Metformin Impairs Breast Cancer Growth through the Inhibition of PRMT6

作者：Yinsheng Wu, Xinlin Xu, Tong Yue, Min Wang, Feng Ge, Min Wu, Yunlong Wang, Gang Chen, Xilan Yu, Shanshan Li · 发表于：Advanced Science · 年份：2025 · DOI：10.1002/advs.202508525 · 被引用次数：2 · 研究领域：Cancer-related gene regulation、Epigenetics and DNA Methylation、Wnt/β-catenin signaling in development and cancer

Metformin is the world's widely prescribed oral medication for the treatment of type 2 diabetes mellitus, which is also shown to repress tumorigenesis without a complete understanding of its therapeutic targets. Here, it is shown that metformin impairs the growth of breast cancer cells by inhibiting PRMT6, a protein arginine methyltransferase primarily responsible for asymmetric dimethylation of histone H3 arginine 2 (H3R2me2a). Mechanistically, metformin directly binds PRMT6 and inhibits its activity to methylate H3R2, leading to PRMT6 transcriptional repression and further reduces H3R2me2a. By decreasing PRMT6-catalyzed H3R2me2a, metformin enhances the chromatin association of UHRF1, an accessory factor of DNMT1 to promote DNA methylation and repress the transcription of DNA replication-associated genes, resulting in retarded DNA replication and cell cycle arrest. Metformin and a DNA replication inhibitor synergistically inhibit tumor growth. Furthermore, genetic disruption of the interaction between metformin and PRMT6 attenuates the inhibitory effect of metformin on breast cancer growth. Together, this work identifies a previously unrecognized mechanism for metformin to inhibit breast cancer growth.