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The CCHCR1 (HCR) gene is relevant for skin steroidogenesis and downregulated in cultured psoriatic keratinocytes

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Abstract

The HCR gene, officially called Coiled-Coil α-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.

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Acknowledgements and funding

We thank Ranja Eklund and Alli Tallqvist for their excellent technical assistance. This study was supported by the Academy of Finland, the Sigrid Juselius Foundation, Finska Läkaresällskapet, the Finnish Konkordia Fund, the Maud Kuistila Memorial Foundation, the Biomedicum Helsinki Foundation, Swedish Research Council, and the Helsinki University Hospital research fund (TYH4226).

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Authors and Affiliations

  1. Department of Medical Genetics, University of Helsinki, Helsinki, Finland

    Inkeri Tiala, Janica Wakkinen, Kati Kainu, Juha Kere & Outi Elomaa

  2. Department of Dermatology, University of Helsinki and Helsinki University Central Hospital, Helsinki, Finland

    Sari Suomela, Jari Huuhtanen, Kati Kainu, Seija-Liisa Karvonen & Ulpu Saarialho-Kere

  3. Institute of Biomedicine/Anatomy, University of Helsinki, Helsinki, Finland

    Maarit Hölttä-Vuori & Elina Ikonen

  4. Laboratory of Women’s Clinic and Department of Clinical Chemistry, University of Helsinki and Helsinki University Central Hospital, Helsinki, Finland

    Sirpa Ranta, Ursula Turpeinen & Esa Hämäläinen

  5. Department of Biosciences and Nutrition, Karolinska Institutet, 14157, Huddinge, Sweden

    Hong Jiao & Juha Kere

  6. Clinical Research Center, Karolinska University Hospital (Huddinge), Stockholm, Sweden

    Juha Kere

  7. Department of Dermatology, Karolinska Institutet at Stockholm Söder Hospital, Stockholm, Sweden

    Ulpu Saarialho-Kere

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  1. Inkeri Tiala
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Correspondence to Juha Kere.

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Tiala, I., Suomela, S., Huuhtanen, J. et al. The CCHCR1 (HCR) gene is relevant for skin steroidogenesis and downregulated in cultured psoriatic keratinocytes. J Mol Med 85, 589–601 (2007). https://doi.org/10.1007/s00109-006-0155-0

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