Oxidative stress-induced ZEB1 acetylation drives a hybrid epithelial-mesenchymal phenotype and promotes lung metastasis in triple-negative breast cancer
- Redox Biol. 2025 Aug 19:86:103834. doi: 10.1016/j.redox.2025.103834.
- 1. Tianjin 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 China.
- 2. Tianjin Key Laboratory of Tumour Microenvironment and Neurovascular Regulation, School of Medicine, Nankai University, Tianjin, 300071, PR China.
- 3. State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy and Tianjin Key Laboratory of Molecular Drug Research, Nankai University, Tianjin, 300000, PR China.
- 4. Department of Cancer Biology, Wake Forest University School of Medicine, Winston-Salem, NC, 27157, USA.
- 5. Tianjin Medical University Cancer Institute & Hospital, Tianjin, 300071, PR China. Electronic address: [email protected].
- 6. Tianjin Key Laboratory of Tumour Microenvironment and Neurovascular Regulation, School of Medicine, Nankai University, Tianjin, 300071, PR China. Electronic address: [email protected].
- 7. Tianjin Key Laboratory of Tumour Microenvironment and Neurovascular Regulation, School of Medicine, Nankai University, Tianjin, 300071, PR China. Electronic address: [email protected].
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.