title: The CCHCR1 (HCR) gene is relevant for skin steroidogenesis and downregulated in cultured psoriatic keratinocytes.
abstract: 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.
authors.affiliation: Department of Medical Genetics, University of Helsinki, Helsinki, Finland.
authors.forename: Inkeri
authors.initials: I
authors.lastname: Tiala
authors.forename: Sari
authors.initials: S
authors.lastname: Suomela
authors.forename: Jari
authors.initials: J
authors.lastname: Huuhtanen
authors.forename: Janica
authors.initials: J
authors.lastname: Wakkinen
authors.forename: Maarit
authors.initials: M
authors.lastname: Hölttä-Vuori
authors.forename: Kati
authors.initials: K
authors.lastname: Kainu
authors.forename: Sirpa
authors.initials: S
authors.lastname: Ranta
authors.forename: Ursula
authors.initials: U
authors.lastname: Turpeinen
authors.forename: Esa
authors.initials: E
authors.lastname: Hämäläinen
authors.forename: Hong
authors.initials: H
authors.lastname: Jiao
authors.forename: Seija-Liisa
authors.initials: SL
authors.lastname: Karvonen
authors.forename: Elina
authors.initials: E
authors.lastname: Ikonen
authors.forename: Juha
authors.initials: J
authors.lastname: Kere
authors.forename: Ulpu
authors.initials: U
authors.lastname: Saarialho-Kere
authors.forename: Outi
authors.initials: O
authors.lastname: Elomaa
mesh_terms: D000818:Animals; D019556:COS Cells; D002478:Cells, Cultured; D002522:Chlorocebus aethiops; D002786:Cholesterol Side-Chain Cleavage Enzyme / Q000378:metabolism; D015536:Down-Regulation / Q000235:genetics*; D006367:HeLa Cells; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics*; D015603:Keratinocytes / Q000378:metabolism* / Q000473:pathology*; D051379:Mice; D008822:Mice, Transgenic; D008954:Models, Biological; D009928:Organ Specificity; D010750:Phosphoproteins / Q000235:genetics; D021381:Protein Transport; D011565:Psoriasis / Q000235:genetics*; D018167:Receptors, Calcitriol / Q000235:genetics; D012867:Skin / Q000378:metabolism*; D013256:Steroids / Q000096:biosynthesis*; D014162:Transfection; D000098682:Steroidogenic Acute Regulatory Protein
chemical_list: C412616:CCHCR1 protein, human; D047908:Intracellular Signaling Peptides and Proteins; D010750:Phosphoproteins; D018167:Receptors, Calcitriol; D013256:Steroids; D000098682:Steroidogenic Acute Regulatory Protein; D002786:Cholesterol Side-Chain Cleavage Enzyme