Tumor-promoting UBR4 coordinates impaired mitophagy-associated senescence and lung adenocarcinoma pathogenesis

• 成果类型: Article
• 署名作者: 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
• 署名单位: Seoul National University (SNU); Seoul National University (SNU); Seoul National University (SNU); Seoul National University Hospital; Seoul National University (SNU); Seoul National University Hospital; United States Department of Energy (DOE); Pacific Northwest National Laboratory; Seoul National University (SNU); Kanazawa Medical University; University of California System; University of California Los Angeles; Seoul National University (SNU)
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-10337
• DOI: 10.1073/pnas.24250151221of11
• 发表日期: 2025-06-24
• 关键词: end rule pathway; cellular senescence; autophagy; cancer; mitochondria; sensitivity; death

摘要

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. UBR4 knockout (Delta UBR4) in A549 lung cancer cells induced cellular senescence with defective mitochondria. Restoration of UBR4 or antioxidant treatment reversed the Delta UBR4 phenotypes caused by impaired mitophagy. Mitochondrial stress exacerbated mitochondrial dysfunction in Delta UBR4 cells, contributing to diverse cellular phenotypes. Additionally, Delta UBR4 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.