KMT2C Induced by FABP5P3 Aggravates Keratinocyte Hyperproliferation and Psoriasiform Skin Inflammation by Upregulating the of PIK3R3
KMT2C Induced by FABP5P3 Aggravates Keratinocyte Hyperproliferation and Psoriasiform Skin Inflammation by Upregulating the of PIK3R3
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DOI：
10.1016/j.jid.2022.06.025
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发表时间：
2022-12-15
影响因子：
6.5
通讯作者：
Sun, Qing
中科院分区：
文献类型：
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作者：
Huang, Shan;Zhen, Yunyue;Sun, Qing
赖氨酸甲基转移酶2C（KMT 2C）广泛参与炎症反应是有据可查的。然而，关于KMT 2C在银屑病中的作用知之甚少。我们发现KMT 2C在银屑病皮损的表皮和银屑病样细胞模型中显著上调。KMT 2C敲低在体外和体内减少角质形成细胞增殖和IL-6、IL-8、CCL 20和S100 A9的分泌。在银屑病样角质形成细胞中，KMT 2C通过调节组蛋白H3赖氨酸4三甲基化在PIK 3R 3启动子处和组蛋白3赖氨酸4单甲基化在增强子处的富集来促进PIK 3R 3的转录。PIK 3 R3/蛋白激酶B/NF-κ B途径是KMT 2C介导的减轻马槟榔引发的炎症的重要步骤。长链非编码RNA FABP 5 P3通过募集人抗原R来维持KMT 2C mRNA的稳定性。此外，抑制KMT 2C减弱银屑病小鼠的表皮增生和皮肤炎症。总之，我们的研究结果表明KMT 2C和银屑病之间的联系，并打开了使用KMT 2C作为银屑病治疗的潜在治疗靶点的可能性。
The extensive involvement of lysine methyltransferase 2C (KMT2C) in the inflammatory response is well-documented. However, little is known about the role of KMT2C in psoriasis. We identified that KMT2C was significantly upregulated in the epidermis of psoriatic skin lesions and the psoriasiform cell model. KMT2C knockdown diminished keratinocyte proliferation and the secretion of IL-6, IL-8, CCL20, and S100A9 in vitro and in vivo. In psoriasiform keratinocytes, KMT2C promoted the transcription of PIK3R3 by regulating the enrichment of histone H3 lysine 4 trimethylation at the PIK3R3 promoter and histone 3 lysine 4 monomethylation at the enhancer. The PIK3R3/protein kinase B/NF-kappa B pathway is a vital step in KMT2C-mediated alleviation of cytokine-primed inflammation. The long noncoding RNA FABP5P3 sustained KMT2C mRNA stability by recruiting human antigen R. Furthermore, inhibition of KMT2C attenuated epidermal hyperplasia and skin inflammation in mice with psoriasis. Taken together, our findings indicated a link between KMT2C and psoriasis and opened the possibility of using KMT2C as a potential therapeutic target for psoriasis treatment.