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

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. <i>UBR4</i> 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.

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Publication Details

Journal
Proceedings of the National Academy of Sciences
Published
2025-06-18
DOI
https://doi.org/10.1073/pnas.2425015122
Citations
4
Primary Topic
Ubiquitin and proteasome pathways
Type
article
Field-Weighted Citation Impact
3.22

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article

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

Yoo Mi Jang, Sung‐Yup Cho, Hyeyoon Kim, Jaemoon Koh et al.
4 citations
Proceedings of the National Academy of Sciences
Ubiquitin and proteasome pathways
3.22
article

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

Yoo Mi Jang, Sung‐Yup Cho, Hyeyoon Kim, Jaemoon Koh, Yong Tae Kwon, Seo Hyeong Park, Takafumi Tasaki, Dawon Jeong, Dohyun Han, Min Jae Lee, Yoon Kyung Jeon, Jiwon Kim
article en
4 citations

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. <i>UBR4</i> 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.

Proceedings of the National Academy of SciencesVol. 122(25)
Seoul National University (KR), Pacific Northwest National Laboratory (US), University of California, Los Angeles (US), Kanazawa Medical University (JP), New Generation University College (ET), Seoul National University Hospital (KR), Convergence Research Center for Diagnosis Treatment and Care System of Dementia (KR), Biomedical Research Institute (US)
National Research Foundation, Seoul National University, National Research Foundation of Korea, Kanazawa Medical University, Seoul National University Hospital, Daegu Gyeongbuk Institute of Science and Technology, Directorate for Biological Sciences, University of California, Los Angeles, College of Medicine, Seoul National University, Japan Society for the Promotion of Science, Pacific Northwest National Laboratory
No poverty
Openalex Percentile: Top 8%
Ubiquitin and proteasome pathways
3.22
DOIOpen Access PDFOpenAlex
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