HDAC inhibition promotes neuronal outgrowth and counteracts growth cone collapse through CBP/p300 and P/CAF-dependent p53 acetylation

Cell Death Differ. 2010 Sep;17(9):1392-408. doi: 10.1038/cdd.2009.216. Epub 2010 Jan 22.


Neuronal outgrowth is guided by both extrinsic and intrinsic factors, involving transcriptional regulation. The acetylation of histones and transcription factors, which facilitates promoter accessibility, ultimately promotes transcription, and depends on the balance between histone deacetylases (HDACs) and histone acetyltransferases (HATs) activities. However, a critical function for specific acetylation modifying enzymes in neuronal outgrowth has yet to be investigated. To address this issue, we have used an epigenetic approach to facilitate gene expression in neurons, by using specific HDAC inhibitors. Neurons treated with a combination of HDAC and transcription inhibitors display an acetylation and transcription-dependent increase in outgrowth and a reduction in growth cone collapse on both 'permissive' (poly-D-lysine, PDL) and 'non-permissive' substrates (myelin and chondroitin sulphate proteoglycans (CSPGs)). Next, we specifically show that the expression of the histone acetyltransferases CBP/p300 and P/CAF is repressed in neurons by inhibitory substrates, whereas it is triggered by HDAC inhibition on both permissive and inhibitory conditions. Gene silencing and gain of function experiments show that CBP/p300 and P/CAF are key players in neuronal outgrowth, acetylate histone H3 at K9-14 and the transcription factor p53, thereby initiating a pro-neuronal outgrowth transcriptional program. These findings contribute to the growing understanding of transcriptional regulation in neuronal outgrowth and may lay the molecular groundwork for the promotion of axonal regeneration after injury.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetylation
  • Animals
  • Cell Enlargement / drug effects*
  • Cells, Cultured
  • Cerebellum / cytology
  • Cerebellum / growth & development
  • Cerebral Cortex / cytology
  • Cerebral Cortex / embryology
  • Cerebral Cortex / growth & development
  • Chondroitin Sulfate Proteoglycans / pharmacology
  • Gene Expression / drug effects
  • Gene Expression / genetics
  • Gene Expression Regulation, Developmental / drug effects
  • Gene Expression Regulation, Developmental / physiology
  • Gene Silencing
  • Growth Cones / drug effects*
  • Histone Deacetylase 1 / antagonists & inhibitors
  • Histone Deacetylase 2 / antagonists & inhibitors
  • Histone Deacetylase Inhibitors / pharmacology*
  • Histone Deacetylases / metabolism
  • Histones / metabolism
  • Models, Neurological
  • Myelin Proteins / pharmacology
  • Neurites / drug effects
  • Neurons / cytology
  • Neurons / drug effects*
  • Neurons / metabolism
  • Promoter Regions, Genetic / drug effects
  • Promoter Regions, Genetic / genetics
  • Rats
  • Rats, Inbred Strains
  • Signal Transduction / drug effects
  • Signal Transduction / physiology
  • Tumor Suppressor Protein p53 / genetics
  • Tumor Suppressor Protein p53 / metabolism*
  • p300-CBP Transcription Factors / genetics
  • p300-CBP Transcription Factors / metabolism*


  • Chondroitin Sulfate Proteoglycans
  • Histone Deacetylase Inhibitors
  • Histones
  • Myelin Proteins
  • Tumor Suppressor Protein p53
  • p300-CBP Transcription Factors
  • p300-CBP-associated factor
  • Hdac1 protein, rat
  • Hdac2 protein, rat
  • Histone Deacetylase 1
  • Histone Deacetylase 2
  • Histone Deacetylases