Retinoic acids and trichostatin A (TSA), a histone deacetylase inhibitor, induce human pyruvate dehydrogenase kinase 4 (PDK4) gene expression

Hye Sook Kwon, Boli Huang, Nam Ho Jeoung, Pengfei Wu, Calvin N. Steussy, Robert A. Harris

Research output: Contribution to journalArticle

27 Scopus citations

Abstract

Induction of pyruvate dehydrogenase kinase 4 (PDK4) conserves glucose and substrates for gluconeogenesis and thereby helps regulate blood glucose levels during starvation. We report here that retinoic acids (RA) as well as Trichostatin A (TSA), an inhibitor of histone deacetylase (HDAC), regulate PDK4 gene expression. Two retinoic acid response elements (RAREs) to which retinoid X receptor α (RXRα) and retinoic acid receptor α (RARα) bind and activate transcription are present in the human PDK4 (hPDK4) proximal promoter. Sp1 and CCAAT box binding factor (CBF) bind to the region between two RAREs. Mutation of either the Sp1 or the CBF site significantly decreases basal expression, transactivation by RXRα/RARα/RA, and the ability of TSA to stimulate hPDK4 gene transcription. By the chromatin immunoprecipitation assay, RA and TSA increase acetylation of histones bound to the proximal promoter as well as occupancy of CBP and Sp1. Interaction of p300/CBP with E1A completely prevented hPDK4 gene activation by RXRα/RARα/RA and TSA. The p300/CBP may enhance acetylation of histones bound to the hPDK4 promoter and cooperate with Sp1 and CBF to stimulate transcription of the hPDK4 gene in response to RA and TSA.

Original languageEnglish (US)
Pages (from-to)141-151
Number of pages11
JournalBiochimica et Biophysica Acta - Gene Structure and Expression
Volume1759
Issue number3-4
DOIs
StatePublished - Mar 1 2006

Keywords

  • Histone
  • Histone acetylation
  • Histone deacetylase
  • Human
  • Pyruvate dehydrogenase
  • Pyruvate dehydrogenase kinase
  • Retinoic acid
  • Retinoic acid receptor
  • Retinoid X receptor
  • Trichostatin A

ASJC Scopus subject areas

  • Biochemistry
  • Genetics
  • Structural Biology
  • Biophysics

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