p15(INK4b) in HDAC inhibitor-induced growth arrest

FEBS Lett. 2003 Nov 20;554(3):347-50. doi: 10.1016/s0014-5793(03)01186-4.

Abstract

Histone deacetylase (HDAC) inhibitors arrest human tumor cells at the G1 phase of the cell cycle and activate the cyclin-dependent kinase inhibitor, p21(WAF1/Cip1). However, several studies have suggested the existence of a p21(WAF1/Cip1)-independent molecular pathway. We report here that HDAC inhibitors, trichostatin A (TSA) and sodium butyrate, activate the p15(INK4b) gene, a member of the INK4 gene family, through its promoter in HaCaT cells. Furthermore, we show that up-regulation of p15(INK4b) by TSA is associated with cell growth inhibition of HCT116 p21 (-/-) cells. Our findings suggest that p15(INK4b) is one of the important molecular targets of HDAC inhibitors.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Blotting, Northern
  • Butyrates / pharmacology*
  • Cell Cycle / drug effects
  • Cell Cycle / physiology*
  • Cell Cycle Proteins / biosynthesis
  • Cell Cycle Proteins / genetics
  • Cell Cycle Proteins / metabolism*
  • Cell Division / drug effects
  • Cyclin-Dependent Kinase Inhibitor p15
  • Cyclin-Dependent Kinase Inhibitor p16 / biosynthesis
  • Cyclin-Dependent Kinase Inhibitor p16 / genetics
  • Cyclin-Dependent Kinase Inhibitor p16 / metabolism*
  • Cyclin-Dependent Kinases / antagonists & inhibitors
  • DNA / analysis
  • Enzyme Inhibitors / pharmacology*
  • Gene Expression Regulation, Neoplastic / drug effects
  • Gene Expression Regulation, Neoplastic / physiology
  • Genetic Vectors / genetics
  • HCT116 Cells
  • Histone Deacetylase Inhibitors*
  • Humans
  • Hydroxamic Acids / pharmacology*
  • Promoter Regions, Genetic / drug effects
  • Promoter Regions, Genetic / genetics
  • RNA, Messenger / biosynthesis
  • RNA, Messenger / genetics
  • Recombinant Proteins / drug effects
  • Recombinant Proteins / genetics
  • Recombinant Proteins / metabolism
  • Transfection
  • Tumor Suppressor Proteins*
  • Up-Regulation

Substances

  • Butyrates
  • CDKN2B protein, human
  • Cell Cycle Proteins
  • Cyclin-Dependent Kinase Inhibitor p15
  • Cyclin-Dependent Kinase Inhibitor p16
  • Enzyme Inhibitors
  • Histone Deacetylase Inhibitors
  • Hydroxamic Acids
  • RNA, Messenger
  • Recombinant Proteins
  • Tumor Suppressor Proteins
  • trichostatin A
  • DNA
  • Cyclin-Dependent Kinases