Department of Cellular and Molecular Medicine and Faculty of Medicine, University of Ottawa, Ottawa, ON Canada.
Cell Cycle. 2012 Dec 15;11(24):4597-612. doi: 10.4161/cc.22871. Epub 2012 Nov 27.
Protein arginine methylation is catalyzed by protein arginine methyltransferases (PRMTs) and plays an important role in many cellular processes. Aberrant PRMT expression has been observed in several common cancer types; however, their precise contribution to the cell transformation process is not well understood. We previously reported that the PRMT1 gene generates several alternatively spliced isoforms, and our initial biochemical characterization of these isoforms revealed that they exhibit distinct substrate specificity and subcellular localization. We focus here on the PRMT1v2 isoform, which is the only predominantly cytoplasmic isoform, and we have found that its relative expression is increased in breast cancer cell lines and tumors. Specific depletion of PRMT1v2 using RNA interference caused a significant decrease in cancer cell survival due to an induction of apoptosis. Furthermore, depletion of PRMT1v2 in an aggressive cancer cell line significantly decreased cell invasion. We also demonstrate that PRMT1v2 overexpression in a non-aggressive cancer cell line was sufficient to render them more invasive. Importantly, this novel activity is specific to PRMT1v2, as overexpression of other isoforms did not enhance invasion. Moreover, this activity requires both proper subcellular localization and methylase activity. Lastly, PRMT1v2 overexpression altered cell morphology and reduced cell-cell adhesion, a phenomenon that we convincingly linked with reduced β-catenin protein expression. Overall, we demonstrate a specific role for PRMT1v2 in breast cancer cell survival and invasion, underscoring the importance of identifying and characterizing the distinct functional differences between PRMT1 isoforms.
蛋白质精氨酸甲基化是由蛋白质精氨酸甲基转移酶（PRMTs）催化的，在许多细胞过程中发挥重要作用。几种常见癌症类型中观察到异常的 PRMT 表达；然而，它们对细胞转化过程的确切贡献还不是很清楚。我们之前报道过 PRMT1 基因产生几种选择性剪接的异构体，我们对这些异构体的初始生化特性分析表明，它们表现出不同的底物特异性和亚细胞定位。我们在这里重点关注 PRMT1v2 异构体，它是唯一主要存在于细胞质中的异构体，我们发现其相对表达在乳腺癌细胞系和肿瘤中增加。使用 RNA 干扰特异性耗尽 PRMT1v2 会导致癌细胞存活显著下降，这是由于细胞凋亡的诱导。此外，在侵袭性癌细胞系中耗尽 PRMT1v2 会显著降低细胞侵袭。我们还证明，在非侵袭性癌细胞系中过表达 PRMT1v2 足以使它们更具侵袭性。重要的是，这种新的活性是 PRMT1v2 特有的，因为过表达其他异构体不会增强侵袭性。此外，这种活性需要适当的亚细胞定位和甲基转移酶活性。最后，PRMT1v2 过表达改变了细胞形态并减少了细胞间粘附，我们令人信服地将这种现象与 β-连环蛋白蛋白表达减少联系起来。总的来说，我们证明了 PRMT1v2 在乳腺癌细胞存活和侵袭中的特定作用，强调了识别和表征 PRMT1 异构体之间不同功能差异的重要性。
