Anandamide regulates keratinocyte differentiation by inducing DNA methylation in a CB1 receptor-dependent manner

J Biol Chem. 2008 Mar 7;283(10):6005-12. doi: 10.1074/jbc.M707964200. Epub 2007 Dec 28.


Anandamide (arachidonoylethanolamide, AEA) belongs to an important class of endogenous lipids including amides and esters of long chain polyunsaturated fatty acids, collectively termed "endocannabinoids." Recently we have shown that AEA inhibits differentiation of human keratinocytes, by binding to type-1 cannabinoid receptors (CB1R). To further characterize the molecular mechanisms responsible for this effect, we investigated the expression of epidermal differentiation-related genes after AEA treatment. We observed that keratin 1 and 10, transglutaminase 5 and involucrin are transcriptionally down-regulated by AEA. Most importantly, we found that AEA is able to decrease differentiating gene expression by increasing DNA methylation in human keratinocytes, through a p38, and to a lesser extent p42/44, mitogen-activated protein kinase-dependent pathway triggered by CB1R. An effect of AEA on DNA methylation because of CB1R-mediated increase of methyltransferase activity is described here for the first time, and we believe that the importance of this effect clearly extends beyond the regulation of skin differentiation. In fact, the modulation of DNA methylation by endocannabinoids may affect the expression of a number of genes that regulate many cell functions in response to these substances.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Arachidonic Acids / pharmacology*
  • Cannabinoid Receptor Modulators / pharmacology*
  • Cell Differentiation / drug effects*
  • Cell Line
  • DNA Methylation / drug effects*
  • DNA Modification Methylases / metabolism
  • Down-Regulation / drug effects
  • Endocannabinoids
  • Epidermal Cells
  • Epidermis / metabolism
  • Humans
  • Keratin-1 / biosynthesis
  • Keratin-10 / biosynthesis
  • Keratinocytes / cytology
  • Keratinocytes / metabolism*
  • MAP Kinase Signaling System / drug effects
  • Mitogen-Activated Protein Kinase 1 / metabolism
  • Polyunsaturated Alkamides / pharmacology*
  • Protein Precursors / biosynthesis
  • Receptor, Cannabinoid, CB1 / agonists*
  • Receptor, Cannabinoid, CB1 / metabolism
  • Transglutaminases / biosynthesis
  • p38 Mitogen-Activated Protein Kinases / metabolism


  • Arachidonic Acids
  • Cannabinoid Receptor Modulators
  • Endocannabinoids
  • KRT1 protein, human
  • KRT10 protein, human
  • Keratin-1
  • Polyunsaturated Alkamides
  • Protein Precursors
  • Receptor, Cannabinoid, CB1
  • Keratin-10
  • involucrin
  • DNA Modification Methylases
  • transglutaminase 5
  • Transglutaminases
  • Mitogen-Activated Protein Kinase 1
  • p38 Mitogen-Activated Protein Kinases
  • anandamide