ERCC6L通过plk1介导的有氧糖酵解促进皮肤黑色素瘤进展：机制和治疗意义。

IF 5.1 2区医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL

Life sciences Pub Date : 2026-03-15 Epub Date: 2026-01-19 DOI:10.1016/j.lfs.2026.124216

Mengdi Zhang , Shengbo Zhou , Bing Han , Yining Ge

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引用次数: 0

摘要

目的：阐明ERCC6L在皮肤黑色素瘤中的致瘤作用及其机制基础，重点研究其对肿瘤代谢和进展的影响。材料和方法：公共数据集（GEO， TCGA）的多组学生物信息学分析定义了ERCC6L的临床相关性。在基因操作后对黑色素瘤细胞系进行体外功能测定（CCK-8，菌落形成，Transwell，流式细胞术）。机制研究采用基因集富集分析、染色质免疫沉淀-定量PCR、双荧光素酶报告基因检测、western blotting和代谢通量分析。ERCC6L-PLK1轴的功能意义在NSG小鼠皮下异种移植模型中得到验证。关键发现：ERCC6L在黑色素瘤组织中显著上调，其高表达是生存率差的独立预后因素。基因消融ERCC6L可有效抑制黑色素瘤细胞增殖、迁移、侵袭和肿瘤生长，同时促进细胞凋亡。从机制上讲，ERCC6L通过直接结合其启动子来激活PLK1。ERCC6L-PLK1轴驱动有氧糖酵解（Warburg效应），上调关键的糖酵解酶（GLUT1、LDHA、PKM2、HK2），并促进乳酸生成和ATP生成。至关重要的是，PLK1抑制或糖酵解阻断有效地逆转了ERCC6L诱导的促肿瘤表型。意义：我们的研究发现ERCC6L是PLK1的一种新的上游转录调节因子，通过重编程葡萄糖代谢来促进黑色素瘤的进展。ercc6l - plk1 -糖酵解轴是一种有前景的预后生物标志物，也是皮肤黑色素瘤的潜在治疗靶点。

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ERCC6L promotes cutaneous melanoma progression via PLK1-mediated aerobic glycolysis: Mechanisms and therapeutic implications

Aims

To elucidate the oncogenic role and mechanistic basis of ERCC6L in cutaneous melanoma, focusing on its impact on tumor metabolism and progression.

Materials and methods

Multi-omics bioinformatics analysis of public datasets (GEO, TCGA) defined the clinical relevance of ERCC6L. In vitro functional assays (CCK-8, colony formation, Transwell, flow cytometry) were performed in melanoma cell lines following genetic manipulation. Mechanistic studies employed gene set enrichment analysis, chromatin immunoprecipitation-quantitative PCR, dual-luciferase reporter assays, western blotting, and metabolic flux analysis. The functional significance of the ERCC6L-PLK1 axis was validated in an NSG mouse subcutaneous xenograft model.

Key findings

ERCC6L is significantly upregulated in melanoma tissues, and its high expression is an independent prognostic factor for poor survival. Genetic ablation of ERCC6L potently inhibited melanoma cell proliferation, migration, invasion, and tumor growth, while promoting apoptosis. Mechanistically, ERCC6L transcriptionally activates PLK1 by directly binding to its promoter. This ERCC6L-PLK1 axis drives aerobic glycolysis (the Warburg effect), upregulating key glycolytic enzymes (GLUT1, LDHA, PKM2, HK2) and enhancing lactate production and ATP generation. Crucially, PLK1 inhibition or glycolysis blockade effectively reversed the tumor-promoting phenotypes induced by ERCC6L.

Significance

Our study identifies ERCC6L as a novel upstream transcriptional regulator of PLK1 that fuels melanoma progression by reprogramming glucose metabolism. The ERCC6L-PLK1-glycolysis axis represents a promising prognostic biomarker and a potential therapeutic target for cutaneous melanoma.

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来源期刊

Life sciences 医学-药学

CiteScore

12.20

自引率

1.60%

发文量

841

审稿时长

6 months

期刊介绍： Life Sciences is an international journal publishing articles that emphasize the molecular, cellular, and functional basis of therapy. The journal emphasizes the understanding of mechanism that is relevant to all aspects of human disease and translation to patients. All articles are rigorously reviewed. The Journal favors publication of full-length papers where modern scientific technologies are used to explain molecular, cellular and physiological mechanisms. Articles that merely report observations are rarely accepted. Recommendations from the Declaration of Helsinki or NIH guidelines for care and use of laboratory animals must be adhered to. Articles should be written at a level accessible to readers who are non-specialists in the topic of the article themselves, but who are interested in the research. The Journal welcomes reviews on topics of wide interest to investigators in the life sciences. We particularly encourage submission of brief, focused reviews containing high-quality artwork and require the use of mechanistic summary diagrams.