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Proc. Natl. Acad. Sci. USA, Jun 24 2025, 122 (25) | https://doi.org/10.1073/pnas.2425015122
Tumor-promoting UBR4 coordinates impaired mitophagy-associated senescence and lung adenocarcinoma pathogenesis
Dawon Jeong 1 2 †, Seo Hyeong Park 3 †, Jiwon Kim 1 2 †, Hyeyoon Kim 4 5 †, Yejin Jang 1 2, Jaemoon Koh 6, Yoon Kyung Jeon 6, Takafumi Tasaki 7, Yong Tae Kwon 2 *, Dohyun Han 4 *, Sung-Yup Cho 1 2 *, Min Jae Lee 1 2 8 9 *
1Department of Biochemistry and Molecular Biology, Seoul National University College of Medicine, Seoul 03080, Korea.
2Department of Biomedical Sciences, Seoul National University Graduate School, Seoul 03080, Korea.
3Genomics Core Facility, Transdisciplinary Research & Collaboration Division, Biomedical Research Institute, Seoul National University Hospital, Seoul 03080, Korea.
4Proteomics Core Facility, Transdisciplinary Research & Collaboration Division, Biomedical Research Institute, Seoul National University Hospital, Seoul 03080, Korea.
5Biological Sciences Division, Pacific Northwest National Laboratory, Richland, WA 99354.
6Department of Pathology, Seoul National University College of Medicine, Seoul 03080, Korea.
7Department of Life Sciences, Kanazawa Medical University, Ishikawa 920-0293, Japan.
8Department of Pathology and Laboratory Medicine, University of California, Los Angeles, CA 90095.
9Ischemic/Hypoxic Disease Institute, Convergence Research Center for Dementia, Medical Research Center, Seoul National University, Seoul 03080, Korea.
2Department of Biomedical Sciences, Seoul National University Graduate School, Seoul 03080, Korea.
3Genomics Core Facility, Transdisciplinary Research & Collaboration Division, Biomedical Research Institute, Seoul National University Hospital, Seoul 03080, Korea.
4Proteomics Core Facility, Transdisciplinary Research & Collaboration Division, Biomedical Research Institute, Seoul National University Hospital, Seoul 03080, Korea.
5Biological Sciences Division, Pacific Northwest National Laboratory, Richland, WA 99354.
6Department of Pathology, Seoul National University College of Medicine, Seoul 03080, Korea.
7Department of Life Sciences, Kanazawa Medical University, Ishikawa 920-0293, Japan.
8Department of Pathology and Laboratory Medicine, University of California, Los Angeles, CA 90095.
9Ischemic/Hypoxic Disease Institute, Convergence Research Center for Dementia, Medical Research Center, Seoul National University, Seoul 03080, Korea.
†These authors contributed equally
*Corresponding authors: correspondence to Yong Tae Kwon, Dohyun Han, Sung-Yup Cho or Min Jae Lee
Abstract
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 (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.
논문정보
- Research article
- 2025년 06월 (BRIC 등록일 2025-06-19)
- 국내(교신)+국외 연구진
- 생명과학 > 생화학
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