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J. Biol. Chem., Vol. 283, Issue 10, 6005-6012, March 7, 2008

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Anandamide Regulates Keratinocyte Differentiation by Inducing DNA Methylation in a CB1 Receptor-dependent Manner^*

Andrea Paradisi¹, Nicoletta Pasquariello¹, Daniela Barcaroli^¶2, and Mauro Maccarrone^¶3

From the Department of Biomedical Sciences, University of Teramo, 64100 Teramo, Italy, the Department of Experimental Medicine and Biochemical Sciences, University of Rome "Tor Vergata", 00133 Rome, Italy, and the ^¶European Center for Brain Research (CERC), Istituto di Ricovero e Cura a Carattere Scientifico Santa Lucia Foundation, 00196 Rome, Italy

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.

Received for publication, September 24, 2007 , and in revised form, December 7, 2007.

^* This work was supported in part by grants from Fondazione Cassa di Risparmio di Teramo (Tercas, 2004 and 2005), Agenzia Spaziale Italiana (DCMC and MoMa Projects 2006), and Ministero dell'Università e della ricerca (PRIN and FIRB Projects 2006). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ Both authors contributed equally to this work.

² Recipient of an AIRC (Associazione Italiana per la Ricerca sul Cancro) fellowship.

³ To whom correspondence should be addressed: Dept. of Biomedical Sciences, University of Teramo, Piazza A. Moro 45, I-64100 Teramo, Italy. Tel.: 39-0861-266875; Fax: 39-0861-266877; E-mail: mmaccarrone{at}unite.it.

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