NEDD4L通过调节YY1泛素化介导的糖酵解代谢重编程抑制瘢痕成纤维细胞的增殖和迁移

IF 3.5 3区 医学 Q1 DERMATOLOGY Experimental Dermatology Pub Date : 2024-11-04 DOI:10.1111/exd.70008
Jun Jin, Kai Wang, Chenxi Lu, Chenghao Yao, Feng Xie
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引用次数: 0

摘要

瘢痕疙瘩是一种复杂的纤维增生性疾病,其特点是成纤维细胞过度增殖。抑制细胞糖酵解可有效抑制瘢痕疙瘩成纤维细胞(KFs)的增殖。神经前体细胞表达的发育下调基因4样(NEDD4L)是一种泛素连接酶,在不同疾病中调节细胞增殖。本研究探讨了 NEDD4L 对 KFs 糖代谢、增殖和迁移的影响。从活动期瘢痕疙瘩患者的瘢痕疙瘩皮肤组织中分离出原代KFs。利用细胞转染技术上调或下调 KFs 中的 NEDD4L 和阴阳 1(YY1)。蛋白表达通过免疫组织化学和免疫印迹法进行评估。分别用 MTT 法、EdU 法和伤口愈合法评估了 KFs 的活力、增殖能力和迁移能力。共沉淀法检测了NEDD4L对YY1泛素化的调控作用。双荧光素酶报告实验证实了 YY1 与己糖激酶 2(HK2)之间的相互作用。与正常皮肤相比,瘢痕疙瘩组织中NEDD4L下调,而YY1和HK2高表达。过表达 NEDD4L 可抑制 KFs 的增殖和迁移。NEDD4L通过诱导YY1的泛素化促进其在KFs中降解。YY1的上调通过转录调控HK2诱导KFs的葡萄糖消耗和乳酸生成。YY1表达量的增加逆转了过表达NEDD4L的KFs活力、增殖和迁移能力的降低。YY1 还能逆转 NEDD4L 诱导的对 KFs 葡萄糖消耗和乳酸生成的抑制。此外,一项体内研究证实了 NEDD4L 过表达和 YY1 敲除对瘢痕疙瘩形成的抑制作用。NEDD4L通过HK2调节YY1泛素化介导的糖酵解,从而抑制了KFs的活力、增殖和迁移。这些研究结果表明,NEDD4L/YY1/HK2这一新型调控轴介导了瘢痕疙瘩形成过程中的糖代谢。
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NEDD4L Inhibits the Proliferation and Migration of Keloid Fibroblasts by Regulating YY1 Ubiquitination-Mediated Glycolytic Metabolic Reprogramming

Keloid scarring is a complex fibroproliferative disorder characterised by excessive fibroblast proliferation. Inhibition of cellular glycolysis effectively suppresses the proliferation of keloid fibroblasts (KFs). Neural precursor cell-expressed developmentally downregulated gene 4-like (NEDD4L), a ubiquitin ligase, regulates cell proliferation in different diseases. This study investigated the effects of NEDD4L on glucose metabolism, proliferation and migration in KFs. Primary KFs were isolated from keloid skin tissues obtained from patients with active-stage keloids. Cell transfection was used to upregulate or downregulate NEDD4L and Yin Yang 1 (YY1) in KFs. Protein expression was assessed by immunohistochemistry and western blotting. The viability, proliferative capacity and migration ability of KFs were evaluated using the MTT method and the EdU and wound healing assays, respectively. The regulatory effect of NEDD4L on YY1 ubiquitination was examined by coimmunoprecipitation. The interaction between YY1 and hexokinase 2 (HK2) was confirmed by a dual-luciferase reporter assay. NEDD4L was downregulated, whereas YY1 and HK2 were highly expressed in keloid tissues compared with normal skin. Overexpression of NEDD4L inhibited the proliferation and migration of KFs. NEDD4L promoted YY1 degradation in KFs by inducing its ubiquitination. Upregulation of YY1 induced glucose consumption and lactate production in KFs via the transcriptional regulation of HK2. Increased expression of YY1 reversed the reduced viability, proliferation, and migration of KFs overexpressing NEDD4L. YY1 also reversed the NEDD4L-induced inhibition of glucose consumption and lactate production in KFs. Additionally, an in vivo study confirmed the inhibitory roles of NEDD4L overexpression and YY1 knockdown in keloid formation. NEDD4L suppressed the viability, proliferation and migration of KFs by regulating YY1 ubiquitination-mediated glycolysis through HK2. These findings suggest a novel regulatory axis, NEDD4L/YY1/HK2, that mediates glucose metabolism in keloid formation.

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来源期刊
Experimental Dermatology
Experimental Dermatology 医学-皮肤病学
CiteScore
6.70
自引率
5.60%
发文量
201
审稿时长
2 months
期刊介绍: Experimental Dermatology provides a vehicle for the rapid publication of innovative and definitive reports, letters to the editor and review articles covering all aspects of experimental dermatology. Preference is given to papers of immediate importance to other investigators, either by virtue of their new methodology, experimental data or new ideas. The essential criteria for publication are clarity, experimental soundness and novelty. Letters to the editor related to published reports may also be accepted, provided that they are short and scientifically relevant to the reports mentioned, in order to provide a continuing forum for discussion. Review articles represent a state-of-the-art overview and are invited by the editors.
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