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.