Details

Autor(en) / Beteiligte

• Sun, Wenyue
• Liu, Yan
• Glazer, Chad A.
• Shao, Chunbo
• Bhan, Sheetal
• Demokan, Semra
• Zhao, Ming
• Rudek, Michelle A.
• Ha, Patrick K.
• Califano, Joseph A.

Titel

Abstract 63: TKTL1 is activated by promoter hypomethylation and contributes to head and neck squamous cell carcinoma carcinogenesis via increased aerobic glycolysis and HIF1-alpha stabilization

Ist Teil von

• Cancer research (Chicago, Ill.), 2010-04, Vol.70 (8_Supplement), p.63-63

Erscheinungsjahr

2010

Quelle

EZB Electronic Journals Library

Beschreibungen/Notizen

• Abstract Described decades ago, the “Warburg effect”, an elevation in aerobic glycolysis, is a fundamental property of cancer cells. Lactate and pyruvate, the end products of glycolysis, are highly produced by cancer cells even in the presence of oxygen. Previously, we observed promoter hypomethylation and overexpression of TKTL1 (Transkelolase-like 1) in Head and Neck Squamous Cell Carcinoma (HNSCC). This study aimed to investigate whether aberrant expression of TKTL1 contributes to HNSCC tumorigenesis and whether this is associated with aerobic glycolytic metabolism. We found that TKTL1 exhibits high frequency of promoter hypomethylation in HNSCC tumors compared with the normal oral epithelial mucosa, correlating with its overexpression in HNSCC. Overexpression of TKTL1 in HNSCC cells promoted cellular proliferation and enhanced tumor growth in vitro and in vivo. Further, in a murine xoenograft and human model of HNSCC, we found that overexpression of TKTL1 increased the production of fructose-6-phosphate and glyceraldehyde-3-phosphate, in turn elevating the production of pyruvate and lactate production accompanied by the elevated glucose uptake and ATP production. Importantly, overexpression of TKTL1 is associated with the normoxic stabilization of the malignancy-promoting transcription factor HIF1α by aerobic glycolytic metabolites including pyruvate and lactate. Notably, reduction of TKTL1 expression decreased HIF1α accumulation, and inhibition of HIF1α could abrogate the growth effects mediated by TKTL1 overexpression. These findings suggest that TKTL1 is a novel protooncogene that is epigenetically activated by aberrant hypomethylation and contributes to a malignant phenotype via altered glycolytic metabolism and HIF1α accumulation, providing opportunities for therapeutic targeting of metabolic pathways in cancer. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 63.