HDAC4 inhibits the transcriptional activation of mda-7/IL-24 induced by Sp1

Cell Mol Immunol. 2010 May;7(3):221-6. doi: 10.1038/cmi.2010.12. Epub 2010 Apr 12.

Abstract

Melanoma differentiation-associated gene/interleukin-24 (mda-7/IL-24) is a cytokine that can activate monocytes and T helper 2 cells. The expression of mda-7/IL-24 gradually fades with the progression of melanoma, and it is undetectable at the metastatic stage. Ectopic expression of mda-7/IL-24 selectively suppresses growth and induces apoptosis in cancer cells with little harm to normal cells. However, the transcriptional regulation of the mda-7/IL-24 gene has not been extensively studied. In this study, we show that the expression of mda-7/IL-24 was upregulated by the histone deacetylase (HDAC) inhibitors trichostatin A (TSA) and sodium butyrate (NaBu), whereas it was downregulated by HDAC4. We also found that the histone acetylation level and the binding of the transcriptional factor Sp1 to the mad-7 promoter were reduced upon HDAC4 treatment. Moreover, the HDAC inhibitor TSA induced histone hyperacetylation and stimulated Sp1 binding to the mda-7/IL-24 promoter, which in turn enhanced the expression of mda-7/IL-24. Therefore, we conclude that histone acetylation modification plays an important role in the regulation of mda-7/IL-24 and that the transcription factor Sp1 participates in this process.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetylation
  • Cell Line, Tumor
  • Histone Deacetylases / metabolism*
  • Humans
  • Hydroxamic Acids / pharmacology
  • Interleukins / genetics*
  • Protein Binding
  • Repressor Proteins / antagonists & inhibitors
  • Repressor Proteins / metabolism*
  • Sp1 Transcription Factor / genetics
  • Sp1 Transcription Factor / metabolism*
  • Transcriptional Activation*
  • Up-Regulation / drug effects

Substances

  • Hydroxamic Acids
  • Interleukins
  • Repressor Proteins
  • Sp1 Transcription Factor
  • interleukin-24
  • trichostatin A
  • HDAC4 protein, human
  • Histone Deacetylases