McArdle Laboratory for Cancer Research, University of Wisconsin-Madison, Madison, WI 53706, USA.
Department of Biochemistry, University of Wisconsin-Madison, Madison, WI 53706, USA.
Cancer Cell. 2014 Jan 13;25(1):21-36. doi: 10.1016/j.ccr.2013.12.007.
Coactivator-associated arginine methyltransferase 1 (CARM1), a coactivator for various cancer-relevant transcription factors, is overexpressed in breast cancer. To elucidate the functions of CARM1 in tumorigenesis, we knocked out CARM1 from several breast cancer cell lines using Zinc-Finger Nuclease technology, which resulted in drastic phenotypic and biochemical changes. The CARM1 KO cell lines enabled identification of CARM1 substrates, notably the SWI/SNF core subunit BAF155. Methylation of BAF155 at R1064 was found to be an independent prognostic biomarker for cancer recurrence and to regulate breast cancer cell migration and metastasis. Furthermore, CARM1-mediated BAF155 methylation affects gene expression by directing methylated BAF155 to unique chromatin regions (e.g., c-Myc pathway genes). Collectively, our studies uncover a mechanism by which BAF155 acquires tumorigenic functions via arginine methylation.
辅激活因子相关精氨酸甲基转移酶 1（CARM1）是多种与癌症相关转录因子的辅激活因子，在乳腺癌中过表达。为了阐明 CARM1 在肿瘤发生中的作用，我们使用锌指核酸酶技术从几种乳腺癌细胞系中敲除了 CARM1，这导致了明显的表型和生化变化。CARM1 KO 细胞系能够鉴定 CARM1 的底物，特别是 SWI/SNF 核心亚基 BAF155。发现 BAF155 在 R1064 上的甲基化是癌症复发的独立预后生物标志物，并调节乳腺癌细胞迁移和转移。此外，CARM1 介导的 BAF155 甲基化通过将甲基化的 BAF155 引导到独特的染色质区域（例如，c-Myc 通路基因）来影响基因表达。总之，我们的研究揭示了一种机制，即通过精氨酸甲基化，BAF155 获得致癌功能。
