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

Histone lysine demethylase 1 (LSD1), the first identified histone demethylase, is overexpressed in multiple tumor types, including breast cancer. However, the mechanisms that cause LSD1 dysregulation in breast cancer remain largely unclear. Here, we report that protein arginine methyltransferase 4 (PRMT4 or CARM1) dimethylates LSD1 at R838, which promotes the binding of the deubiquitinase USP7, resulting in the deubiquitination and stabilization of LSD1. Moreover, CARM1- and USP7- dependent LSD1 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, LSD1 arginine methylation levels correlate with tumor grade in human malignant breast carcinoma samples. Our findings unveil a unique mechanism controlling LSD1 stability by arginine methylation, also highlighting the role of the CARM1-USP7-LSD1 axis in breast cancer progression.

组蛋白赖氨酸去甲基化酶1（Histone lysine demethylase 1, LSD1）是首个被鉴定的组蛋白去甲基化酶，在乳腺癌等多种肿瘤类型中呈现过表达状态。然而，乳腺癌中导致LSD1失调的分子机制目前仍未完全阐明。本研究发现，蛋白质精氨酸甲基转移酶4（protein arginine methyltransferase 4, PRMT4又称CARM1）可在LSD1的第838位精氨酸残基处催化二甲基化修饰，该修饰能够促进去泛素化酶USP7（deubiquitinase USP7）与LSD1的结合，进而介导LSD1的去泛素化并提升其蛋白稳定性。此外，依赖于CARM1与USP7的LSD1稳定化通路，可分别通过启动子区域组蛋白H3赖氨酸4二甲基化（H3K4Me2）与组蛋白H3赖氨酸9二甲基化（H3K9Me2）的去甲基化，实现对E-钙粘蛋白（E-cadherin）表达的抑制与波形蛋白（vimentin）转录的激活，最终促进乳腺癌细胞的侵袭与转移。临床样本验证结果一致显示，人类恶性乳腺癌组织中LSD1的精氨酸甲基化水平与肿瘤分级呈正相关。本研究揭示了一条通过精氨酸甲基化调控LSD1稳定性的独特分子机制，同时凸显了CARM1-USP7-LSD1信号轴在乳腺癌进展中的关键作用。