Epigenetic control of skin differentiation genes by phytocannabinoids
Version of Record online: 17 SEP 2013
© 2013 The British Pharmacological Society
British Journal of Pharmacology
Volume 170, Issue 3, pages 581–591, October 2013
How to Cite
Pucci, M., Rapino, C., Di Francesco, A., Dainese, E., D'Addario, C. and Maccarrone, M. (2013), Epigenetic control of skin differentiation genes by phytocannabinoids. British Journal of Pharmacology, 170: 581–591. doi: 10.1111/bph.12309
- Issue online: 17 SEP 2013
- Version of Record online: 17 SEP 2013
- Accepted manuscript online: 19 JUL 2013 05:53AM EST
- Manuscript Accepted: 3 JUL 2013
- Manuscript Revised: 28 JUN 2013
- Manuscript Received: 25 JAN 2013
- GW Pharmaceuticals
- endocannabinoid system;
- gene expression;
- DNA methylation;
Background and Purpose
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.
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.
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 and Implications
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.