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Tristetraprolin-mediated hexokinase 2 expression regulation contributes to glycolysis in cancer cells

Dong Jun Kim1, Mai-Tram Vo1, Seong Hee Choi1

  • 1Department of Biological Sciences, University of Ulsan, Ulsan 680-749, Korea.

Molecular Biology of the Cell
|January 17, 2019
PubMed

Insights

Tristetraprolin (TTP) suppresses cancer cell glycolysis by targeting Hexokinase 2 (HK2) mRNA for degradation. TTP overexpression lowers HK2 levels, reducing cancer cell glucose metabolism and energy production.

Area of Science:

  • Biochemistry
  • Molecular Biology
  • Cancer Research

Background:

  • Hexokinase 2 (HK2) is upregulated in cancer, promoting glycolysis, but its regulatory mechanisms are not fully understood.
  • Tristetraprolin (TTP) is an RNA-binding protein that typically downregulates gene expression by promoting mRNA decay, and its expression is often reduced in cancers.

Purpose of the Study:

  • To investigate the role of Tristetraprolin (TTP) in regulating Hexokinase 2 (HK2) expression and its impact on cancer cell metabolism.
  • To elucidate the molecular mechanism by which TTP affects HK2 mRNA stability.

Main Methods:

  • Analysis of HK2 mRNA 3'-untranslated region (UTR) for AU-rich elements (AREs).
  • TTP binding assays to HK2 3'-UTR.
  • Overexpression of TTP in cancer cells to assess effects on HK2 expression, glucose uptake, and metabolite production.
  • Measurement of extracellular acidification rate (ECAR) and oxygen consumption rate (OCR) to evaluate cellular metabolic activity.
  • Complementation studies with ectopic HK2 expression to confirm TTP's mechanism.

Main Results:

  • HK2 mRNA was found to contain an ARE in its 3'-UTR, serving as a binding site for TTP.
  • TTP directly binds to the HK2 3'-UTR, leading to enhanced HK2 mRNA degradation.
  • TTP overexpression significantly decreased HK2 expression, glucose uptake, and production of key glycolytic intermediates (glucose-6-phosphate, pyruvate, lactate).
  • TTP overexpression reduced both ECAR and OCR, indicating suppressed glycolysis and oxidative metabolism.
  • Ectopic HK2 expression partially rescued the metabolic suppression caused by TTP overexpression.

Conclusions:

  • TTP functions as a critical negative regulator of Hexokinase 2 (HK2) expression in cancer cells.
  • TTP-mediated degradation of HK2 mRNA suppresses cancer cell glycolysis and overall metabolic capacity.
  • These findings highlight TTP as a potential therapeutic target for modulating cancer metabolism.

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