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Suppression of FADS1 Induces ROS Generation, Cell Cycle Arrest, and Apoptosis in Melanocytes: Implications for Vitiligo

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Suppression of FADS1 Induces ROS Generation, Cell Cycle Arrest, and Apoptosis in Melanocytes: Implications for Vitiligo www.aging-us.com AGING 2019, Vol. 11, No. 24 Research Paper Suppression of FADS1 induces ROS generation, cell cycle arrest, and apoptosis in melanocytes: implications for vitiligo Luyan Tang1, Jian Li1, Wenwen Fu1, Wenyu Wu1, Jinhua Xu1 1Department of Dermatology, Huashan Hospital Affiliated to Fudan University, Shanghai 200040, China Correspondence to: Jinhua Xu; email: [email protected] Keywords: vitiligo, microarray, fatty acid desaturase 1, apoptosis, melanocyte Received: May 6, 2019 Accepted: November 7, 2019 Published: December 21, 2019 Copyright: Tang et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. ABSTRACT Vitiligo is a potentially serious condition characterized by loss of melanin and death of melanocytes. To identify potential therapeutic targets for vitiligo, we conducted a microarray analysis of three human vitiligo specimens and paired adjacent normal tissues. Because we found that the fatty acid desaturase 1 (FADS1) gene was downregulated in vitiligo specimens, we carried out experiments to assess its role in melanocyte replication and survival. RT-qPCR was used to verify that FADS1 expression was lower in vitiligo-affected tissues and vitiligo melanocyte PIG3V cells than in matched controls or normal human epidermal PIG1 melanocytes. In addition, CCK-8, immunofluorescence, western blot and flow cytometry assay were used to detect the proliferation and apoptosis in PIG1 cells respectively. Overexpression of FADS1 promoted proliferation of PIG3V melanocytes, while FADS1 silencing inhibited proliferation and induced cell death in PIG1 melanocytes. Increased ROS generation; induction of mitochondrial-mediated apoptosis via upregulation of Bax and active caspases 3 and 9 and downregulation of Bcl-2; and cell cycle arrest via downregulation of c-Myc and Cyclin D1 and upregulation of p21 were all enhanced after FADS1 silencing in PIG1 melanocytes. These findings implicate FADS1 downregulation in the pathogenesis of vitiligo and may open new avenues for its treatment. INTRODUCTION We previously conducted a microarray analysis to identify differentially expressed genes (DEGs) in With a worldwide prevalence of about 1%, vitiligo is an clinical vitiligo tissue specimens. We found that acquired, chronic skin depigmentation disorder compared with adjacent normal controls, vitiligo characterized by dysfunction or death of melanocytes clinical specimens exhibit significant downregulation of [1, 2]. The pigmentation of skin and hair is determined fatty acid desaturase 1 (FADS1), a member of the fatty by melanin synthesis, and its reduction can have serious acid desaturase gene family located along with FADS2 health effects in patients with vitiligo [3, 4]. However, at locus 11q12-13.1 [9]. FADS1 is a rate-limiting the molecular mechanism underlying the disappearance enzyme in the conversion of essential polyunsaturated of melanocytes during vitiligo remains incompletely fatty acids (PUFAs; e.g., omega-6 linoleic acid and characterized. Topical corticosteroids and calcineurin omega-3 α-linolenic acid) into long-chain PUFAs (LC- inhibitors are commonly used in the treatment of PUFAs; e.g., arachidonic acid (ARA) and eico- vitiligo [5]. However, these therapies have severe side sapentaenoic acid (EPA) [10]. These molecules effects when used for a long time [6]. As research on contribute to various cell structures and biological vitiligo continues to unveil molecular factors involved processes, influencing membrane composition, signal in its progression, upregulation of melanogenesis and transduction, cell division, and regulation of lipid promotion of melanocyte proliferation are primary goals metabolism, among others [11]. Moreover, PUFAs of therapeutic strategies for this condition [7, 8]. serve as energy sources and regulate the phospholipid www.aging-us.com 11829 AGING composition of mitochondrial membranes [12]. FADS1 catalyzes the final step in the formation of EPA and localizes to the endoplasmic reticulum and mito- ARA from PUFAs (Figure 2A). In addition, the content chondria [13]. Mitochondria are vital organelles in of free fatty acid was significantly decreased in vitiligo eukaryotic cells, generating ATP for cellular reactions lesions (P = 0.01002, Figure 2B). We also used qRT- and also participating in signal transduction, regulation PCR to detect the expression of FADS1 in two human of apoptosis, and metabolism of fatty acids [14, 15]. A epidermal cell lines, namely PIG3V vitiligo melano- recent study indicated that TRPM2, a Ca2+ channel cytes and normal PIG1 melanocytes. As shown in sensitive to oxidative stress, is upregulated in vitiligo Figure 2C, mRNA levels of FADS1 were markedly melanocytes and that its inhibition in normal epidermal decreased in PIG3V cells compared to PIG1 cells (P = cells prevents Ca2+ influx, ROS accumulation, and 0.05114). These results indicated that the expression of apoptosis induced by oxidative stress [16]. Variation in FADS1 is downregulated in vitiligo melanocytes. To tissue-specific FADS1 and FADS2 gene expression was determine the function of FADS1 in melanocytes, we recently associated with vitiligo through genome-wide used two different siRNAs (FADS1-siRNA1 and analysis Qi et al 2018. However, whether FADS1 FADS1-siRNA2) to knock down its expression in PIG1 dysregulation contributes to vitiligo remains uncertain. cells. Through qRT-PCR, we confirmed that FADS1 In the present study, we investigated the effects of mRNA level decreased by approximately 27% in PIG1 FADS1 expression on proliferation, apoptosis, and cells after transfection with FADS1-siRNA1 (P = markers of mitochondrial oxidative stress in normal and 0.1123), whereas the level of FADS1 decreased by vitiligo melanocytes. Our findings may be relevant to approximately 57% in PIG1 cells after transfection with the design of new therapeutic strategies for this FADS1-siRNA2 (P = 0.0025, Figure 2D). In addition, condition. we stably overexpressed FADS1 in PIG3V cells (P = 0.0198, Figure 2E) and tested the effects of these RESULTS procedures using several assays. Differential gene expression analysis in clinical Overexpression of FADS1 promotes proliferation of vitiligo specimens PIG3V vitiligo melanocytes Three lesional and non-lesional, paired epidermal The CCK-8 assay showed that overexpression of samples from patients with vitiligo were collected and FADS1 significantly promoted the proliferation (56% subjected to microarray and clustering analyses. Using a increase) of PIG3V melanocytes (P < 0.01, Figure 3A). threshold of fold change (FC) ≥ 2.0 and a p-value < 0.0, Accordingly, in immunofluorescence assays the Ki67 the expression of 2317 genes was found to be positive cell rate in PIG3V cells transfected with lenti- significantly altered in vitiligo samples compared to NC or lenti-FADS1 were approximately 35% and 52%, normal controls. Specifically, 1350 genes were demonstrating that upregulation of FADS1 markedly upregulated, and 967 genes were downregulated in increased the number of Ki67-postive PIG3V cells vitiligo lesions as evidenced by hierarchical clustering compared with controls (lenti-NC transduced cells) (P = and MA plot (Figure 1A and 1B). 0.0004, Figure 3B and 3C). Confirmation of FADS1 upregulation in lenti-FADS1 transduced cells was Next, Gene ontology (GO) enrichment and Kyoto obtained by western blot (P < 0.01, Figure 3D and 3E). Encyclopedia of Genes and Genomes (KEGG) pathway These data showed that FADS1 expression affects the analyses were used to identify the function of these proliferative capacity of vitiligo cells. DEGs. GO analysis demonstrated that most DEGs were correlated with the melanosome membrane, lipase Downregulation of FADS1 induces apoptosis of binding, very long-chain fatty acid metabolic process, normal PIG1 melanocytes linoleic acid metabolic process, and alpha-linolenic acid metabolic process (Figure 1C). KEGG pathway analysis CCK-8 and Ki67 immunofluorescence assays were showed that three KEGG pathways, i.e. fatty acid performed to assess the role of FADS1 on the metabolism, fatty acid elongation, and fatty acid proliferation of normal epidermal PIG1 cells. CCK-8 biosynthesis, were related to the dysregulated DEGs assay results indicated that FADS1-siRNA1 induced (Figure 1D). approximately 30% growth inhibition in PIG1 cells, whereas FADS1-siRNA2 induced approximately 61% FADS1 expression is downregulated in vitiligo growth inhibition in PIG1 cells (P < 0.01, Figure 4A). melanocytes Therefore, FADS1-siRNA2 was used in further experiments. In addition, Ki67 immunofluorescence Among the DEGs identified in vitiligo specimens was assay indicated that the Ki67 positive cell rate in PIG1 FADS1, which encodes a fatty acid desaturase that cells transfected with siRNA-NC or FADS1-siRNA2 www.aging-us.com 11830 AGING were approximately 46% and 12%, indicating that Downregulation of FADS1 decreased melanogenesis downregulation of FADS1 significantly inhibited in PIG1 melanocytes proliferation of PIG1 cells (P < 0.01, Figure 4B and 4C). Moreover, increased cell death was observed on a To investigate the effect of FADS1 in PIG1 cells on trypan blue staining assay (P < 0.0001, Figure 4D and melanin synthesis, melanin ELISA kit was used. As shown 4E). The apoptosis rate in siRNA NC group was 3%, in Figure 5A, downregulation of FADS1 markedly and the apoptosis rate in FADS1-siRNA2 group
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