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  3. Oxidative stress-induced ZEB1 acetylation drives a hybrid epithelial-mesenchymal phenotype and promotes lung metastasis in triple-negative breast cancer

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.
Min Guo 1,  Yan-Jing Wang 2,  Jie Shi 2,  Li-Xia Cao 2,  Yang Ou 2,  Xiao Jia 3,  Chun-Chun Qi 2,  Zhao-Xian Li 2,  Yu-Xin Liu 2,  Si-Yu Zuo 2,  Qiu-Ying Shuai 2,  Tian-Wen Yu 2,  Hua-Yu Hu 2,  Xiao Chen 2,  Meng-Dan Feng 2,  Yao Xue 2,  Hang Wang 2,  Pei-Qing Sun 4,  Lei Liu 5,  Yi Shi 6,  Shuang Yang 7
Affiliations

Affiliations

  • 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: liuleidoc@126.com.
  • 6 Tianjin Key Laboratory of Tumour Microenvironment and Neurovascular Regulation, School of Medicine, Nankai University, Tianjin, 300071, PR China. Electronic address: yishi@nankai.edu.cn.
  • 7 Tianjin Key Laboratory of Tumour Microenvironment and Neurovascular Regulation, School of Medicine, Nankai University, Tianjin, 300071, PR China. Electronic address: yangshuang@nankai.edu.cn.
PMID: 40850192 DOI: 10.1016/j.redox.2025.103834
Abstract

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.

Keywords

Acetylation; Hybrid epithelial-mesenchymal phenotype; Lung metastasis; Oxidative stress; TNBC; ZEB1.

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