Human Hairless Protein Roles in Skin/Hair and Emerging Connections to Brain and Other Cancers

The mammalian hairless protein (HR) is a 130 kDa nuclear transcription factor that is essential for proper skin and hair follicle function. Previous studies have focused on the role of HR in skin maintenance and hair cycling. However, the hairless gene (HR) is also expressed in brain and other tissues, where its role remains poorly understood. HR has been reported to contain functional domains that potentially serve in DNA binding, histone demethylation, nuclear translocation and protein–protein interactions. Indeed, HR has been shown to interact with and repress the action of the nuclear receptors for vitamin D and thyroid hormone as well as RAR-related orphan receptor alpha, possibly via recruitment of histone deacetylases. HR may also have important functions in non-skin tissues given that nearly 200 HR mutations have been identified in patients with various cancers, including prostate, breast, lung, melanoma, uterine, and glioma. This suggests that HR and/or mutants thereof have relevance to the growth and survival of cancer cells. For example, the reported intrinsic histone H3K9 demethylase activity of HR may activate dormant genes to contribute to carcinogenesis. Alternatively, the demonstrated ability of HR to interact with p53 and/or the p53 DNA response element to influence p53-regulated pathways may explain, at least in part, why many cancers express mutated HR proteins. In this review, we summarize the current knowledge of HR bioactions, how HR mutations may be contributing to alopecia as well as to cancer, and, finally, outline future directions in the study of this largely enigmatic nuclear protein. J. Cell. Biochem. 119: 69–80, 2018.