Epigenetic control of skin differentiation genes by phytocannabinoids. (17th September 2013)

• Record Type: Journal Article
• Authors: Pucci, Mariangela; Rapino, Cinzia; Di Francesco, Andrea; Dainese, Enrico; D'Addario, Claudio; Maccarrone, Mauro
• Is Part Of: British journal of pharmacology. Volume 170:Number 3(2013:Oct.)
• Page Start: 581
• Page End: 591
• Publication Date: 2013-09-17
• Subjects: Pharmacology -- Periodicals; Chemotherapy -- Periodicals; Drug Therapy -- Periodicals; Pharmacology -- Periodicals; 615.1
• DOI: 10.1111/bph.12309
• Languages: English
• ISSNs: 0007-1188

Abstract

<abstract abstract-type="main"> <title> <x xml:space="preserve">Abstract</x> </title> <sec id="bph12309-sec-0001" sec-type="section"> <title>Background and Purpose</title> <p>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.</p> </sec> <sec id="bph12309-sec-0002" sec-type="section"> <title>Experimental Approach</title> <p>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.</p> </sec> <sec id="bph12309-sec-0003" sec-type="section"> <title>Key Results</title> <p>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 (CB<sub>1</sub>) receptor‐dependent mechanism, whereas cannabigerol did not affect either CB<sub>1</sub> or CB<sub>2</sub> 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.</p> </sec> <sec id="bph12309-sec-0004" sec-type="section"> <title>Conclusions and Implications</title> <p>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.</p> </sec> </abstract>