A new study entitled “Terminal epidermal differentiation is regulated by the interaction of Fra-2/AP-1 with Ezh2 and ERK1/2” reveals a new mechanism by which keratinocyte differentiation is regulated, the key process for the formation of human epidermis. The study was published in the journal Genes & Development.
Keratinocytes are the main cells that constitute the epidermis, the skin’s most outer-layer, whose main function is to ensure a barrier against pathogens, water loss and UV radiations. The epidermis is a dynamic skin layer that is continuously renewing through a process known as keratinocyte differentiation. Here, keratinocytes undergo a process of maturation as they migrate from the epidermis inner layer to its suprabasal layer, a crucial step for epidermis to acquire its barrier functions.
Notably, alterations in epidermal differentiation occur in more than 25% of all human skin disorders, including skin cancer. The maturation of human epidermis is dependent on several proteins and transcription factors that constitute the epidermal differentiation complex (EDC).
In this study, a team of researchers from the Spanish National Cancer Research Centre (CNIO), aimed to further understand the interactions occurring at the EDC. The authors focused on EDCs’ Fos-related proteins, namely Fra-2, whose functions are not competely understood. The team discovered that Fra-2 is a crucial regulator of epidermal differentiation. Specifically,Fra-2 present in keratinocytes regulates the expression of EDC genes.
Using mice deficient for Fra-2, the authors observed that loosing this gene in suprabasal keratinocytes was sufficient to disrupt skin barrier functions by reducing the expression of EDC genes. These observations were translated to a tumor mice model. Specifically, the authors showed that mice with papillomas – benign skin tumors – had a reduction in tumor size upon Fra-2 activation. The team also uncovered the mechanisms behing Fra-2 regulatory properties, showing that Fra-2 is regulated by a two-step mechanism: Fra-2 interaction with Ezh2 (leading to its inactivation) and Fra-2 interaction withERK1/2, resulting in its activation.
These findings reveal new insights into skin functions with clear implications in human health, as skin cancer is the most common of all cancers, with more than 3.5 million cases being diagnosed every year in the United States alone, according to the American Cancer Society.
Stefanie Wurm, study first author commented in a news release, “We describe a novel interaction of Fra-2 with Ezh2. Using mass spectrometry approaches, we identified a novel post-translational modification of Fra-2: when methylated by Ezh2 [methylation is a chemical modification when the molecule gains a methyl group], Fra-2 remains inactive in basal cells and when it is phosphorylated by ERK1/2 [addition of a phosphate group], it becomes active.”