The retinoid-related orphan receptor ROR? promotes keratinocyte differentiation via FOXN1.

ABSTRACT: ROR? 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 ROR? gene expression in human keratinocytes (HKCs), we have found that this transcription factor functions as a regulator of epidermal differentiation. Among the 4 ROR? isoforms, ROR?4 is prominently expressed by keratinocytes in a manner that increases with differentiation. In contrast, ROR? levels are significantly lower in skin squamous cell carcinoma tumors (SCCs) and cell lines. Increasing the levels of ROR?4 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 ROR? impaired the ability of keratinocytes to differentiate in an in vivo epidermal cyst model. The pro-differentiation function of ROR? is mediated at least in part by FOXN1, a well-known pro-differentiation transcription factor that we establish as a novel direct target of ROR? in keratinocytes. Our results point to ROR? as a novel node in the keratinocyte differentiation network and further suggest that the identification of ROR? ligands may prove useful for treating skin disorders that are associated with abnormal keratinocyte differentiation, including cancer.

SUBMITTER: Dai J 

PROVIDER: S-EPMC3726659 | biostudies-other | 2013

REPOSITORIES: biostudies-other