Glucose metabolism as a target of histone deacetylase inhibitors.
The therapeutic efficacy of histone deacetylase inhibitors (HDACI) is generally attributed to their ability to alter gene expression secondary to their effects on the acetylation status of transcription factors and histones. However, because HDACIs exhibit similar transcriptional effects in most cells, the molecular basis for their therapeutic selectivity toward malignant cells is largely unknown. In this study, we report that HDACI, of distinct chemotypes, quantitatively inhibit glucose transporter 1 (GLUT1)-mediated glucose transport into multiple myeloma cells through both down-regulation of GLUT1 and inhibition of hexokinase 1 (HXK1) enzymatic activity. Unexpectedly, however, this inhibition of glucose utilization is accompanied by an increase in amino acid catabolism with no increase in fatty acid oxidation. Our findings suggest that an HDACI-induced change in carbon source preference could contribute to the therapeutic efficacy of these drugs by creating a pattern of fuel utilization that is incompatible with rapid tumor growth and survival. Furthermore, these results, which implicate glucose metabolism as a target of HDACI, suggest that caution should be exercised in attributing effects of this class of drug to primary alterations in gene transcription.
Wardell
Suzanne E
SE
Duke University Medical Center, Pharmacology and Cancer Biology, Box 3813, Durham, North Carolina 27710, USA.
Ilkayeva
Olga R
OR
Wieman
Heather L
HL
Frigo
Daniel E
DE
Rathmell
Jeffrey C
JC
Newgard
Christopher B
CB
McDonnell
Donald P
DP
D000105:Acetyl Coenzyme A / Q000378:metabolism; D000596:Amino Acids / Q000378:metabolism; D017209:Apoptosis / Q000187:drug effects; D050260:Carbohydrate Metabolism / Q000187:drug effects*; D015536:Down-Regulation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005947:Glucose / Q000378:metabolism*; D051272:Glucose Transporter Type 1 / Q000037:antagonists & inhibitors / Q000378:metabolism; D006593:Hexokinase / Q000037:antagonists & inhibitors / Q000378:metabolism; D056572:Histone Deacetylase Inhibitors; D006801:Humans; D008954:Models, Biological; D009101:Multiple Myeloma / Q000378:metabolism; D010084:Oxidation-Reduction / Q000187:drug effects; D014407:Tumor Cells, Cultured
D000596:Amino Acids; D004791:Enzyme Inhibitors; D051272:Glucose Transporter Type 1; D056572:Histone Deacetylase Inhibitors; C495677:SLC2A1 protein, human; D000105:Acetyl Coenzyme A; D006593:Hexokinase; D005947:Glucose