Oxidative stress-induced ZEB1 acetylation drives a hybrid epithelial-mesenchymal phenotype and promotes lung metastasis in triple-negative breast cancer
While epithelial-mesenchymal plasticity (EMP) drives cancer metastasis, its regulation by redox dynamics remains poorly understood. Herein, we identified an oxidative stress-responsive CBP/SIRT1 axis that coordinated ZEB1 acetylation at K1108 to promote lung metastasis in triple-negative breast canc...
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Elsevier
2025-10-01
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| Series: | Redox Biology |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2213231725003477 |
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| author | Min Guo Yan-Jing Wang Jie Shi Li-Xia Cao Yang Ou Xiao Jia Chun-Chun Qi Zhao-Xian Li Yu-Xin Liu Si-Yu Zuo Qiu-Ying Shuai Tian-Wen Yu Hua-Yu Hu Xiao Chen Meng-Dan Feng Yao Xue Hang Wang Pei-Qing Sun Lei Liu Yi Shi Shuang Yang |
| author_facet | Min Guo Yan-Jing Wang Jie Shi Li-Xia Cao Yang Ou Xiao Jia Chun-Chun Qi Zhao-Xian Li Yu-Xin Liu Si-Yu Zuo Qiu-Ying Shuai Tian-Wen Yu Hua-Yu Hu Xiao Chen Meng-Dan Feng Yao Xue Hang Wang Pei-Qing Sun Lei Liu Yi Shi Shuang Yang |
| author_sort | Min Guo |
| collection | DOAJ |
| description | While epithelial-mesenchymal plasticity (EMP) drives cancer metastasis, its regulation by redox dynamics remains poorly understood. Herein, we identified an oxidative stress-responsive CBP/SIRT1 axis that coordinated ZEB1 acetylation at K1108 to promote lung metastasis in triple-negative breast cancer (TNBC). Mechanistically, the biochemical and functional analyses revealed that the dual-acetyltransferase CBP, through stabilization and autoacetylation by oxidative stress, formed a dynamic partnership with SIRT1 to execute precision lysine modification. This post-translational rheostat triggered the functional metamorphosis of ZEB1. During this process, ZEB1 dissociation from the transcriptional corepressor CtBP, while recruiting CBP, converts ZEB1 into a transcriptional activator of epithelial genes. The resulting hybrid epithelial‒mesenchymal phenotype orchestrated dual metastatic competence-maintaining stromal interaction capacity through partial epithelial‒mesenchymal transition (EMT) while establishing NADPH-driven redox supremacy to circumvent ferroptosis. Importantly, this acetyl switch of ZEB1 revealed a metastasis-specific therapeutic vulnerability in TNBC. Our work thus highlighted ZEB1 acetylation as a redox-interpreted mechanism coupling phenotypic plasticity with stress resistance, proposing targeted disruption of this protein post-translational modification (PTM) circuit as a precision strategy against metastatic progression. |
| format | Article |
| id | doaj-art-24bf273c438f4a0dacd8355c7cae196a |
| institution | Kabale University |
| issn | 2213-2317 |
| language | English |
| publishDate | 2025-10-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Redox Biology |
| spelling | doaj-art-24bf273c438f4a0dacd8355c7cae196a2025-08-25T04:14:25ZengElsevierRedox Biology2213-23172025-10-018610383410.1016/j.redox.2025.103834Oxidative stress-induced ZEB1 acetylation drives a hybrid epithelial-mesenchymal phenotype and promotes lung metastasis in triple-negative breast cancerMin Guo0Yan-Jing Wang1Jie Shi2Li-Xia Cao3Yang Ou4Xiao Jia5Chun-Chun Qi6Zhao-Xian Li7Yu-Xin Liu8Si-Yu Zuo9Qiu-Ying Shuai10Tian-Wen Yu11Hua-Yu Hu12Xiao Chen13Meng-Dan Feng14Yao Xue15Hang Wang16Pei-Qing Sun17Lei Liu18Yi Shi19Shuang Yang20Tianjin Key Laboratory of Tumour Microenvironment and Neurovascular Regulation, School of Medicine, Nankai University, Tianjin, 300071, PR China; Department of Clinical Laboratory, Tianjin Union Medical Center of Nankai University, Tianjin, 300121, PR ChinaTianjin Key Laboratory of Tumour Microenvironment and Neurovascular Regulation, School of Medicine, Nankai University, Tianjin, 300071, PR ChinaTianjin Key Laboratory of Tumour Microenvironment and Neurovascular Regulation, School of Medicine, Nankai University, Tianjin, 300071, PR ChinaTianjin Key Laboratory of Tumour Microenvironment and Neurovascular Regulation, School of Medicine, Nankai University, Tianjin, 300071, PR ChinaTianjin Key Laboratory of Tumour Microenvironment and Neurovascular Regulation, School of Medicine, Nankai University, Tianjin, 300071, PR ChinaState Key Laboratory of Medicinal Chemical Biology, College of Pharmacy and Tianjin Key Laboratory of Molecular Drug Research, Nankai University, Tianjin, 300000, PR ChinaTianjin Key Laboratory of Tumour Microenvironment and Neurovascular Regulation, School of Medicine, Nankai University, Tianjin, 300071, PR ChinaTianjin Key Laboratory of Tumour Microenvironment and Neurovascular Regulation, School of Medicine, Nankai University, Tianjin, 300071, PR ChinaTianjin Key Laboratory of Tumour Microenvironment and Neurovascular Regulation, School of Medicine, Nankai University, Tianjin, 300071, PR ChinaTianjin Key Laboratory of Tumour Microenvironment and Neurovascular Regulation, School of Medicine, Nankai University, Tianjin, 300071, PR ChinaTianjin Key Laboratory of Tumour Microenvironment and Neurovascular Regulation, School of Medicine, Nankai University, Tianjin, 300071, PR ChinaTianjin Key Laboratory of Tumour Microenvironment and Neurovascular Regulation, School of Medicine, Nankai University, Tianjin, 300071, PR ChinaTianjin Key Laboratory of Tumour Microenvironment and Neurovascular Regulation, School of Medicine, Nankai University, Tianjin, 300071, PR ChinaTianjin Key Laboratory of Tumour Microenvironment and Neurovascular Regulation, School of Medicine, Nankai University, Tianjin, 300071, PR ChinaTianjin Key Laboratory of Tumour Microenvironment and Neurovascular Regulation, School of Medicine, Nankai University, Tianjin, 300071, PR ChinaTianjin Key Laboratory of Tumour Microenvironment and Neurovascular Regulation, School of Medicine, Nankai University, Tianjin, 300071, PR ChinaTianjin Key Laboratory of Tumour Microenvironment and Neurovascular Regulation, School of Medicine, Nankai University, Tianjin, 300071, PR ChinaDepartment of Cancer Biology, Wake Forest University School of Medicine, Winston-Salem, NC, 27157, USATianjin Medical University Cancer Institute & Hospital, Tianjin, 300071, PR China; Corresponding author.Tianjin Key Laboratory of Tumour Microenvironment and Neurovascular Regulation, School of Medicine, Nankai University, Tianjin, 300071, PR China; Corresponding author. School of Medicine, Nankai University, Tianjin, 300071, PR China.Tianjin Key Laboratory of Tumour Microenvironment and Neurovascular Regulation, School of Medicine, Nankai University, Tianjin, 300071, PR China; Corresponding author. School of Medicine, Nankai University, Tianjin, 300071, PR China.While epithelial-mesenchymal plasticity (EMP) drives cancer metastasis, its regulation by redox dynamics remains poorly understood. Herein, we identified an oxidative stress-responsive CBP/SIRT1 axis that coordinated ZEB1 acetylation at K1108 to promote lung metastasis in triple-negative breast cancer (TNBC). Mechanistically, the biochemical and functional analyses revealed that the dual-acetyltransferase CBP, through stabilization and autoacetylation by oxidative stress, formed a dynamic partnership with SIRT1 to execute precision lysine modification. This post-translational rheostat triggered the functional metamorphosis of ZEB1. During this process, ZEB1 dissociation from the transcriptional corepressor CtBP, while recruiting CBP, converts ZEB1 into a transcriptional activator of epithelial genes. The resulting hybrid epithelial‒mesenchymal phenotype orchestrated dual metastatic competence-maintaining stromal interaction capacity through partial epithelial‒mesenchymal transition (EMT) while establishing NADPH-driven redox supremacy to circumvent ferroptosis. Importantly, this acetyl switch of ZEB1 revealed a metastasis-specific therapeutic vulnerability in TNBC. Our work thus highlighted ZEB1 acetylation as a redox-interpreted mechanism coupling phenotypic plasticity with stress resistance, proposing targeted disruption of this protein post-translational modification (PTM) circuit as a precision strategy against metastatic progression.http://www.sciencedirect.com/science/article/pii/S2213231725003477Oxidative stressZEB1AcetylationHybrid epithelial-mesenchymal phenotypeLung metastasisTNBC |
| spellingShingle | Min Guo Yan-Jing Wang Jie Shi Li-Xia Cao Yang Ou Xiao Jia Chun-Chun Qi Zhao-Xian Li Yu-Xin Liu Si-Yu Zuo Qiu-Ying Shuai Tian-Wen Yu Hua-Yu Hu Xiao Chen Meng-Dan Feng Yao Xue Hang Wang Pei-Qing Sun Lei Liu Yi Shi Shuang Yang Oxidative stress-induced ZEB1 acetylation drives a hybrid epithelial-mesenchymal phenotype and promotes lung metastasis in triple-negative breast cancer Redox Biology Oxidative stress ZEB1 Acetylation Hybrid epithelial-mesenchymal phenotype Lung metastasis TNBC |
| title | Oxidative stress-induced ZEB1 acetylation drives a hybrid epithelial-mesenchymal phenotype and promotes lung metastasis in triple-negative breast cancer |
| title_full | Oxidative stress-induced ZEB1 acetylation drives a hybrid epithelial-mesenchymal phenotype and promotes lung metastasis in triple-negative breast cancer |
| title_fullStr | Oxidative stress-induced ZEB1 acetylation drives a hybrid epithelial-mesenchymal phenotype and promotes lung metastasis in triple-negative breast cancer |
| title_full_unstemmed | Oxidative stress-induced ZEB1 acetylation drives a hybrid epithelial-mesenchymal phenotype and promotes lung metastasis in triple-negative breast cancer |
| title_short | Oxidative stress-induced ZEB1 acetylation drives a hybrid epithelial-mesenchymal phenotype and promotes lung metastasis in triple-negative breast cancer |
| title_sort | oxidative stress induced zeb1 acetylation drives a hybrid epithelial mesenchymal phenotype and promotes lung metastasis in triple negative breast cancer |
| topic | Oxidative stress ZEB1 Acetylation Hybrid epithelial-mesenchymal phenotype Lung metastasis TNBC |
| url | http://www.sciencedirect.com/science/article/pii/S2213231725003477 |
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