Arginine methylation‐dependent LSD1 stability promotes invasion and metastasis of breast cancer

Histone lysine demethylase 1 ( LSD 1), the first identified histone demethylase, is overexpressed in multiple tumor types, including breast cancer. However, the mechanisms that cause LSD 1 dysregulation in breast cancer remain largely unclear. Here, we report that protein arginine methyltransferase 4 ( PRMT 4 or CARM 1) dimethylates LSD 1 at R838, which promotes the binding of the deubiquitinase USP 7, resulting in the deubiquitination and stabilization of LSD 1. Moreover, CARM 1‐ and USP 7‐dependent LSD 1 stabilization plays a key role in repressing E‐cadherin and activating vimentin transcription through promoter H3K4me2 and H3K9me2 demethylation, respectively, which promotes invasion and metastasis of breast cancer cells. Consistently, LSD 1 arginine methylation levels correlate with tumor grade in human malignant breast carcinoma samples. Our findings unveil a unique mechanism controlling LSD 1 stability by arginine methylation, also highlighting the role of the CARM 1‐ USP 7‐ LSD 1 axis in breast cancer progression.