Downregulation of carnitine acetyltransferase by promoter hypermethylation regulates ultraviolet-induced matrix metalloproteinase-1 expression in human dermal fibroblasts

IF 4.6

Journal of dermatological science Pub Date : 2024-11-01 DOI:10.1016/j.jdermsci.2024.09.005

Min Ji Song , Min-Kyoung Kim , Chi-Hyun Park , Haesoo Kim , Si Hyung Lee , Dong Hun Lee , Jin Ho Chung

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引用次数: 0

Abstract

Background

Overexposure to ultraviolet (UV) radiation accelerates skin aging, resulting in wrinkle formation, reduced skin elasticity, and hyperpigmentation. UV irradiation induces increased matrix metalloproteinases (MMPs) that degrade collagen in the extracellular matrix. Skin aging is also accompanied by epigenetic alterations such as promoter methylation by DNA methyltransferases, leading to the activation or suppression of gene expression. Although carnitine acetyltransferase (CRAT) is implicated in aging, the effect of UV on the expression of CRAT and regulatory mechanisms of UV-induced MMP-1 expression remain unknown.

Objective

We investigated changes in CRAT expression upon UV irradiation and its effect on MMP-1 expression.

Methods

Primary human dermal fibroblasts were UV irradiated with either control or 5-AZA-dC. CRAT knockdown or overexpression was performed to investigate its effect on MMP-1 expression. The mRNA level was analyzed by quantitative real-time PCR, and protein level by western blotting.

Results

The expression of CRAT was decreased in UV-irradiated human skin in vivo and in human dermal fibroblasts in vitro. CRAT was downregulated upon UV irradiation by hypermethylation, and treatment with 5-Aza-2′-deoxycytidine, a DNA methyltransferase inhibitor, reversed UV-induced downregulation of CRAT. CRAT knockdown activated the JNK, ERK, and p38 MAPK signaling pathways, which increased MMP-1 expression. Stable overexpression of CRAT alleviated UV-induced MMP-1 induction.

Conclusion

CRAT downregulation caused by promoter hypermethylation may play an important role in UV-induced skin aging via upregulation of MMP-1 expression.

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启动子超甲基化对肉碱乙酰转移酶的下调调节了紫外线诱导的人真皮成纤维细胞中基质金属蛋白酶-1的表达。

背景：过度暴露于紫外线（UV）辐射会加速皮肤老化，导致皱纹形成、皮肤弹性降低和色素沉着。紫外线照射会诱导基质金属蛋白酶（MMPs）增加，从而降解细胞外基质中的胶原蛋白。皮肤老化还伴随着表观遗传学的改变，如 DNA 甲基转移酶导致启动子甲基化，从而激活或抑制基因表达。虽然肉碱乙酰转移酶（CRAT）与衰老有关，但紫外线对 CRAT 表达的影响以及紫外线诱导 MMP-1 表达的调控机制仍不清楚：我们研究了紫外线照射时 CRAT 表达的变化及其对 MMP-1 表达的影响：方法：用对照组或 5-AZA-dC 对原代人真皮成纤维细胞进行紫外线照射。方法：用对照组或 5-AZA-dC 对原代人真皮成纤维细胞进行紫外线照射，敲除或过表达 CRAT，以研究其对 MMP-1 表达的影响。mRNA水平通过实时定量PCR分析，蛋白水平通过Western印迹分析：结果：CRAT在体内紫外线照射的人类皮肤和体外人类真皮成纤维细胞中的表达均下降。用 DNA 甲基转移酶抑制剂 5-Aza-2'-deoxycytidine 处理可逆转紫外线诱导的 CRAT 下调。CRAT 下调激活了 JNK、ERK 和 p38 MAPK 信号通路，从而增加了 MMP-1 的表达。稳定过表达 CRAT 可减轻紫外线诱导的 MMP-1 诱导：结论：启动子高甲基化导致的CRAT下调可能通过上调MMP-1的表达在紫外线诱导的皮肤老化中扮演重要角色。

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来源期刊

Journal of dermatological science Dermatology

CiteScore

7.60

自引率

0.00%

发文量