The HCR gene, officially called Coiled-Coil alpha-Helical Rod
protein 1 (CCHCR1), located within the major
psoriasis susceptibility locus PSORS1, is a plausible candidate gene for the risk effect. Recently, CCHCR1 was shown to promote steroidogenesis by interacting with the steroidogenic acute regulator
protein (StAR). Here, we examined the role of CCHCR1 in
psoriasis and cutaneous
steroid metabolism. We found that CCHCR1 and StAR are expressed in basal keratinocytes in overlapping areas of the human skin, and CCHCR1 stimulated
pregnenolone production in steroidogenesis assay. Overexpression of either the CCHCR1*WWCC risk allele or the non-risk allele enhanced
steroid synthesis in vitro. Furthermore, the
cytochrome P450scc enzyme was expressed in human keratinocytes and was induced by
forskolin, a known activator of steroidogenesis, and
forskolin also upregulated CCHCR1. CCHCR1 has an altered expression pattern in lesional psoriatic skin compared to normal healthy skin, suggesting its dysregulation in
psoriasis. We found that the expression of CCHCR1 is downregulated twofold at the
mRNA level in cultured non-lesional psoriatic keratinocytes when compared to non-psoriatic healthy cells. Our results also suggest a connection between CCHCR1 and
vitamin D metabolism in keratinocytes. The expression of the
vitamin D receptor (VDR) gene was lower in non-lesional psoriatic keratinocytes than in healthy cells. Furthermore, Vdr expression was downregulated in the keratinocytes of mice overexpressing the CCHCR1*WWCC risk allele when compared to keratinocytes from mice with the non-risk allele of CCHCR1. Finally, we demonstrate that other agents relevant for
psoriasis and/or the regulation of steroidogenesis influence CCHCR1 expression in keratinocytes, including
insulin,
EGF,
cholesterol,
estrogen, and
cyclosporin A. Taken the role of
steroid hormones, including
vitamin D and
estrogen, in cell proliferation, epidermal barrier homeostasis, differentiation, and immune response, our results suggest a role for CCHCR1 in the pathogenesis of
psoriasis via the regulation of skin
steroid metabolism.