Methylation of C/EBPa by PRMT1 Inhibits Its Tumor-Suppressive Function in Breast Cancer
Methylation of C/EBPa by PRMT1 Inhibits Its Tumor-Suppressive Function in Breast Cancer
复制标题
PRMT1对C/EBPα的甲基化抑制其在乳腺癌中的肿瘤抑制功能
DOI：
10.1158/0008-5472.can-18-3211
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发表时间：
2019-06-01
期刊：
影响因子：
11.2
通讯作者：
Zhang, Ye
中科院分区：
文献类型：
--
作者：
Liu, Li-Ming;Sun, Wen-Zheng;Zhang, Ye
C/EBPa是参与调节某些细胞周期调节剂（包括乳腺癌细胞）的表达或功能的重要转录因子。虽然蛋白质精氨酸甲基转移酶已被证明在多种癌症中发挥致癌作用，但关于精氨酸甲基化在调节C/EBPa的抗增殖活性中的作用知之甚少。在这里，我们报告，蛋白质精氨酸甲基转移酶1（PRMT 1）在人类乳腺癌中过表达，PRMT 1升高与癌症恶性程度相关。RNA测序分析显示，乳腺癌细胞中PRMT 1的敲除伴随着促增殖基因（包括细胞周期蛋白D1）表达的减少。此外，串联亲和纯化，然后质谱鉴定PRMT 1作为C/EBPa复合物的组分。C/EBPa与PRMT 1相关，并在三个精氨酸残基（R35，R156和R165）处被PRMT 1甲基化。PRMT 1依赖的C/EBPa甲基化通过阻断C/EBPa与其辅阻遏物HDAC 3的相互作用促进cyclin D1的表达，从而导致乳腺癌发病过程中肿瘤细胞的快速生长。PRMT 1的抑制显著阻碍了三阴性乳腺癌患者癌细胞的生长。PRMT 1介导C/EBPa甲基化的证据揭示了乳腺癌中的新途径和潜在治疗靶点。意义：本研究为精氨酸甲基转移酶PRMT 1在乳腺癌发病机制中的作用提供了新的机制见解。
C/EBPa is an essential transcription factor involved in regulating the expression or function of certain cell-cycle regulators, including in breast cancer cells. Although protein arginine methyltransferases have been shown to play oncogenic roles in a variety of cancers, little is known about the role of arginine methylation in regulating the antiproliferation activity of C/EBPa. Here, we report that the protein arginine methyltransferase 1 (PRMT1) is overexpressed in human breast cancer and that elevated PRMT1 correlates with cancer malignancy. RNA-sequencing analysis revealed that knockdown of PRMT1 in breast cancer cells is accompanied by a decrease in the expression of pro-proliferative genes, including cyclin D1. Furthermore, tandem affinity purification followed by mass spectrometry identified PRMT1 as a component of the C/EBPa complex. C/EBPa associated with and was methylated by PRMT1 at three arginine residues (R35, R156, and R165). PRMT1-dependent methylation of C/EBPa promoted the expression of cyclin D1 by blocking the interaction between C/EBPa and its corepressor HDAC3, which resulted in rapid growth of tumor cells during the pathogenesis of breast cancer. Inhibition of PRMT1 significantly impeded the growth of cancer cells from patients with triple-negative breast cancer. This evidence that PRMT1 mediates C/EBPa methylation sheds light on a novel pathway and potential therapeutic target in breast cancer. Significance: This study provides novel mechanistic insight of the role of the arginine methyltransferase PRMT1 in breast cancer pathogenesis.