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- W4361818127 abstract "<div>Abstract<p><b>Purpose:</b> This study aims to investigate the role of the aberrant expression of <i>Transkelolase-like 1</i> (<i>TKTL1</i>) in head and neck squamous cell carcinoma (HNSCC) tumorigenesis and to characterize TKTL1 contribution to HNSCC tumorigenesis through aerobic glycolysis and HIF1α stabilization.</p><p><b>Experimental Design:</b> <i>TKTL1</i> 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 <i>TKTL1</i> expression construct. The metabolite levels of fructose-6-phosphate, glyceraldehydes-3-phosphate, pyruvate, lactate, and the levels of HIF1α protein and its downsteam glycolytic targets were compared between the TKTL1-expressing and vehicle-expressing HNSCC cells. Meanwhile, the effects of HIF1α/glycolytic inhibitors were evaluated on the <i>TKTL1</i> transfectants.</p><p><b>Results:</b> <i>TKTL1</i> 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 <i>in vitro</i> and <i>in vivo</i>. 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 HIF1α and the upregulation of downstream glycolytic enzymes. Notably, the reduction of TKTL1 expression decreased HIF1α accumulation and inhibition with HIF1α and/or the glycolysis inhibitor could abrogate the growth effects mediated by TKTL1 overexpression.</p><p><b>Conclusion:</b> <i>TKTL1</i> is a novel candidate oncogene that is epigenetically activated by aberrant hypomethlation and contributes to a malignant phenotype through altered glycolytic metabolism and HIF1α accumulation. Clin Cancer Res; 16(3); 857–66</p></div>" @default.
- W4361818127 created "2023-04-05" @default.
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- W4361818127 date "2023-03-31" @default.
- W4361818127 modified "2023-09-27" @default.
- W4361818127 title "Data from <i>TKTL1</i> Is Activated by Promoter Hypomethylation and Contributes to Head and Neck Squamous Cell Carcinoma Carcinogenesis through Increased Aerobic Glycolysis and HIF1α Stabilization" @default.
- W4361818127 doi "https://doi.org/10.1158/1078-0432.c.6519419.v1" @default.
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