Olfactory Receptor OR7A17 Expression Correlates with All-Trans Retinoic Acid (ATRA)-Induced Suppression of Proliferation in Human Keratinocyte Cells

Hyeyoun Kim,Sae Woong Oh,See-Hyoung Park,Jung Yoen Park,Seoyoun Yang,Seyoung Yang,Jae Youl Cho,Minkyung Song,Eunbi Yu,Kitae Kwon,Su Bin Han,Jongsung Lee,Se Jung Park,Seoyoung Choi

doi:10.3390/ijms222212304

Abstract

Olfactory receptors (ORs), which belong to the G-protein-coupled receptor family, have been widely studied as ectopically expressed receptors in various human tissues, including the skin. However, the physiological functions of only a few OR types have been elucidated in skin cells. All-trans retinoic acid (ATRA) is a well-known medication for various skin diseases. However, many studies have shown that ATRA can have adverse effects, resulting from the suppression of cell proliferation. Here, we investigated the involvement of OR7A17 in the ATRA-induced suppression of human keratinocyte (HaCaT) proliferation. We demonstrated that OR7A17 is expressed in HaCaT keratinocytes, and its expression was downregulated by ATRA. The ATRA-induced downregulation of OR7A17 was attenuated via RAR α or RAR γ antagonist treatment, indicating that the effects of ATRA on OR7A17 expression were mediated through nuclear retinoic acid receptor signaling. Moreover, we found that the overexpression of OR7A17 induced the proliferation of HaCaT cells while counteracting the antiproliferative effect of ATRA. Mechanistically, OR7A17 overexpression reversed the ATRA-induced attenuation of Ca2+ entry. Our findings indicated that ATRA suppresses cell proliferation through the downregulation of OR7A17 via RAR α- and γ-mediated retinoid signaling. Taken together, OR7A17 is a potential therapeutic target for ameliorating the anti-proliferative effects of ATRA.

Highlights

Olfactory receptors (ORs)—members of the G-protein-coupled receptor (GPCR)superfamily—are predominantly expressed in the olfactory sensory neurons (OSNs) of the olfactory epithelium for smell detection and sensation [1]
We investigated the ectopic expression of OR—OR7A17—in human keratinocytes; the gene encoding OR7A17 has recently been identified as one of the genes associated with infectious skin traits in Holstein dairy cattle [20]
We hypothesized that All-trans retinoic acid (ATRA) would suppress OR7A17 expression, based on a report by Jung et al [16], who demonstrated that the expression of different ORs was repressed during the ATRA-induced differentiation of HL-60 leukemia cells

Summary

Introduction

Olfactory receptors (ORs)—members of the G-protein-coupled receptor (GPCR)superfamily—are predominantly expressed in the olfactory sensory neurons (OSNs) of the olfactory epithelium for smell detection and sensation [1]. While ORs were first described as being exclusively expressed in the nasal epithelium, various recent studies have reported their presence in nonolfactory tissues, including the skin [2,3]. A subset of ectopically expressed olfactory receptors, including OR2AT4, OR2A4/OR2A7, OR51B5, OR51E2, and OR10G7, have been identified and functionally characterized in human skin cells [4,5,6,7]. The regulation of skin cell proliferation and differentiation is mediated via two specific nuclear receptors, namely RA receptors (RARs), which include α, β, and γ subtypes, and retinoid X receptors (RXRs). Upon binding to ATRA, RARs heterodimerize with RXRs, allowing the former to function as ligand-inducible transcriptional regulators. The heterodimers bind to the RA response elements (RAREs) in the DNA, facilitating the further recruitment of transcriptional activators or repressors, which regulate target gene expression [14]

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Conclusion