Abstract 2336: Interplay of Fra-2/AP-1 and Ezh2/PRC2 orchestrates epidermal differentiation

Disrupted epidermal differentiation characterizes numerous inflammatory skin diseases and skin cancer that impact >25% of the population. In search for a key mediator of differentiation, we identified Fra-2/AP-1 as a dominant regulator of terminal epidermal differentiation. Loss of Fra-2 in suprabasal keratinocytes was sufficient to give rise to epidermal differentiation defects, keratinocyte hyperproliferation as well as skin inflammation. Additionally, the epithelial-restricted, ectopic expression of Fra-2 in papilloma prone K5-SOS-F transgenic mice resulted in reduced tumor burden due to precocious differentiation. Fra-2 transcriptionally controlled genes located within the Epidermal Differentiation Complex (EDC), encoding structural proteins, which form the skin barrier as well as keratinocyte derived chemokines. We found that Fra-2 induced EDC genes by binding to conserved AP-1 consensus sites in promoter regions. These consensus sites were also bound by the transcriptional repressor Ezh2. Besides binding to the same consensus sites, the methyl-transferase Ezh2 methylated Fra-2 on lysine residues in basal epithelial progenitor cells. Interestingly, the interaction of Fra-2 and Ezh2 was disrupted in the time course of keratinocyte differentiation, suggesting that the transcriptional activity of Fra-2 is modulated by Ezh2. Collectively, we identify Fra-2 as an effector of terminal keratinocyte differentiation and uncover a distinct mechanism of how Ezh2 regulates epidermal differentiation by methylation of the transcription factor Fra-2. Citation Format: Stefanie Wurm, Juan Guinea-Viniegra, Jisheng Zhang, Elena Ezhkova, Erwin Friedrich Wagner. Interplay of Fra-2/AP-1 and Ezh2/PRC2 orchestrates epidermal differentiation. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2336. doi:10.1158/1538-7445.AM2014-2336