PRMT5 甲基化 SMAD4 激活 TGF-β 信号通路并促进结直肠癌转移。
PRMT5 methylating SMAD4 activates TGF-β signaling and promotes colorectal cancer metastasis.
发表日期：2023 Mar 29
作者：
Anyi Liu, Chengxin Yu, Cheng Qiu, Qi Wu, Changsheng Huang, Xun Li, Xiaowei She, Kairui Wan, Lang Liu, Mao Li, Zhihong Wang, Yaqi Chen, Fuqing Hu, Da Song, Kangdi Li, Chongchong Zhao, Haiteng Deng, Xuling Sun, Feng Xu, Senyan Lai, Xuelai Luo, Junbo Hu, Guihua Wang
来源：
ONCOGENE
摘要：
转化生长因子-β（TGF-β）信号通路的干扰可能导致多种疾病，包括癌症。SMAD复合物的配体突变和翻译后修饰（PTMs）有助于TGF-β信号的失调。我们报道了SMAD4的一种PTM——R361甲基化，在SMAD复合物的形成和TGF-β信号的激活中发挥关键作用。通过质谱、共免疫沉淀（Co-IP）和免疫荧光（IF）分析，我们发现在TGF-β1处理下，致癌基因精氨酸甲基转移酶5（PRMT5）与SMAD4相互作用。机械上，PRMT5触发SMAD4在R361处的甲基化，诱导SMAD复合物的形成和核导入。此外，我们强调了PRMT5相互作用和甲基化SMAD4在TGF-β1诱导的上皮-间充质转化（EMT）和结直肠癌（CRC）转移中的必要性，SMAD4 R361突变减弱了PRMT5和TGF-β1诱导的转移。此外，高表达PRMT5或高水平的SMAD4 R361甲基化在临床样本分析中预示着更糟的结果。总之，我们的研究凸显了PRMT5和SMAD4的关键互动以及SMAD4 R361甲基化在转移过程中控制TGF-β信号的作用。我们为SMAD4的激活提供了新的见解。这项研究表明，阻断PRMT5-SMAD4信号传导可能是治疗SMAD4野生型CRC的有效策略。©2023年。作者（们）独家许可Springer Nature有限公司。
Perturbations in transforming growth factor-β (TGF-β) signaling can lead to a plethora of diseases, including cancer. Mutations and posttranslational modifications (PTMs) of the partner of SMAD complexes contribute to the dysregulation of TGF-β signaling. Here, we reported a PTM of SMAD4, R361 methylation, that was critical for SMAD complexes formation and TGF-β signaling activation. Through mass spectrometric, co-immunoprecipitation (Co-IP) and immunofluorescent (IF) assays, we found that oncogene protein arginine methyltransferase 5 (PRMT5) interacted with SMAD4 under TGF-β1 treatment. Mechanically, PRMT5 triggered SMAD4 methylation at R361 and induced SMAD complexes formation and nuclear import. Furthermore, we emphasized that PRMT5 interacting and methylating SMAD4 was required for TGF-β1-induced epithelial-mesenchymal transition (EMT) and colorectal cancer (CRC) metastasis, and SMAD4 R361 mutation diminished PRMT5 and TGF-β1-induced metastasis. In addition, highly expressed PRMT5 or high level of SMAD4 R361 methylation indicated worse outcomes in clinical specimens analysis. Collectively, our study highlights the critical interaction of PRMT5 and SMAD4 and the roles of SMAD4 R361 methylation for controlling TGF-β signaling during metastasis. We provided a new insight for SMAD4 activation. And this study indicated that blocking PRMT5-SMAD4 signaling might be an effective targeting strategy in SMAD4 wild-type CRC.© 2023. The Author(s), under exclusive licence to Springer Nature Limited.