title: Epigenetic control of skin differentiation genes by phytocannabinoids.
abstract: OBJECTIVE
  Endocannabinoid signalling has been shown to have a role in the control of epidermal physiology, whereby anandamide is able to regulate the expression of skin differentiation genes through DNA methylation. Here, we investigated the possible epigenetic regulation of these genes by several phytocannabinoids, plant-derived cannabinoids that have the potential to be novel therapeutics for various human diseases.
  
  
  METHODS
  The effects of cannabidiol, cannabigerol and cannabidivarin on the expression of skin differentiation genes keratins 1 and 10, involucrin and transglutaminase 5, as well as on DNA methylation of keratin 10 gene, were investigated in human keratinocytes (HaCaT cells). The effects of these phytocannabinoids on global DNA methylation and the activity and expression of four major DNA methyltransferases (DNMT1, 3a, 3b and 3L) were also examined.
  
  
  RESULTS
  Cannabidiol and cannabigerol significantly reduced the expression of all the genes tested in differentiated HaCaT cells, by increasing DNA methylation of keratin 10 gene, but cannabidivarin was ineffective. Remarkably, cannabidiol reduced keratin 10 mRNA through a type-1 cannabinoid (CB1 ) receptor-dependent mechanism, whereas cannabigerol did not affect either CB1 or CB2 receptors of HaCaT cells. In addition, cannabidiol, but not cannabigerol, increased global DNA methylation levels by selectively enhancing DNMT1 expression, without affecting DNMT 3a, 3b or 3L.
  
  
  CONCLUSIONS
  These findings show that the phytocannabinoids cannabidiol and cannabigerol are transcriptional repressors that can control cell proliferation and differentiation. This indicates that they (especially cannabidiol) have the potential to be lead compounds for the development of novel therapeutics for skin diseases.
authors.affiliation: Department of Biomedical Sciences, University of Teramo, Teramo, Italy.
authors.forename: Mariangela
authors.initials: M
authors.lastname: Pucci
authors.forename: Cinzia
authors.initials: C
authors.lastname: Rapino
authors.forename: Andrea
authors.initials: A
authors.lastname: Di Francesco
authors.forename: Enrico
authors.initials: E
authors.lastname: Dainese
authors.forename: Claudio
authors.initials: C
authors.lastname: D'Addario
authors.forename: Mauro
authors.initials: M
authors.lastname: Maccarrone
mesh_terms: D002185:Cannabidiol / Q000494:pharmacology; D002186:Cannabinoids / Q000494:pharmacology*; D002454:Cell Differentiation / Q000187:drug effects* / Q000235:genetics; D002460:Cell Line; D019175:DNA Methylation / Q000187:drug effects*; D000090205:DNA Methyltransferase 3A; D015254:DNA Modification Methylases / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation; D044127:Epigenesis, Genetic / Q000187:drug effects*; D006801:Humans; D053556:Keratin-1 / Q000235:genetics; D053550:Keratin-10 / Q000235:genetics; D015603:Keratinocytes / Q000187:drug effects* / Q000378:metabolism; D064209:Phytochemicals / Q000494:pharmacology*; D011498:Protein Precursors / Q000235:genetics; D012333:RNA, Messenger / Q000378:metabolism; D012867:Skin / Q000187:drug effects* / Q000378:metabolism; D014158:Transcription, Genetic / Q000187:drug effects; D011503:Transglutaminases / Q000235:genetics
chemical_list: D002186:Cannabinoids; C000717967:DNMT3A protein, human; C491616:KRT1 protein, human; C507493:KRT10 protein, human; D053556:Keratin-1; D064209:Phytochemicals; D011498:Protein Precursors; D012333:RNA, Messenger; D053550:Keratin-10; D002185:Cannabidiol; C032253:involucrin; D015254:DNA Modification Methylases; D000090205:DNA Methyltransferase 3A; C418703:transglutaminase 5; D011503:Transglutaminases; C580853:cannabidivarin; C037036:cannabigerol
keywords: DNA methylation; endocannabinoid system; gene expression; phytocannabinoids; skin