Arginine methylation-dependent LSD1 stability promotes invasion and metastasis of breast cancer
Arginine methylation-dependent LSD1 stability promotes invasion and metastasis of breast cancer
复制标题
精氨酸甲基化依赖性LSD1稳定性促进乳腺癌侵袭和转移
DOI：
10.15252/embr.201948597
复制
发表时间：
2019-12-12
期刊：
影响因子：
7.7
通讯作者：
Lu, Jun
中科院分区：
文献类型：
--
作者：
Liu, Jiwei;Feng, Jingxin;Lu, Jun
组蛋白赖氨酸去甲基化酶1（LSD 1）是第一个被鉴定的组蛋白去甲基化酶，在多种肿瘤类型中过表达，包括乳腺癌。然而，导致乳腺癌中LSD 1失调的机制在很大程度上仍不清楚。在这里，我们报告了蛋白质精氨酸甲基转移酶4（PRMT 4或CARM 1）在R838处二甲基化LSD 1，这促进了去泛素化酶USP 7的结合，导致LSD 1的去泛素化和稳定化。此外，CARM 1和USP 7依赖性LSD 1稳定化分别通过启动子H3 K4 me 2和H3 K9 me 2去甲基化在抑制E-钙粘蛋白和激活波形蛋白转录中起关键作用，这促进了乳腺癌细胞的侵袭和转移。一致地，LSD 1精氨酸甲基化水平与人类恶性乳腺癌样品中的肿瘤分级相关。我们的发现揭示了通过精氨酸甲基化控制LSD 1稳定性的独特机制，也强调了CARM 1-USP 7-LSD 1轴在乳腺癌进展中的作用。
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.