Human Cell

, Volume 32, Issue 2, pp 193–201 | Cite as

SIRT1 promotes GLUT1 expression and bladder cancer progression via regulation of glucose uptake

  • Jia Chen
  • Lin Cao
  • Zhiqiu Li
  • Yuanwei LiEmail author
Research Article


Bladder cancer (BC) is one of the most common tumors. Metabolic reprogramming is a feature of neoplasia and tumor growth. Understanding the metabolic alterations in bladder cancer may provide new directions for bladder cancer treatment. Sirtuin 1 (SIRT1) is a lysine deacetylase of multiple targets including metabolic regulators. In pancreatic cancer, the loss of SIRT1 is accompanied by a decreased expression of proteins in the glycolysis pathway, such as GLUT1, and cancer cell proliferation. Thus, we hypothesize that SIRT1 may interact with GLUT1 to modulate the proliferation and glycolysis phenotype in bladder cancer. In the present study, the expression of SIRT1 and GLUT1 was upregulated in BC tissues and cell lines and positively correlated in tissue samples. SIRT1 overexpression or GLUT1 overexpression alone was sufficient to promote cell proliferation and glucose uptake in BC cells. EX527, a specific inhibitor of SIRT1, exerted an opposing effect on bladder cancer proliferation and glucose uptake. The effect of EX527 could be partially reversed by GLUT1 overexpression. More importantly, SIRT1 overexpression significantly promoted the transcriptional activity and expression of GLUT1, indicating that SIRT1 increases the transcription activity and expression of GLUT1, therefore, promoting the cell proliferation and glycolysis in BC cells. Our study first reported that SIRT1/GLUT1 axis promotes bladder cancer progression via regulation of glucose uptake.


Bladder cancer SIRT1 GLUT1 Glucose Cell proliferation 



This study was supported by Hunan Provincial Natural Science Fund (2017JJ3108).

Compliance with ethical standards

Conflict of interest


Supplementary material

13577_2019_237_MOESM1_ESM.tif (170 kb)
Supplementary material 1 (TIF 169 KB)


  1. 1.
    Burger M, Catto JW, Dalbagni G, et al. Epidemiology and risk factors of urothelial bladder cancer. Eur Urol. 2013;63:234–41.CrossRefPubMedGoogle Scholar
  2. 2.
    Ferlay J, Soerjomataram I, Dikshit R, et al. Cancer incidence and mortality worldwide: sources, methods and major patterns in GLOBOCAN 2012. Int J Cancer. 2015;136:E359-86.CrossRefPubMedGoogle Scholar
  3. 3.
    von Rundstedt FC, Rajapakshe K, Ma J, et al. Integrative pathway analysis of metabolic signature in bladder cancer: a linkage to the cancer genome atlas project and prediction of survival. J Urol. 2016;195:1911–9.CrossRefGoogle Scholar
  4. 4.
    Deng SP, Zhu L, Huang DS. Mining the bladder cancer-associated genes by an integrated strategy for the construction and analysis of differential co-expression networks. BMC Genom. 2015;16(Suppl 3):4.CrossRefGoogle Scholar
  5. 5.
    Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell. 2011;144:646–74.CrossRefPubMedGoogle Scholar
  6. 6.
    Vazquez A, Liu J, Zhou Y, Oltvai ZN. Catabolic efficiency of aerobic glycolysis: the Warburg effect revisited. BMC Syst Biol. 2010;4:58.CrossRefPubMedGoogle Scholar
  7. 7.
    Frye RA. Characterization of five human cDNAs with homology to the yeast SIR2 gene: Sir2-like proteins (sirtuins) metabolize NAD and may have protein ADP-ribosyltransferase activity. Biochem Biophys Res Commun. 1999;260:273–9.CrossRefPubMedGoogle Scholar
  8. 8.
    Kaeberlein M, McVey M, Guarente L. The SIR2/3/4 complex and SIR2 alone promote longevity in Saccharomyces cerevisiae by two different mechanisms. Genes Dev. 1999;13:2570–80.CrossRefPubMedGoogle Scholar
  9. 9.
    Preyat N, Leo O. Sirtuin deacylases: a molecular link between metabolism and immunity. J Leukoc Biol. 2013;93:669–80.CrossRefPubMedGoogle Scholar
  10. 10.
    Hu Q, Wang G, Peng J, et al. Knockdown of SIRT1 suppresses bladder cancer cell proliferation and migration and induces cell cycle arrest and antioxidant response through FOXO3a-mediated pathways. Biomed Res Int. 2017; 2017:3781904.Google Scholar
  11. 11.
    Pinho AV, Mawson A, Gill A, et al. Sirtuin 1 stimulates the proliferation and the expression of glycolysis genes in pancreatic neoplastic lesions. Oncotarget. 2016;7:74768–78.CrossRefPubMedGoogle Scholar
  12. 12.
    Ancey PB, Contat C, Meylan E. Glucose transporters in cancer—from tumor cells to the tumor microenvironment. FEBS J. 2018.Google Scholar
  13. 13.
    Yoshizaki T, Milne JC, Imamura T, et al. SIRT1 exerts anti-inflammatory effects and improves insulin sensitivity in adipocytes. Mol Cell Biol. 2009;29:1363–74.CrossRefPubMedGoogle Scholar
  14. 14.
    Bai L, Pang WJ, Yang YJ, Yang GS. Modulation of Sirt1 by resveratrol and nicotinamide alters proliferation and differentiation of pig preadipocytes. Mol Cell Biochem. 2008;307:129–40.CrossRefPubMedGoogle Scholar
  15. 15.
    Backesjo CM, Li Y, Lindgren U, Haldosen LA. Activation of Sirt1 decreases adipocyte formation during osteoblast differentiation of mesenchymal stem cells. Cells Tissues Organs. 2009;189:93–7.CrossRefPubMedGoogle Scholar
  16. 16.
    Lappas M, Mitton A, Lim R, Barker G, Riley C, Permezel M. SIRT1 is a novel regulator of key pathways of human labor. Biol Reprod. 2011;84:167–78.CrossRefPubMedGoogle Scholar
  17. 17.
    Lappas M, Andrikopoulos S, Permezel M. Hypoxanthine-xanthine oxidase down-regulates GLUT1 transcription via SIRT1 resulting in decreased glucose uptake in human placenta. J Endocrinol. 2012;213:49–57.CrossRefPubMedGoogle Scholar
  18. 18.
    Zhang C, Liu J, Wu R, et al. Tumor suppressor p53 negatively regulates glycolysis stimulated by hypoxia through its target RRAD. Oncotarget. 2014;5:5535–46.PubMedGoogle Scholar
  19. 19.
    Joo HY, Yun M, Jeong J, et al. SIRT1 deacetylates and stabilizes hypoxia-inducible factor-1alpha (HIF-1alpha) via direct interactions during hypoxia. Biochem Biophys Res Commun. 2015;462:294–300.CrossRefPubMedGoogle Scholar
  20. 20.
    Wardell SE, Ilkayeva OR, Wieman HL, et al. Glucose metabolism as a target of histone deacetylase inhibitors. Mol Endocrinol. 2009;23:388–401.CrossRefPubMedGoogle Scholar
  21. 21.
    Amann T, Maegdefrau U, Hartmann A, et al. GLUT1 expression is increased in hepatocellular carcinoma and promotes tumorigenesis. Am J Pathol. 2009;174:1544–52.CrossRefPubMedGoogle Scholar
  22. 22.
    Oh S, Kim H, Nam K, Shin I. Glut1 promotes cell proliferation, migration and invasion by regulating epidermal growth factor receptor and integrin signaling in triple-negative breast cancer cells. BMB Rep. 2017;50:132–37.CrossRefPubMedGoogle Scholar
  23. 23.
    Chan DA, Sutphin PD, Nguyen P, et al. Targeting GLUT1 and the Warburg effect in renal cell carcinoma by chemical synthetic lethality. Sci Transl Med. 2011;3:94ra70.PubMedGoogle Scholar
  24. 24.
    Li P, Yang X, Cheng Y, et al. MicroRNA-218 increases the sensitivity of bladder cancer to Cisplatin by targeting Glut1. Cell Physiol Biochem Int J Exp Cell Physiol Biochem Pharmacol. 2017;41:921.CrossRefGoogle Scholar
  25. 25.
    North BJ, Verdin E. Sirtuins. Sir2-related NAD-dependent protein deacetylases. Genome Biol. 2004;5:224.CrossRefPubMedGoogle Scholar
  26. 26.
    Boren J, Lee WN, Bassilian S, et al. The stable isotope-based dynamic metabolic profile of butyrate-induced HT29 cell differentiation. J Biol Chem. 2003;278:28395–402.CrossRefPubMedGoogle Scholar

Copyright information

© Japan Human Cell Society 2019

Authors and Affiliations

  1. 1.Department of Urology Surgery, Hunan People’s HospitalThe First Affiliated Hospital of Hunan Normal UniversityChangshaChina
  2. 2.Department of Geriatrics, Hunan People’s HospitalThe First Affiliated Hospital of Hunan Normal UniversityChangshaChina

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