title: TKTL1 is activated by promoter hypomethylation and contributes to head and neck squamous cell carcinoma carcinogenesis through increased aerobic glycolysis and HIF1alpha stabilization.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Otolaryngology, Sidney Kimmel Comprehensive Cancer Center, Baltimore, MD, USA.
authors.forename: Wenyue
authors.initials: W
authors.lastname: Sun
authors.forename: Yan
authors.initials: Y
authors.lastname: Liu
authors.forename: Chad A
authors.initials: CA
authors.lastname: Glazer
authors.forename: Chunbo
authors.initials: C
authors.lastname: Shao
authors.forename: Sheetal
authors.initials: S
authors.lastname: Bhan
authors.forename: Semra
authors.initials: S
authors.lastname: Demokan
authors.forename: Ming
authors.initials: M
authors.lastname: Zhao
authors.forename: Michelle A
authors.initials: MA
authors.lastname: Rudek
authors.forename: Patrick K
authors.initials: PK
authors.lastname: Ha
authors.forename: Joseph A
authors.initials: JA
authors.lastname: Califano
mesh_terms: D000332:Aerobiosis; D000818:Animals; D002294:Carcinoma, Squamous Cell / Q000378:metabolism* / Q000473:pathology; D019175:DNA Methylation; D006019:Glycolysis; D006258:Head and Neck Neoplasms / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics*; D051379:Mice; D016688:Mice, Inbred NOD; D011401:Promoter Regions, Genetic / Q000235:genetics*; D014174:Transketolase / Q000235:genetics* / Q000378:metabolism; D015854:Up-Regulation
chemical_list: C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; C505431:TKTL1 protein, human; D014174:Transketolase