# Metformin Impairs Breast Cancer Growth through the Inhibition of PRMT6

## TL;DR

Metformin fights breast cancer by inhibiting PRMT6, a protein that affects DNA methylation and cell replication.

## Contribution

PRMT6 is identified as a novel anti-cancer target for metformin.

## Key findings

- Metformin directly binds and inhibits PRMT6 activity, reducing H3R2me2a.
- PRMT6 inhibition by metformin enhances DNA methylation and causes DNA replication defects.
- Disrupting metformin-PRMT6 interaction reduces metformin's anti-cancer effect.

## Abstract

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.

Metformin has a biological activity against breast cancer. However, it is largely unknown about its precise therapeutic targets. Here, histone arginine methyltransferase PRMT6 is identified as a new anti‐cancer target for metformin. Metformin directly binds PRMT6 and inhibits its ability to catalyze histone H3R2 asymmetric dimethylation (H3R2me2a), which then enhances DNMT1‐catalyzed DNA methylation (5mC), resulting in DNA replication defects and cell cycle arrest.