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.

中文翻译：

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精氨酸甲基化依赖性LSD1稳定性促进乳腺癌的侵袭和转移。

组蛋白赖氨酸去甲基化酶 1 (LSD1) 是第一个被识别的组蛋白去甲基化酶，在包括乳腺癌在内的多种肿瘤类型中过度表达。然而，导致乳腺癌中 LSD1 失调的机制仍不清楚。在此，我们报道蛋白质精氨酸甲基转移酶4（PRMT4或CARM1）在R838位点二甲基化LSD1，从而促进去泛素化酶USP7的结合，从而导致LSD1去泛素化和稳定化。此外，CARM1和USP7依赖的LSD1稳定在分别通过启动子H3K4me2和H3K9me2去甲基化抑制E-钙粘蛋白和激活波形蛋白转录方面发挥关键作用，从而促进乳腺癌细胞的侵袭和转移。一致地，LSD1 精氨酸甲基化水平与人类恶性乳腺癌样本中的肿瘤分级相关。我们的研究结果揭示了一种通过精氨酸甲基化控制 LSD1 稳定性的独特机制，也强调了 CARM1-USP7-LSD1 轴在乳腺癌进展中的作用。