Metformin sensitizes triple-negative breast cancer to histone deacetylase inhibitors by targeting FGFR4

作者：Zhangyuan Gu, Fugui Ye, Hong Luo, Xiaoguang Li, Yue Gong, Shiqi Mao, Xiaoqing Jia, Xiangchen Han, Bo-yue Han, Yun Fu, Xiaolin Cheng, Jiejing Li, Zhi‐Ming Shao, Peizhen Wen, Xin Hu, Zhigang Zhuang · 发表于：Journal of Biomedical Science · 年份：2025 · DOI：10.1186/s12929-025-01129-7 · 被引用次数：12 · 研究领域：Metabolism, Diabetes, and Cancer、GDF15 and Related Biomarkers、Fibroblast Growth Factor Research

BACKGROUND: Triple-negative breast cancer (TNBC) is characterized by high malignancy, strong invasiveness, and a propensity for distant metastasis, leading to poor prognosis and relatively limited treatment options. Metformin, as a first-line oral hypoglycemic agent, has garnered widespread research interest in recent years due to its potential in cancer prevention and treatment. However, its efficacy varies significantly across different tumor types. Histone deacetylase inhibitors (HDACi), such as SAHA, have demonstrated antitumor activity, but TNBC responds poorly to HDACi monotherapy, possibly due to feedback activation of the JAK-STAT pathway. Exploring the synergistic potential and underlying mechanisms of combining metformin with HDACi in TNBC treatment is crucial. METHODS: We predicted the synergistic effects of metformin and SAHA in TNBC using multiple computational methods (CMap, DTsyn, and DrugComb). We also developed a cancer-specific compound mimic library (CDTSL) and applied a three-step strategy to identify genes fitting the "metformin sensitization" model. Subsequently, we evaluated the synergistic effects of metformin and SAHA in TNBC cell lines through cell proliferation, colony formation, and apoptosis assays. Furthermore, we investigated the molecular mechanisms of the combined treatment using techniques such as transcriptome sequencing, chromatin immunoprecipitation (ChIP), Western blotting, and measurement of extracellular acidification rate (ECAR). Addit...