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Title: Transketolase-like 1 ectopic expression is associated with DNA hypomethylation and induces the Warburg effect in melanoma cells.
Austin Authors: Jayachandran, Aparna;Lo, Pu-Han;Chueh, Anderly C;Prithviraj, Prashanth;Molania, Ramyar;Davalos-Salas, Mercedes;Anaka, Matthew;Walkiewicz, Marzena;Cebon, Jonathan S ;Behren, Andreas
Affiliation: Ludwig Institute for Cancer Research, Melbourne-Austin Branch, Heidelberg, Victoria, Australia
Olivia Newton-John Cancer Research Institute, Heidelberg, Victoria, Australia
Department of Medicine, University of Melbourne, Melbourne, Victoria, Australia
School of Cancer Medicine, Latrobe University, Melbourne, Victoria, Australia
School of Medicine and the Gallipoli Medical Research Foundation, The University of Queensland, Brisbane, QLD, Australia
ACRF Chemical Biology Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, Melbourne, Australia
Department of Medical Biology, University of Melbourne, Parkville, Melbourne, Australia
Cancer Immuno-biology Laboratory, Olivia Newton-John Cancer Research Institute, Olivia Newton-John Cancer and Wellness Centre, Heidelberg, Victoria, Australia
Issue Date: 22-Feb-2016 2016
Publication information: BMC cancer 2016; 16: 134
Abstract: 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 of TKTL1 as a mediator of disease progression in melanoma associated with a defective methylation phenotype. The expression of TKTL1 in metastatic melanoma tumors and cell lines was analysed by qRT-PCR and immunohistochemistry. The promoter methylation status of TKTL1 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 of TKTL1 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 of TKTL1 in melanoma cells. Expression of TKTL1 was highly restricted in normal adult tissues and was overexpressed in a subset of metastatic melanoma tumors and derived cell lines. The TKTL1 promoter was activated by hypomethylation and treatment with 5aza induced TKTL1 expression in melanoma cells. Augmented expression of TKTL1 in melanoma cells was associated with a glycolytic phenotype. Loss and gain of function studies revealed that TKTL1 contributed to enhanced invasion of melanoma cells. Our data provide evidence for an important role of TKTL1 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 elevated TKTL1 expression.
DOI: 10.1186/s12885-016-2185-5
ORCID: 0000-0001-5329-280X
PubMed URL: 26907172
Type: Journal Article
Appears in Collections:Journal articles

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