Transketolase-like 1 ectopic expression is associated with DNA hypomethylation and induces the Warburg effect in melanoma cells. Issue 1 (December 2016)

• Record Type: Journal Article
• Authors: Jayachandran, Aparna; Lo, Pu-Han; Chueh, Anderly; Prithviraj, Prashanth; Molania, Ramyar; Davalos-Salas, Mercedes; Anaka, Matthew; Walkiewicz, Marzena; Cebon, Jonathan; Behren, Andreas
• Is Part Of: BMC cancer. Volume 16:Issue 1(2016)
• Page Start: 1
• Page End: 15
• Publication Date: 2016-12
• Subjects: TKTL1 -- Warburg effect -- Aerobic glycolysis -- Melanoma -- Hypomethylation; Cancer -- Periodicals; 616.994005
• DOI: 10.1186/s12885-016-2185-5
• Languages: English
• ISSNs: 1471-2407

Abstract

Abstract Background The metabolism of cancer cells is often reprogrammed by dysregulation of metabolic enzymes. Transketolase-like 1 (TKTL1) is a homodimeric transketolase linking the pentose-phosphate pathway with the glycolytic pathway. It is generally silenced at a transcriptional level in somatic tissues. However, in human cancers its expression is associated with the acquisition of a glycolytic phenotype (the Warburg effect) by cancer cells that contributes to the progression of malignant tumors. In melanoma, defective promoter methylation results in the expression of genes and their products that can affect the tumor cell's phenotype including the modification of immune and functional characteristics. The present study evaluates the role ofTKTL1 as a mediator of disease progression in melanoma associated with a defective methylation phenotype. Methods The expression of TKTL1 in metastatic melanoma tumors and cell lines was analysed by qRT-PCR and immunohistochemistry. The promoter methylation status ofTKTL1 in melanoma cells was evaluated by quantitative methylation specific PCR. Using qRT-PCR, the effect of a DNA demethylating agent 5-aza-2'-deoxycytidine (5aza) on the expression ofTKTL1 was examined. Biochemical and molecular analyses such as glucose consumption, lactate production, invasion, proliferation and cell cycle progression together with ectopic expression and siRNA mediated knockdown were used to investigate the role ofTKTL1 in melanoma cells. Results Expression ofTKTL1 was highly restricted in normal adult tissues and was overexpressed in a subset of metastatic melanoma tumors and derived cell lines. TheTKTL1 promoter was activated by hypomethylation and treatment with 5aza inducedTKTL1 expression in melanoma cells. Augmented expression ofTKTL1 in melanoma cells was associated with a glycolytic phenotype. Loss and gain of function studies revealed thatTKTL1 contributed to enhanced invasion of melanoma cells. Conclusions Our data provide evidence for an important role ofTKTL1 in aerobic glycolysis and tumor promotion in melanoma that may result from defective promoter methylation. This epigenetic change may enable the natural selection of tumor cells with a metabolic phenotype and thereby provide a potential therapeutic target for a subset of melanoma tumors with elevatedTKTL1 expression.