were performed to investigate whether GLUT4 plays a role in HNSCC cell migration and invasion in vitro and in vivo. The detailed molecular mechanism of the function of GLUT4 in inducing HNSCC cell metastasis was determined.
  
  
  
  Our clinicopathologic analysis showed that increased GLUT4 expression in oral squamous cell carcinoma patients was significantly associated with a poor overall survival (OS, P = 0.035) and recurrence-free survival (RFS, P = 0.001). Furthermore, the ectopic overexpression of GLUT4 in cell lines with low endogenous GLUT4 expression resulted in a significant increase in migratory ability both in vitro and in vivo, whereas the reverse phenotype was observed in GLUT4-silenced cells. Utilizing a GLUT4 overexpression model, we performed gene expression microarray and Ingenuity Pathway Analysis (IPA) to determine that the transcription factor tripartite motif-containing 24 (TRIM24) was the main downstream regulator of GLUT4. In addition, DDX58 was confirmed to be the downstream target of TRIM24, whose downregulation is essential for the migratory phenotype induced by GLUT4-TRIM24 activation in HNSCC cells.
  
  
  
  Here, we identified altered glucose metabolism in the progression of HNSCC and showed that it could be partially attributed to the novel link between GLUT4 and TRIM24. This novel signaling axis may be used for the prognosis and therapeutic treatment of HNSCC in the future.
authors.affiliation: Graduate Institute of Life Sciences, National Defense Medical Center, Taipei, Taiwan.|Genomics Research Center, Academia Sinica, Taipei, Taiwan.
authors.forename: Yu-Chan
authors.initials: YC
authors.lastname: Chang
authors.affiliation: Genomics Research Center, Academia Sinica, Taipei, Taiwan.|The Ph.D. Program for Translational Medicine, Taipei Medical University, Taipei, Taiwan.
authors.forename: Li-Hsing
authors.initials: LH
authors.lastname: Chi
authors.affiliation: Genomics Research Center, Academia Sinica, Taipei, Taiwan.|Graduate Institute of Medical Sciences, National Defense Medical Center, Taipei, Taiwan.
authors.forename: Wei-Ming
authors.initials: WM
authors.lastname: Chang
authors.affiliation: Genomics Research Center, Academia Sinica, Taipei, Taiwan.
authors.forename: Chia-Yi
authors.initials: CY
authors.lastname: Su
authors.affiliation: Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan.
authors.forename: Yuang-Feng
authors.initials: YF
authors.lastname: Lin
authors.affiliation: Department of Pathology, Taipei Medical University Hospital, Taipei Medical University, Taipei, Taiwan.|Department of Pathology, College of Medicine, Taipei Medical University, Taipei, Taiwan.
authors.forename: Chi-Long
authors.initials: CL
authors.lastname: Chen
authors.affiliation: Department of Oncology, Taipei Veterans General Hospital, Taipei, Taiwan.|Faculty of Medicine, National Yang Ming University, Taipei, Taiwan.
authors.forename: Ming-Huang
authors.initials: MH
authors.lastname: Chen
authors.affiliation: Department of Oncology, Taipei Veterans General Hospital, Taipei, Taiwan.|Faculty of Medicine, National Yang Ming University, Taipei, Taiwan.
authors.forename: Peter Mu-Hsin
authors.initials: PM
authors.lastname: Chang
authors.affiliation: The Ph.D. Program for Translational Medicine, Taipei Medical University, Taipei, Taiwan.
authors.forename: Alex T H
authors.initials: AT
authors.lastname: Wu
authors.affiliation: Graduate Institute of Life Sciences, National Defense Medical Center, Taipei, Taiwan. mhsiao@gate.sinica.edu.tw.|Genomics Research Center, Academia Sinica, Taipei, Taiwan. mhsiao@gate.sinica.edu.tw.|Department of Biochemistry, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan. mhsiao@gate.sinica.edu.tw.
authors.forename: Michael
authors.initials: M
authors.lastname: Hsiao
mesh_terms: D002294:Carcinoma, Squamous Cell / Q000139:chemically induced* / Q000473:pathology; D002352:Carrier Proteins / Q000378:metabolism* / Q000502:physiology; D045744:Cell Line, Tumor; D002465:Cell Movement; D003198:Computer Simulation; D000071457:DEAD Box Protein 58 / Q000187:drug effects / Q000378:metabolism*; D020869:Gene Expression Profiling; D005947:Glucose / Q000378:metabolism; D051275:Glucose Transporter Type 4 / Q000032:analysis* / Q000378:metabolism; D006258:Head and Neck Neoplasms / Q000139:chemically induced* / Q000473:pathology; D006801:Humans; D009362:Neoplasm Metastasis; D011379:Prognosis; D011971:Receptors, Immunologic; D000077195:Squamous Cell Carcinoma of Head and Neck; D046888:Tissue Array Analysis
chemical_list: D002352:Carrier Proteins; D051275:Glucose Transporter Type 4; D011971:Receptors, Immunologic; C495692:SLC2A4 protein, human; C555317:TRIM24 protein, human; C452820:RIGI protein, human; D000071457:DEAD Box Protein 58; D005947:Glucose
keywords: DDX58; GLUT4; HNSCC; Metastasis; TRIM24