A nitric oxide-dependent cross-talk between class I and III histone deacetylases accelerates skin repair

Francesco Spallotta, Chiara Cencioni, Stefania Straino, Simona Nanni, Jessica Rosati, Simona Artuso, Isabella Manni, Claudia Colussi, Giulia Piaggio, Fabio Martelli, Sergio Valente, Antonello Mai, Maurizio C. Capogrossi, Antonella Farsetti, Carlo Gaetano

Research output: Contribution to journalArticlepeer-review

43 Citations (Scopus)

Abstract

In a mouse model of skin repair we found that the class I-IIa histone deacetylase inhibitor trichostatin A accelerated tissue regeneration. Unexpectedly, this effect was suppressed by Sirtinol, a class III histone deacetylase (HDAC) (sirtuin)-selective inhibitor. The role of sirtuins (SIRTs) was then investigated by using resveratrol and a novel SIRT1-2-3 activator, the MC2562 compound we synthesized recently. Both resveratrol and MC2562 were effective in accelerating wound repair. The local administration of natural or synthetic SIRT activators, in fact, significantly accelerated skin regeneration by increasing keratinocyte proliferation. In vitro experiments revealed that the activation of SIRTs stimulated keratinocyte proliferation via endothelial NO synthase phosphorylation and NO production. In this condition, the class I member HDAC2 was found S-nitrosylated on cysteine, a post-transduction modification associated with loss of activity and DNA binding capacity. After deacetylase inhibitor or SIRT activator treatment, ChIP showed, in fact, a significant HDAC2 detachment from the promoter region of insulin growth factor I (IGF-I), fibroblast growth factor 10 (FGF-10), and Epithelial Growth Factor (EGF), which may be the final recipients and effectors of the SIRT-NO-HDAC signaling cascade. Consistently, the effect of SIRT activators was reduced in the presence of NG-nitro-L-arginine methyl ester (L-NAME), a general inhibitor of NO synthesis. In conclusion, the NO-dependent cross-talk among class III and I histone deacetylases suggests an unprecedented signaling pathway important for skin repair.
Original languageEnglish
Pages (from-to)11004-11012
Number of pages9
JournalJournal of Biological Chemistry
Volume288
DOIs
Publication statusPublished - 2013

Keywords

  • Animals
  • Cell Line, Transformed
  • Enzyme Activators
  • Enzyme Inhibitors
  • Fibroblast Growth Factor 10
  • Group III Histone Deacetylases
  • Histone Deacetylase 2
  • Humans
  • Insulin-Like Growth Factor I
  • Male
  • Mice
  • NG-Nitroarginine Methyl Ester
  • Nitric Oxide
  • Signal Transduction
  • Skin
  • Wound Healing

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