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Glucose metabolism as a target of histone deacetylase inhibitors.

Publication ,  Journal Article
Wardell, SE; Ilkayeva, OR; Wieman, HL; Frigo, DE; Rathmell, JC; Newgard, CB; McDonnell, DP
Published in: Mol Endocrinol
March 2009

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.

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Published In

Mol Endocrinol

DOI

ISSN

0888-8809

Publication Date

March 2009

Volume

23

Issue

3

Start / End Page

388 / 401

Location

United States

Related Subject Headings

  • Tumor Cells, Cultured
  • Oxidation-Reduction
  • Multiple Myeloma
  • Models, Biological
  • Humans
  • Histone Deacetylase Inhibitors
  • Hexokinase
  • Glucose Transporter Type 1
  • Glucose
  • Enzyme Inhibitors
 

Citation

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Wardell, S. E., Ilkayeva, O. R., Wieman, H. L., Frigo, D. E., Rathmell, J. C., Newgard, C. B., & McDonnell, D. P. (2009). Glucose metabolism as a target of histone deacetylase inhibitors. Mol Endocrinol, 23(3), 388–401. https://doi.org/10.1210/me.2008-0179
Wardell, Suzanne E., Olga R. Ilkayeva, Heather L. Wieman, Daniel E. Frigo, Jeffrey C. Rathmell, Christopher B. Newgard, and Donald P. McDonnell. “Glucose metabolism as a target of histone deacetylase inhibitors.Mol Endocrinol 23, no. 3 (March 2009): 388–401. https://doi.org/10.1210/me.2008-0179.
Wardell SE, Ilkayeva OR, Wieman HL, Frigo DE, Rathmell JC, Newgard CB, et al. Glucose metabolism as a target of histone deacetylase inhibitors. Mol Endocrinol. 2009 Mar;23(3):388–401.
Wardell, Suzanne E., et al. “Glucose metabolism as a target of histone deacetylase inhibitors.Mol Endocrinol, vol. 23, no. 3, Mar. 2009, pp. 388–401. Pubmed, doi:10.1210/me.2008-0179.
Wardell SE, Ilkayeva OR, Wieman HL, Frigo DE, Rathmell JC, Newgard CB, McDonnell DP. Glucose metabolism as a target of histone deacetylase inhibitors. Mol Endocrinol. 2009 Mar;23(3):388–401.

Published In

Mol Endocrinol

DOI

ISSN

0888-8809

Publication Date

March 2009

Volume

23

Issue

3

Start / End Page

388 / 401

Location

United States

Related Subject Headings

  • Tumor Cells, Cultured
  • Oxidation-Reduction
  • Multiple Myeloma
  • Models, Biological
  • Humans
  • Histone Deacetylase Inhibitors
  • Hexokinase
  • Glucose Transporter Type 1
  • Glucose
  • Enzyme Inhibitors