Liu Chang, He Weiming, Zhao Hantong, Wang Shuguang, Qian Zhiyuan
Department of Neurosurgery, The Second Affiliated Hospital of Soochow University, 1055 Sanxiang Road, Suzhou, China.
Department of Neurosurgery, Affiliated Hospital of Inner Mongolia Minzu University, Tongliao, China.
Neurochem Res. 2025 Mar 27;50(2):128. doi: 10.1007/s11064-025-04380-4.
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.
胶质母细胞瘤（GBM）是一种高度恶性且侵袭性强的脑肿瘤，预后极差，是神经外科领域面临的最大挑战之一。角蛋白80（KRT80）主要在上皮细胞中表达，参与细胞结构的稳定性和完整性维持。尽管它在皮肤和毛囊发育中发挥作用，但其在连接癌细胞与代谢途径方面的功能正逐渐被揭示，比如其激活糖酵解途径以促进肿瘤增殖。环指蛋白8（RNF8）是一种E3泛素连接酶，其表达在胶质瘤中已被证明显著降低。多个数据库的预测表明KRT80可能与RNF8特异性结合。本研究旨在探讨KRT80在GBM进程中的功能以及RNF8与KRT80之间的调控机制。我们通过构建过表达和敲除细胞系证实KRT80促进细胞增殖。体内肿瘤形成实验也证明了这一点。此外，敲除KRT80诱导的较高的caspase3/9活性促使细胞发生主动凋亡，流式细胞术显示凋亡率增加证实了这一点。结果还发现，通过实时PCR检测，KRT80过表达导致糖酵解途径（葡萄糖转运蛋白1、己糖激酶2和乳酸脱氢酶A）激活，非靶向代谢组学检测显示代谢物水平升高。免疫荧光共定位和免疫共沉淀实验表明，RNF8通过影响KRT80的泛素化降解减弱其诱导的不良影响。总之，KRT80受RNF8介导的泛素化调控，促进糖酵解及GBM进展。
