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

This paper showed for the first time that anandamide (AEA) can inhibit keratinocyte differentiation through the induction of the DNA methylation of keratinocyte differentiating genes, and it outlined a new activity of endocannabinoids as transcriptional regulators.

In the epidermis, the uppermost compartment of the skin, cell proliferation and differentiation occur sequentially and are characterized by the expression of specific proteins, such as keratins and transglutaminases. The epidermal differentiation begins with the migration of keratinocytes from the basal layer, composed of proliferating cells, and ends with the formation of the cornified cell envelope found in differentiated keratinocytes. DNA methylation levels have also been reported to change during keratinocyte differentiation. Additionally, in previous articles, agents reported to inhibit DNA methylation were shown to inhibit growth and to promote differentiation of keratinocytes {1-3}. Therefore, there is a possibility that a certain signaling pathway to induce DNA methylation might be able to regulate keratinocyte differentiation. Concerning keratinocyte differentiation, the authors have previously reported that exogenous AEA inhibits keratinocyte differentiation in vitro, leading to a type-1 cannabinoid receptor (CB1R)-dependent reduction of cornified envelope formation and transglutaminase activity. On the basis of this previous article, here they investigated whether AEA would be able to modulate the DNA methylation or not. As a result, using a HaCat keratinocyte culture model, they showed that keratin 1 and 10, transglutaminase 5 and involucrin are transcriptionally down-regulated by the treatment of AEA via a CB1R-dependent manner. They also showed that AEA can induce the DNA methylation of keratinocyte-differentiating genes by increasing the activity of DNA methyltransferase activity through CB1R. Furthermore, they showed that this methylation is induced through a p38, and to a lesser extent p42/44, mitogen-activated protein kinase-dependent pathway triggered by CB1R. They described here for the first time that CB1 signaling can regulate DNA methylation in human keratinocytes. Although these experiments were performed using an artificially immortalized keratinocyte cell line, this article provides a new insight into the mechanism of how endocannabinoids can modulate the differentiation of human keratinocytes. And this result also implies that it might be possible to clinically use cannabinoid signaling to regulate DNA methylation in a variety of human pathologies, such as skin cancer.

References: {1} Roesl et al. EMBO J 1988, 7:1321-8 [PMID:2457495]. {2} Elder et al. Exp Dermatol 2002, 11:406-12 [PMID:12366693]. {3} Balasubramanian et al. Toxicol Appl Pharmacol 2007, 224:214-9 [PMID:17493651].

Acknowledgements: I would like to thank Koji Sugawara for their assistance in the preparation of this evaluation.