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Assays for Validating Histone Acetyltransferase Inhibitors
09:11

Assays for Validating Histone Acetyltransferase Inhibitors

Published on: August 6, 2020

Glucose metabolism as a target of histone deacetylase inhibitors

Suzanne E Wardell1, Olga R Ilkayeva, Heather L Wieman

  • 1Duke University Medical Center, Pharmacology and Cancer Biology, Box 3813, Durham, North Carolina 27710, USA.

Molecular Endocrinology (Baltimore, Md.)
|December 25, 2008
PubMed

Insights

Histone deacetylase inhibitors (HDACI) reduce glucose uptake in multiple myeloma cells by inhibiting glucose transporter 1 (GLUT1) and hexokinase 1 (HXK1). This metabolic shift enhances therapeutic efficacy against cancer.

Area of Science:

  • Oncology
  • Molecular Biology
  • Biochemistry

Background:

  • Histone deacetylase inhibitors (HDACI) are known for their therapeutic effects, often attributed to altering gene expression.
  • The precise molecular mechanisms underlying the selective therapeutic action of HDACI against malignant cells remain largely undefined.
  • Understanding HDACI's impact on cellular metabolism is crucial for elucidating their efficacy.

Purpose of the Study:

  • To investigate the effects of distinct chemotype HDACI on glucose metabolism in multiple myeloma cells.
  • To determine if HDACI influence glucose transporter 1 (GLUT1) and hexokinase 1 (HXK1) activity.
  • To explore the compensatory metabolic pathways activated by HDACI.

Main Methods:

  • Treatment of multiple myeloma cells with various HDACI.
  • Quantification of glucose transport mediated by GLUT1.
  • Assay of hexokinase 1 (HXK1) enzymatic activity.
  • Measurement of amino acid and fatty acid oxidation rates.

Main Results:

  • HDACI significantly inhibited GLUT1-mediated glucose transport in multiple myeloma cells.
  • HDACI reduced GLUT1 expression and inhibited HXK1 enzymatic activity.
  • Inhibition of glucose utilization was accompanied by increased amino acid catabolism, not fatty acid oxidation.
  • HDACI induced a shift in cellular carbon source preference.

Conclusions:

  • HDACI directly target glucose metabolism in multiple myeloma cells by down-regulating GLUT1 and inhibiting HXK1.
  • The observed shift in carbon source preference, favoring amino acid catabolism, may contribute to the therapeutic efficacy of HDACI.
  • These findings suggest that glucose metabolism is a key target of HDACI and caution against solely attributing their effects to transcriptional alterations.

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