Transketolase-like 1 ectopic expression is associated with DNA hypomethylation and induces the Warburg effect in melanoma cells

Jayachandran, Aparna, Lo, Pu-Han, Chueh, Anderly C., Prithviraj, Prashanth, Molania, Ramyar, Davalos-Salas, Mercedes, Anaka, Matthew, Walkiewicz, Marzena, Cebon, Jonathan and Behren, Andreas (2016) Transketolase-like 1 ectopic expression is associated with DNA hypomethylation and induces the Warburg effect in melanoma cells. Bmc Cancer, 16 . doi:10.1186/s12885-016-2185-5


Author Jayachandran, Aparna
Lo, Pu-Han
Chueh, Anderly C.
Prithviraj, Prashanth
Molania, Ramyar
Davalos-Salas, Mercedes
Anaka, Matthew
Walkiewicz, Marzena
Cebon, Jonathan
Behren, Andreas
Title Transketolase-like 1 ectopic expression is associated with DNA hypomethylation and induces the Warburg effect in melanoma cells
Journal name Bmc Cancer   Check publisher's open access policy
ISSN 1471-2407
Publication date 2016-02-22
Year available 2016
Sub-type Article (original research)
DOI 10.1186/s12885-016-2185-5
Open Access Status DOI
Volume 16
Total pages 15
Place of publication London, United Kingdom
Publisher BioMed Central
Collection year 2017
Language eng
Formatted 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 of TKTL1 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 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.

Results: 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.

Conclusions: 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.
Keyword Tktl1
Warburg effect
Aerobic glycolysis
Melanoma
Hypomethylation
Q-Index Code C1
Q-Index Status Provisional Code
Institutional Status UQ

Document type: Journal Article
Sub-type: Article (original research)
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