Histone deacetylase inhibitor, Trichostatin A, activates p21WAF1/CIP1 expression through downregulation of c-myc and release of the repression of c-myc from the promoter in human cervical cancer cells

Biochem Biophys Res Commun. 2004 Nov 12;324(2):860-7. doi: 10.1016/j.bbrc.2004.09.130.


Histone deacetylase (HDAC) inhibitors have shown promise in clinical cancer therapy and to consistently induce p21WAF1/CIP1 expression in a p53-independent manner and via increased acetylation of the chromatin at the Sp1 sites in the p21WAF1/CIP1 promoter region. However, the exact mechanism by which HDAC inhibitors induce p21WAF1/CIP1 remains unclear. In this study, we observed that Trichostatin A (TSA), a HDAC inhibitor, induced strikingly p21WAF1/CIP1 expression in human cervical cancer (HeLa) cells, and this induction correlated with downregulation of c-myc expression. Coincident with this observation, knock down of c-myc with a c-myc specific small interfering RNA dramatically induced expression of p21WAF1/CIP1 in these cancer cells. These data suggest that c-myc may play a critical role in repression of p21WAF1/CIP1 expression in HeLa cells. More importantly, using chromatin immunoprecipitation assay, we observed for the first time that c-myc bound to the endogenous p21WAF1/CIP1 promoter in untreated HeLa cells, but not in TSA-treated cells. Taken together, TSA induced c-myc downregulation and release from the endogenous p21WAF1/CIP1 promoter contributes, at least partially, to transcriptional activation of the p21WAF1/CIP1 in HeLa cells.

MeSH terms

  • Blotting, Western
  • Cell Cycle Proteins / metabolism*
  • Cell Line, Tumor
  • Chromatin Immunoprecipitation
  • Cyclin-Dependent Kinase Inhibitor p21
  • Down-Regulation
  • Enzyme Activation
  • Enzyme Inhibitors / pharmacology*
  • Female
  • HeLa Cells
  • Histone Deacetylase Inhibitors*
  • Humans
  • Hydroxamic Acids / pharmacology*
  • Promoter Regions, Genetic
  • Protein Synthesis Inhibitors / pharmacology
  • Proto-Oncogene Proteins c-myc / metabolism*
  • RNA, Small Interfering / metabolism
  • Reverse Transcriptase Polymerase Chain Reaction
  • Sp1 Transcription Factor / chemistry
  • Transcription, Genetic
  • Transcriptional Activation
  • Transfection
  • Tumor Suppressor Protein p53 / metabolism
  • Uterine Cervical Neoplasms / enzymology*


  • CDKN1A protein, human
  • Cell Cycle Proteins
  • Cyclin-Dependent Kinase Inhibitor p21
  • Enzyme Inhibitors
  • Histone Deacetylase Inhibitors
  • Hydroxamic Acids
  • Protein Synthesis Inhibitors
  • Proto-Oncogene Proteins c-myc
  • RNA, Small Interfering
  • Sp1 Transcription Factor
  • Tumor Suppressor Protein p53
  • trichostatin A