Expression of p21(WAF1/Cip1) through Sp1 sites by histone deacetylase inhibitor apicidin requires PI 3-kinase-PKC epsilon signaling pathway

Oncogene. 2003 Sep 4;22(38):6023-31. doi: 10.1038/sj.onc.1206875.


We previously reported that the activation of p21(WAF1/Cip1) transcription by histone deacetylase inhibitor apicidin was mediated through Sp1 sites and pointed to the possible participation of protein kinase C (PKC). In this study, we investigated the role and identity of the specific isoforms of PKC involved and identified phosphatidylinositol 3-kinase (PI 3-kinase) as an upstream effector in HeLa cells. Using an isoform-specific pharmacological inhibitor of PKC, a PKC epsilon dominant-negative mutant, and antisense oligonucleotide to inhibit PKC epsilon specifically, we found that among PKC isoforms, PKC epsilon was required for the p21(WAF1/Cip1) expression by apicidin. In addition to PKC epsilon, PI 3-kinase appeared to participate in the activation of p21(WAF1/Cip1) promoter by apicidin, since inactivation of PI 3-kinase either by transient expression of dominant-negative mutant of PI 3-kinase or its specific inhibitors, LY294002 and wortmannin, attenuated the activation of p21(WAF1/Cip1) promoter and p21(WAF1/Cip1) protein expression by apicidin. Furthermore, membrane translocation of PKC epsilon in response to apicidin was blocked by the PI 3-kinase inhibitor, indicating the role of PI 3-kinase as an upstream molecule of PKC epsilon in the p21(WAF1/Cip1) promoter activation by apicidin. However, the p21(WAF1/Cip1) expression by apicidin appeared to be independent of the histone hyperacetylation, since apicidin-induced histone hyperacetylation of p21(WAF1/Cip1) promoter region was not affected by inhibition of PI 3-kinase and PKC, suggesting that the chromatin remodeling through the histone hyperacetylation alone might not be sufficient for the expression of p21(WAF1/Cip1) by apicidin. Taken together, these results suggest that the PI 3-kinase-PKC epsilon signaling pathway plays a pivotal role in the expression of the p21(WAF1/Cip1) by apicidin.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetylation / drug effects
  • Binding Sites
  • Cyclin-Dependent Kinase Inhibitor p21
  • Cyclins / biosynthesis
  • Cyclins / drug effects
  • Cyclins / genetics*
  • Enzyme Inhibitors / metabolism
  • Enzyme Inhibitors / pharmacology*
  • Gene Expression / drug effects
  • HeLa Cells
  • Histone Deacetylase Inhibitors
  • Humans
  • Peptides, Cyclic / metabolism
  • Peptides, Cyclic / pharmacology*
  • Phosphatidylinositol 3-Kinases / drug effects
  • Phosphatidylinositol 3-Kinases / metabolism*
  • Phosphoinositide-3 Kinase Inhibitors
  • Plicamycin / pharmacology
  • Promoter Regions, Genetic
  • Protein Kinase C / antagonists & inhibitors
  • Protein Kinase C / drug effects
  • Protein Kinase C / metabolism*
  • Protein Kinase C-epsilon
  • Signal Transduction / drug effects
  • Sp1 Transcription Factor / antagonists & inhibitors
  • Sp1 Transcription Factor / metabolism*


  • CDKN1A protein, human
  • Cyclin-Dependent Kinase Inhibitor p21
  • Cyclins
  • Enzyme Inhibitors
  • Histone Deacetylase Inhibitors
  • Peptides, Cyclic
  • Phosphoinositide-3 Kinase Inhibitors
  • Sp1 Transcription Factor
  • apicidin
  • PRKCE protein, human
  • Protein Kinase C
  • Protein Kinase C-epsilon
  • Plicamycin