Glucose metabolism as a target of histone deacetylase inhibitors

Suzanne E. Wardell, Olga R. Ilkayeva, Heather L. Wieman, Daniel E. Frigo, Jeffrey C. Rathmell, Christopher B. Newgard, Donald P. McDonnell

Research output: Contribution to journalArticle

51 Scopus citations

Abstract

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 similartranscriptional 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 catab- olism with no increase in fatty acid oxidation. Ourfindings suggestthat 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.

Original languageEnglish (US)
Pages (from-to)388-401
Number of pages14
JournalMolecular Endocrinology
Volume23
Issue number3
DOIs
StatePublished - Mar 2009

ASJC Scopus subject areas

  • Molecular Biology
  • Endocrinology

Fingerprint Dive into the research topics of 'Glucose metabolism as a target of histone deacetylase inhibitors'. Together they form a unique fingerprint.

Cite this