Jeong Dawon, Park Seo Hyeong, Kim Jiwon, Kim Hyeyoon, Jang Yejin, Koh Jaemoon, Jeon Yoon Kyung, Tasaki Takafumi, Kwon Yong Tae, Han Dohyun, Cho Sung-Yup, Lee Min Jae
Department of Biochemistry and Molecular Biology, Seoul National University College of Medicine, Seoul 03080, Korea.
Department of Biomedical Sciences, Seoul National University Graduate School, Seoul 03080, Korea.
Proc Natl Acad Sci U S A. 2025 Jun 24;122(25):e2425015122. doi: 10.1073/pnas.2425015122. Epub 2025 Jun 18.
Cellular senescence, an irreversible cell cycle arrest, plays a pivotal role in development, aging, and tumor suppression. However, the fundamental pathway coordinating senescence and neoplastic transformation remains unclear. Here, we describe the tumorigenic involvement of ubiquitin protein ligase E3 component n-recognin 4 (UBR4), an E3 ubiquitin ligase of the N-degron pathway, in lung adenocarcinoma (LUAD). Public genome databases revealed high UBR4 expression in LUAD patients, associated with a dysregulated cell cycle and impaired mitochondrial homeostasis. knockout (ΔUBR4) in A549 lung cancer cells induced cellular senescence with defective mitochondria. Restoration of UBR4 or antioxidant treatment reversed the ΔUBR4 phenotypes caused by impaired mitophagy. Mitochondrial stress exacerbated mitochondrial dysfunction in ΔUBR4 cells, contributing to diverse cellular phenotypes. Additionally, ΔUBR4 cells exhibited substantially slow tumor growth in mouse xenograft models. In LUAD patients, UBR4 levels correlated with tumor stage, mitophagy markers, and poor survival. These findings suggest a tumor-promoting function of UBR4 in LUAD by regulating mitochondrial quality control. Further research into the pharmacological inhibition of UBR4 could open promising avenues for developing effective antitumor therapies targeting LUAD.
细胞衰老，一种不可逆的细胞周期停滞，在发育、衰老和肿瘤抑制中起关键作用。然而，协调衰老和肿瘤转化的基本途径仍不清楚。在这里，我们描述了泛素蛋白连接酶E3组分n-识别蛋白4（UBR4），一种N-端规则途径的E3泛素连接酶，在肺腺癌（LUAD）中的致瘤作用。公共基因组数据库显示LUAD患者中UBR4高表达，与细胞周期失调和线粒体稳态受损有关。在A549肺癌细胞中敲除（ΔUBR4）诱导了线粒体缺陷的细胞衰老。UBR4的恢复或抗氧化治疗逆转了由线粒体自噬受损引起的ΔUBR4表型。线粒体应激加剧了ΔUBR4细胞中的线粒体功能障碍，导致多种细胞表型。此外，ΔUBR4细胞在小鼠异种移植模型中表现出显著缓慢的肿瘤生长。在LUAD患者中，UBR4水平与肿瘤分期、线粒体自噬标志物和不良生存率相关。这些发现表明UBR4通过调节线粒体质量控制在LUAD中具有促进肿瘤的功能。对UBR4的药理学抑制的进一步研究可能为开发针对LUAD的有效抗肿瘤疗法开辟有前景的途径。
