TKTL1 is Activated by Promoter Hypomethylation and Contributes to Head and Neck Squamous Cell Carcinoma Carcinogenesis Through Increased Aerobic Glycolysis and HIF1alpha Stabilization

Overview

Journal Clin Cancer Res

Specialty Oncology

Date 2010 Jan 28

PMID 20103683

Citations 72

Authors

Wenyue Sun

Yan Liu

Chad A Glazer

Chunbo Shao

Sheetal Bhan

Semra Demokan

Ming Zhao

Michelle A Rudek

Patrick K Ha

Joseph A Califano

Affiliations

Soon will be listed here.

Abstract

Purpose: This study aims to investigate the role of the aberrant expression of Transkelolase-like 1 (TKTL1) in head and neck squamous cell carcinoma (HNSCC) tumorigenesis and to characterize TKTL1 contribution to HNSCC tumorigenesis through aerobic glycolysis and HIF1alpha stabilization.

Experimental Design: TKTL1 promoter hypomethylation and mRNA/protein aberrant expression were studied in human HNSCC tumor samples and normal mucosas. Oncogenic functions of TKTL1 were examined in HNSCC cell line panels and tumor xenograft models with TKTL1 expression construct. The metabolite levels of fructose-6-phosphate, glyceraldehydes-3-phosphate, pyruvate, lactate, and the levels of HIF1alpha protein and its downsteam glycolytic targets were compared between the TKTL1-expressing and vehicle-expressing HNSCC cells. Meanwhile, the effects of HIF1alpha/glycolytic inhibitors were evaluated on the TKTL1 transfectants.

Results: TKTL1 exhibits high frequency of promoter hypomethylation in HNSCC tumors compared with the normal mucosas, correlating with its overexpression in HNSCC. Overexpression of TKTL1 in HNSCC cells promoted cellular proliferation and enhanced tumor growth in vitro and in vivo. Overexpression of TKTL1 increased the production of fructose-6-phosphate and glyceraldehyde-3-phosphate, in turn elevating the production of pyruvate and lactate, resulting in the normoxic stabilization of the malignancy-promoting transcription factor HIF1alpha and the upregulation of downstream glycolytic enzymes. Notably, the reduction of TKTL1 expression decreased HIF1alpha accumulation and inhibition with HIF1alpha and/or the glycolysis inhibitor could abrogate the growth effects mediated by TKTL1 overexpression.

Conclusion: TKTL1 is a novel candidate oncogene that is epigenetically activated by aberrant hypomethlation and contributes to a malignant phenotype through altered glycolytic metabolism and HIF1alpha accumulation.

Citing Articles

SNHG1: Redefining the Landscape of Hepatocellular Carcinoma through Long Noncoding RNAs.

Fonseca T, Martins R, Rolo A, Palmeira C Biomedicines. 2024; 12(8).

PMID: 39200161 PMC: 11351223. DOI: 10.3390/biomedicines12081696.

Synthesis of 4-Deoxy-4-Fluoro-d-Sedoheptulose: A Promising New Sugar to Apply the Principle of Metabolic Trapping.

Scheibelberger L, Stankovic T, Puhringer M, Kahlig H, Balber T, Patronas E Chemistry. 2023; 29(62):e202302277.

PMID: 37552007 PMC: 10946558. DOI: 10.1002/chem.202302277.

Long noncoding RNAs: glycolysis regulators in gynaecologic cancers.

Lv N, Shen S, Chen Q, Tong J Cancer Cell Int. 2023; 23(1):4.

PMID: 36639695 PMC: 9838043. DOI: 10.1186/s12935-023-02849-2.

New horizons in modulating the radio-sensitivity of head and neck cancer - 100 years after Warburg' effect discovery.

Mirestean C, Iancu R, Iancu D Front Oncol. 2022; 12:908695.

PMID: 36568220 PMC: 9780029. DOI: 10.3389/fonc.2022.908695.

Identification of Hypoxia-Related Prognostic Signature and Competing Endogenous RNA Regulatory Axes in Hepatocellular Carcinoma.

Tang Y, Zhang H, Chen L, Zhang T, Xu N, Huang Z Int J Mol Sci. 2022; 23(21).

PMID: 36362375 PMC: 9658439. DOI: 10.3390/ijms232113590.

References

Oshimo Y, Nakayama H, Ito R, Kitadai Y, Yoshida K, Chayama K . Promoter methylation of cyclin D2 gene in gastric carcinoma. Int J Oncol. 2003; 23(6):1663-70. View

Liu Y, Sun W, Zhang K, Zheng H, Ma Y, Lin D . Identification of genes differentially expressed in human primary lung squamous cell carcinoma. Lung Cancer. 2007; 56(3):307-17. DOI: 10.1016/j.lungcan.2007.01.016. View

Horecker B . The pentose phosphate pathway. J Biol Chem. 2002; 277(50):47965-71. DOI: 10.1074/jbc.X200007200. View

Hsu P, Sabatini D . Cancer cell metabolism: Warburg and beyond. Cell. 2008; 134(5):703-7. DOI: 10.1016/j.cell.2008.08.021. View

Xu X, Zur Hausen A, Coy J, Lochelt M . Transketolase-like protein 1 (TKTL1) is required for rapid cell growth and full viability of human tumor cells. Int J Cancer. 2008; 124(6):1330-7. DOI: 10.1002/ijc.24078. View

Hanada M, Delia D, Aiello A, Stadtmauer E, Reed J . bcl-2 gene hypomethylation and high-level expression in B-cell chronic lymphocytic leukemia. Blood. 1993; 82(6):1820-8. View

Smith I, Mydlarz W, Mithani S, Califano J . DNA global hypomethylation in squamous cell head and neck cancer associated with smoking, alcohol consumption and stage. Int J Cancer. 2007; 121(8):1724-8. DOI: 10.1002/ijc.22889. View

Carvalho A, Jeronimo C, Kim M, Henrique R, Zhang Z, Hoque M . Evaluation of promoter hypermethylation detection in body fluids as a screening/diagnosis tool for head and neck squamous cell carcinoma. Clin Cancer Res. 2008; 14(1):97-107. DOI: 10.1158/1078-0432.CCR-07-0722. View

Yun J, Rago C, Cheong I, Pagliarini R, Angenendt P, Rajagopalan H . Glucose deprivation contributes to the development of KRAS pathway mutations in tumor cells. Science. 2009; 325(5947):1555-9. PMC: 2820374. DOI: 10.1126/science.1174229. View

10.

Langbein S, Zerilli M, Hausen A, Staiger W, Rensch-Boschert K, Lukan N . Expression of transketolase TKTL1 predicts colon and urothelial cancer patient survival: Warburg effect reinterpreted. Br J Cancer. 2006; 94(4):578-85. PMC: 2361175. DOI: 10.1038/sj.bjc.6602962. View

11.

Chau N, Rogers P, Aherne W, Carroll V, Collins I, McDonald E . Identification of novel small molecule inhibitors of hypoxia-inducible factor-1 that differentially block hypoxia-inducible factor-1 activity and hypoxia-inducible factor-1alpha induction in response to hypoxic stress and growth factors. Cancer Res. 2005; 65(11):4918-28. DOI: 10.1158/0008-5472.CAN-04-4453. View

12.

Coy J, Dressler D, Wilde J, Schubert P . Mutations in the transketolase-like gene TKTL1: clinical implications for neurodegenerative diseases, diabetes and cancer. Clin Lab. 2005; 51(5-6):257-73. View

13.

Livak K, Schmittgen T . Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) Method. Methods. 2002; 25(4):402-8. DOI: 10.1006/meth.2001.1262. View

14.

Kroemer G, Pouyssegur J . Tumor cell metabolism: cancer's Achilles' heel. Cancer Cell. 2008; 13(6):472-82. DOI: 10.1016/j.ccr.2008.05.005. View

15.

Lu H, Dalgard C, Mohyeldin A, McFate T, Tait A, Verma A . Reversible inactivation of HIF-1 prolyl hydroxylases allows cell metabolism to control basal HIF-1. J Biol Chem. 2005; 280(51):41928-39. DOI: 10.1074/jbc.M508718200. View

16.

Tokumaru Y, Yamashita K, Osada M, Nomoto S, Sun D, Xiao Y . Inverse correlation between cyclin A1 hypermethylation and p53 mutation in head and neck cancer identified by reversal of epigenetic silencing. Cancer Res. 2004; 64(17):5982-7. DOI: 10.1158/0008-5472.CAN-04-0993. View

17.

Tong X, Zhao F, Thompson C . The molecular determinants of de novo nucleotide biosynthesis in cancer cells. Curr Opin Genet Dev. 2009; 19(1):32-7. PMC: 2707261. DOI: 10.1016/j.gde.2009.01.002. View

18.

Volker H, Scheich M, Schmausser B, Kammerer U, Eck M . Overexpression of transketolase TKTL1 is associated with shorter survival in laryngeal squamous cell carcinomas. Eur Arch Otorhinolaryngol. 2007; 264(12):1431-6. DOI: 10.1007/s00405-007-0394-x. View

19.

Samudio I, Fiegl M, McQueen T, Clise-Dwyer K, Andreeff M . The warburg effect in leukemia-stroma cocultures is mediated by mitochondrial uncoupling associated with uncoupling protein 2 activation. Cancer Res. 2008; 68(13):5198-205. PMC: 2562568. DOI: 10.1158/0008-5472.CAN-08-0555. View

20.

Sun W, Zhou S, Chang S, McFate T, Verma A, Califano J . Mitochondrial mutations contribute to HIF1alpha accumulation via increased reactive oxygen species and up-regulated pyruvate dehydrogenease kinase 2 in head and neck squamous cell carcinoma. Clin Cancer Res. 2009; 15(2):476-84. PMC: 2729126. DOI: 10.1158/1078-0432.CCR-08-0930. View