{"title":"KRT80, Regulated by RNF8-Mediated Ubiquitination, Contributes to Glucose Metabolic Reprogramming and Progression of Glioblastoma","authors":"Chang Liu, Weiming He, Hantong Zhao, Shuguang Wang, Zhiyuan Qian","doi":"10.1007/s11064-025-04380-4","DOIUrl":null,"url":null,"abstract":"<div><p>Glioblastoma (GBM) is a highly malignant and aggressive brain tumor with a remarkably poor prognosis and is one of the greatest challenges in the field of neurosurgery. Keratin 80 (KRT80) is primarily expressed in epithelial cells and is involved in the stability and integrity of cellular structures. Although it plays a role in skin and hair follicle development, its function in bridging cancer cells with metabolic pathways is gradually being revealed, such as its activation of glycolysis pathways to promote tumor proliferation. Ring finger protein 8 (RNF8) is an E3 ubiquitin ligase, whose expression has been documented to be significantly reduced in gliomas. Predictions from multiple databases suggest that KRT80 may bind specifically with RNF8. This study aimed to explore the function of KRT80 in GBM procession and the regulatory mechanism between RNF8 and KRT80. We confirmed that KRT80 promoted cell proliferation by constructing overexpression and knockout cell lines. This was also demonstrated by in vivo tumor formation experiments. Besides, higher caspase3/9 activity induced by KRT80 knockout prompted active apoptosis, which was confirmed by flow cytometry showing increased rate of apoptosis. Results also found KRT80 overexpression caused the activation of glycolytic pathways (<i>glucose transporter 1</i>, <i>hexokinase2</i>, and <i>lactate dehydrogenase A</i>) by real-time PCR and the increase of metabolites levels by non-targeted metabolomics. Immunofluorescence co-localization and co-immunoprecipitation assays showed RNF8 attenuated KRT80-induced adverse effects via influencing its ubiquitination degradation. In conclusion, KRT80 is regulated by RNF8-mediated ubiquitination, promoting glycolysis and the progression of GBM.</p><h3>Graphical Abstract</h3><p>KRT80, regulated by RNF8-mediated ubiquitination, plays a key role in glucose metabolic reprogramming, enhancing energy production and promoting the aggressive progression of GBM.</p>\n<div><figure><div><div><picture><source><img></source></picture></div></div></figure></div></div>","PeriodicalId":719,"journal":{"name":"Neurochemical Research","volume":"50 2","pages":""},"PeriodicalIF":3.8000,"publicationDate":"2025-03-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Neurochemical Research","FirstCategoryId":"3","ListUrlMain":"https://link.springer.com/article/10.1007/s11064-025-04380-4","RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q2","JCRName":"BIOCHEMISTRY & MOLECULAR BIOLOGY","Score":null,"Total":0}
引用次数: 0
Abstract
Glioblastoma (GBM) is a highly malignant and aggressive brain tumor with a remarkably poor prognosis and is one of the greatest challenges in the field of neurosurgery. Keratin 80 (KRT80) is primarily expressed in epithelial cells and is involved in the stability and integrity of cellular structures. Although it plays a role in skin and hair follicle development, its function in bridging cancer cells with metabolic pathways is gradually being revealed, such as its activation of glycolysis pathways to promote tumor proliferation. Ring finger protein 8 (RNF8) is an E3 ubiquitin ligase, whose expression has been documented to be significantly reduced in gliomas. Predictions from multiple databases suggest that KRT80 may bind specifically with RNF8. This study aimed to explore the function of KRT80 in GBM procession and the regulatory mechanism between RNF8 and KRT80. We confirmed that KRT80 promoted cell proliferation by constructing overexpression and knockout cell lines. This was also demonstrated by in vivo tumor formation experiments. Besides, higher caspase3/9 activity induced by KRT80 knockout prompted active apoptosis, which was confirmed by flow cytometry showing increased rate of apoptosis. Results also found KRT80 overexpression caused the activation of glycolytic pathways (glucose transporter 1, hexokinase2, and lactate dehydrogenase A) by real-time PCR and the increase of metabolites levels by non-targeted metabolomics. Immunofluorescence co-localization and co-immunoprecipitation assays showed RNF8 attenuated KRT80-induced adverse effects via influencing its ubiquitination degradation. In conclusion, KRT80 is regulated by RNF8-mediated ubiquitination, promoting glycolysis and the progression of GBM.
Graphical Abstract
KRT80, regulated by RNF8-mediated ubiquitination, plays a key role in glucose metabolic reprogramming, enhancing energy production and promoting the aggressive progression of GBM.
期刊介绍：
Neurochemical Research is devoted to the rapid publication of studies that use neurochemical methodology in research on nervous system structure and function. The journal publishes original reports of experimental and clinical research results, perceptive reviews of significant problem areas in the neurosciences, brief comments of a methodological or interpretive nature, and research summaries conducted by leading scientists whose works are not readily available in English.
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