Abstract
RORα is a retinoid-related orphan nuclear receptor that regulates inflammation, lipid metabolism, and cellular differentiation of several non-epithelial tissues. In spite of its high expression in skin epithelium, its functions in this tissue remain unclear. Using gain- and loss-of-function approaches to alter RORα gene expression in human keratinocytes (HKCs), we have found that this transcription factor functions as a regulator of epidermal differentiation. Among the 4 RORα isoforms, RORα4 is prominently expressed by keratinocytes in a manner that increases with differentiation. In contrast, RORα levels are significantly lower in skin squamous cell carcinoma tumors (SCCs) and cell lines. Increasing the levels of RORα4 in HKCs enhanced the expression of structural proteins associated with early and late differentiation, as well as genes involved in lipid barrier formation. Gene silencing of RORα impaired the ability of keratinocytes to differentiate in an in vivo epidermal cyst model. The pro-differentiation function of RORα is mediated at least in part by FOXN1, a well-known pro-differentiation transcription factor that we establish as a novel direct target of RORα in keratinocytes. Our results point to RORα as a novel node in the keratinocyte differentiation network and further suggest that the identification of RORα ligands may prove useful for treating skin disorders that are associated with abnormal keratinocyte differentiation, including cancer.
Highlights
The retinoid related orphan receptor RORa belongs to the steroid nuclear hormone receptor superfamily and functions as a transcription factor by binding as a monomer to the RORa responsive elements (ROREs) in the regulatory region of target genes [1,2,3]
In parallel with its inverse expression in normal keratinocytes and epidermis versus squamous cell carcinoma tumors (SCCs) cells and tumors, we have shown here that RORa plays an essential positive role in keratinocyte differentiation, with FOXN1 as a direct target and mediator
RORa4 is the major RORa isoform expressed in keratinocytes, and its expression is further induced upon differentiation at both mRNA and protein levels
Summary
The retinoid related orphan receptor RORa belongs to the steroid nuclear hormone receptor superfamily and functions as a transcription factor by binding as a monomer to the RORa responsive elements (ROREs) in the regulatory region of target genes [1,2,3]. Very little is known about the functions of RORa in epithelial cell biology. RORa transcripts are highly expressed in the skin, in suprabasal epidermal cells, sebaceous glands, and hair follicles [9]. Mice with homozygous disruption of the RORa gene exhibit sparse pelage, with a slow rate of hair re-growth after shaving, pointing to a possible role of RORa in epidermal differentiation [9]
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