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Open Access 01-12-2017 | Research

Glucose transporter 4 promotes head and neck squamous cell carcinoma metastasis through the TRIM24-DDX58 axis

Authors: Yu-Chan Chang, Li-Hsing Chi, Wei-Ming Chang, Chia-Yi Su, Yuang-Feng Lin, Chi-Long Chen, Ming-Huang Chen, Peter Mu-Hsin Chang, Alex T. H. Wu, Michael Hsiao

Published in: Journal of Hematology & Oncology | Issue 1/2017

Abstract

Background

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.

Methods

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.

Results

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.

Conclusions

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.

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Jemal A, Siegel R, Ward E, Hao Y, Xu J, Thun MJ. Cancer statistics, 2009. CA Cancer J Clin. 2009;59:225–49.CrossRefPubMed

Vermorken JB, Mesia R, Rivera F, Remenar E, Kawecki A, Rottey S, Erfan J, Zabolotnyy D, Kienzer HR, Cupissol D, et al. Platinum-based chemotherapy plus cetuximab in head and neck cancer. N Engl J Med. 2008;359:1116–27.CrossRefPubMed

Li L, Li C, Wang S, Wang Z, Jiang J, Wang W, Li X, Chen J, Liu K, Li C, Zhu G. Exosomes derived from hypoxic oral squamous cell carcinoma cells deliver miR-21 to normoxic cells to elicit a prometastatic phenotype. Cancer Res. 2016;76:1770–80.CrossRefPubMed

Yang MH, Wu MZ, Chiou SH, Chen PM, Chang SY, Liu CJ, Teng SC, Wu KJ. Direct regulation of TWIST by HIF-1alpha promotes metastasis. Nat Cell Biol. 2008;10:295–305.CrossRefPubMed

Sun W, Liu Y, Glazer CA, Shao C, Bhan S, Demokan S, Zhao M, Rudek MA, Ha PK, Califano JA. TKTL1 is activated by promoter hypomethylation and contributes to head and neck squamous cell carcinoma carcinogenesis through increased aerobic glycolysis and HIF1alpha stabilization. Clin Cancer Res. 2010;16:857–66.CrossRefPubMedPubMedCentral

Vander Heiden MG, Cantley LC, Thompson CB. Understanding the Warburg effect: the metabolic requirements of cell proliferation. Science. 2009;324:1029–33.CrossRefPubMedPubMedCentral

Aguilar E, Marin de Mas I, Zodda E, Marin S, Morrish F, Selivanov V, Meca-Cortes O, Delowar H, Pons M, Izquierdo I, et al. Metabolic reprogramming and dependencies associated with epithelial cancer stem cells independent of the epithelial-mesenchymal transition program. Stem Cells. 2016;34:1163–76.CrossRefPubMed

Masin M, Vazquez J, Rossi S, Groeneveld S, Samson N, Schwalie PC, Deplancke B, Frawley LE, Gouttenoire J, Moradpour D, et al. GLUT3 is induced during epithelial-mesenchymal transition and promotes tumor cell proliferation in non-small cell lung cancer. Cancer Metab. 2014;2:11.CrossRefPubMedPubMedCentral

Li SJ, Yang XN, Qian HY. Antitumor effects of WNT2B silencing in GLUT1 overexpressing cisplatin resistant head and neck squamous cell carcinoma. Am J Cancer Res. 2015;5:300–8.PubMed

10.

McBrayer SK, Cheng JC, Singhal S, Krett NL, Rosen ST, Shanmugam M. Multiple myeloma exhibits novel dependence on GLUT4, GLUT8, and GLUT11: implications for glucose transporter-directed therapy. Blood. 2012;119:4686–97.CrossRefPubMedPubMedCentral

11.

James DE, Brown R, Navarro J, Pilch PF. Insulin-regulatable tissues express a unique insulin-sensitive glucose transport protein. Nature. 1988;333:183–5.CrossRefPubMed

12.

Fukuzumi M, Hamakawa H, Onishi A, Sumida T, Tanioka H. Gene expression of GLUT isoforms and VHL in oral squamous cell carcinoma. Cancer Lett. 2000;161:133–40.CrossRefPubMed

13.

Rudich A, Konrad D, Torok D, Ben-Romano R, Huang C, Niu W, Garg RR, Wijesekara N, Germinario RJ, Bilan PJ, Klip A. Indinavir uncovers different contributions of GLUT4 and GLUT1 towards glucose uptake in muscle and fat cells and tissues. Diabetologia. 2003;46:649–58.CrossRefPubMed

14.

Huang S, Lifshitz LM, Jones C, Bellve KD, Standley C, Fonseca S, Corvera S, Fogarty KE, Czech MP. Insulin stimulates membrane fusion and GLUT4 accumulation in clathrin coats on adipocyte plasma membranes. Mol Cell Biol. 2007;27:3456–69.CrossRefPubMedPubMedCentral

15.

Liu L, Jedrychowski MP, Gygi SP, Pilch PF. Role of insulin-dependent cortical fodrin/spectrin remodeling in glucose transporter 4 translocation in rat adipocytes. Mol Biol Cell. 2006;17:4249–56.CrossRefPubMedPubMedCentral

16.

Garrido P, Osorio FG, Moran J, Cabello E, Alonso A, Freije JM, Gonzalez C. Loss of GLUT4 induces metabolic reprogramming and impairs viability of breast cancer cells. J Cell Physiol. 2015;230:191–8.CrossRefPubMed

17.

Zhang LH, Yin AA, Cheng JX, Huang HY, Li XM, Zhang YQ, Han N, Zhang X. TRIM24 promotes glioma progression and enhances chemoresistance through activation of the PI3K/Akt signaling pathway. Oncogene. 2015;34:600–10.CrossRefPubMed

18.

Thenot S, Henriquet C, Rochefort H, Cavailles V. Differential interaction of nuclear receptors with the putative human transcriptional coactivator hTIF1. J Biol Chem. 1997;272:12062–8.CrossRefPubMed

19.

Allton K, Jain AK, Herz HM, Tsai WW, Jung SY, Qin J, Bergmann A, Johnson RL, Barton MC. Trim24 targets endogenous p53 for degradation. Proc Natl Acad Sci U S A. 2009;106:11612–6.CrossRefPubMedPubMedCentral

20.

Christen RD, Hom DK, Porter DC, Andrews PA, MacLeod CL, Hafstrom L, Howell SB. Epidermal growth factor regulates the in vitro sensitivity of human ovarian carcinoma cells to cisplatin. J Clin Invest. 1990;86:1632–40.CrossRefPubMedPubMedCentral

21.

Kamata N, Chida K, Rikimaru K, Horikoshi M, Enomoto S, Kuroki T. Growth-inhibitory effects of epidermal growth factor and overexpression of its receptors on human squamous cell carcinomas in culture. Cancer Res. 1986;46:1648–53.PubMed

22.

Wu HG, Song SY, Kim YS, Oh YT, Lee CG, Keum KC, Ahn YC, Lee SW. Therapeutic effect of recombinant human epidermal growth factor (RhEGF) on mucositis in patients undergoing radiotherapy, with or without chemotherapy, for head and neck cancer: a double-blind placebo-controlled prospective phase 2 multi-institutional clinical trial. Cancer. 2009;115:3699–708.CrossRefPubMed

23.

Chen JY, Chang YL, Yu YC, Chao CC, Kao HW, Wu CT, Lin WC, Ko JY, Jou YS. Specific induction of the high-molecular-weight microtubule-associated protein 2 (hmw-MAP2) by betel quid extract in cultured oral keratinocytes: clinical implications in betel quid-associated oral squamous cell carcinoma (OSCC). Carcinogenesis. 2004;25:269–76.CrossRefPubMed

24.

Chambon M, Orsetti B, Berthe ML, Bascoul-Mollevi C, Rodriguez C, Duong V, Gleizes M, Thenot S, Bibeau F, Theillet C, Cavailles V. Prognostic significance of TRIM24/TIF-1alpha gene expression in breast cancer. Am J Pathol. 2011;178:1461–9.CrossRefPubMedPubMedCentral

25.

Grivennikov SI, Greten FR, Karin M. Immunity, inflammation, and cancer. Cell. 2010;140:883–99.CrossRefPubMedPubMedCentral

26.

Cui XF, Imaizumi T, Yoshida H, Borden EC, Satoh K. Retinoic acid-inducible gene-I is induced by interferon-gamma and regulates the expression of interferon-gamma stimulated gene 15 in MCF-7 cells. Biochem Cell Biol. 2004;82:401–5.CrossRefPubMed

27.

Tisserand J, Khetchoumian K, Thibault C, Dembele D, Chambon P, Losson R. Tripartite motif 24 (Trim24/Tif1alpha) tumor suppressor protein is a novel negative regulator of interferon (IFN)/signal transducers and activators of transcription (STAT) signaling pathway acting through retinoic acid receptor alpha (Raralpha) inhibition. J Biol Chem. 2011;286:33369–79.CrossRefPubMedPubMedCentral

28.

Su ZZ, Sarkar D, Emdad L, Barral PM, Fisher PB. Central role of interferon regulatory factor-1 (IRF-1) in controlling retinoic acid inducible gene-I (RIG-I) expression. J Cell Physiol. 2007;213:502–10.CrossRefPubMed

Title: Glucose transporter 4 promotes head and neck squamous cell carcinoma metastasis through the TRIM24-DDX58 axis
Authors: Yu-Chan Chang
Li-Hsing Chi
Wei-Ming Chang
Chia-Yi Su
Yuang-Feng Lin
Chi-Long Chen
Ming-Huang Chen
Peter Mu-Hsin Chang
Alex T. H. Wu
Michael Hsiao
Publication date: 01-12-2017
Publisher: BioMed Central
Published in: Journal of Hematology & Oncology / Issue 1/2017
Electronic ISSN: 1756-8722
DOI: https://doi.org/10.1186/s13045-016-0372-0

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