Guo Min, Wang Yan-Jing, Shi Jie, Cao Li-Xia, Ou Yang, Jia Xiao, Qi Chun-Chun, Li Zhao-Xian, Liu Yu-Xin, Zuo Si-Yu, Shuai Qiu-Ying, Yu Tian-Wen, Hu Hua-Yu, Chen Xiao, Feng Meng-Dan, Xue Yao, Wang Hang, Sun Pei-Qing, Liu Lei, Shi Yi, Yang Shuang
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.
Tianjin Key Laboratory of Tumour Microenvironment and Neurovascular Regulation, School of Medicine, Nankai University, Tianjin, 300071, PR China.
Redox Biol. 2025 Aug 19;86:103834. doi: 10.1016/j.redox.2025.103834.
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.
虽然上皮-间质可塑性（EMP）驱动癌症转移，但其受氧化还原动力学的调控仍知之甚少。在此，我们鉴定出一种氧化应激反应性CBP/SIRT1轴，该轴协调ZEB1在K1108位点的乙酰化，以促进三阴性乳腺癌（TNBC）的肺转移。从机制上讲，生化和功能分析表明，双乙酰转移酶CBP通过氧化应激实现稳定和自身乙酰化，与SIRT1形成动态伙伴关系，以进行精确的赖氨酸修饰。这种翻译后调节机制引发了ZEB1的功能转变。在此过程中，ZEB1从转录共抑制因子CtBP解离，同时招募CBP，将ZEB1转化为上皮基因的转录激活因子。由此产生的混合上皮-间质表型通过部分上皮-间质转化（EMT）协调双重转移能力，维持基质相互作用能力，同时建立NADPH驱动的氧化还原优势以规避铁死亡。重要的是，ZEB1的这种乙酰开关揭示了TNBC中转移特异性的治疗脆弱性。因此，我们的工作强调了ZEB1乙酰化是一种将表型可塑性与应激抗性相耦合的氧化还原解释机制，提出靶向破坏这种蛋白质翻译后修饰（PTM）回路作为对抗转移进展的精准策略。
