Department of Epigenetics & Molecular Carcinogenesis, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
Department of Epigenetics & Molecular Carcinogenesis, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
J Biol Chem. 2023 Sep;299(9):105124. doi: 10.1016/j.jbc.2023.105124. Epub 2023 Aug 1.
Coactivator-associated arginine methyltransferase 1 (CARM1) is an arginine methyltransferase that posttranslationally modifies proteins that regulate multiple levels of RNA production and processing. Its substrates include histones, transcription factors, coregulators of transcription, and splicing factors. CARM1 is overexpressed in many different cancer types, and often promotes transcription factor programs that are co-opted as drivers of the transformed cell state, a process known as transcription factor addiction. Targeting these oncogenic transcription factor pathways is difficult but could be addressed by removing the activity of the key coactivators on which they rely. CARM1 is ubiquitously expressed, and its KO is less detrimental in embryonic development than deletion of the arginine methyltransferases protein arginine methyltransferase 1 and protein arginine methyltransferase 5, suggesting that therapeutic targeting of CARM1 may be well tolerated. Here, we will summarize the normal in vivo functions of CARM1 that have been gleaned from mouse studies, expand on the transcriptional pathways that are regulated by CARM1, and finally highlight recent studies that have identified oncogenic properties of CARM1 in different biological settings. This review is meant to kindle an interest in the development of human drug therapies targeting CARM1, as there are currently no CARM1 inhibitors available for use in clinical trials.
辅激活因子相关精氨酸甲基转移酶 1（CARM1）是一种精氨酸甲基转移酶，可对调节 RNA 生成和加工多个水平的蛋白质进行翻译后修饰。其底物包括组蛋白、转录因子、转录共激活因子和剪接因子。CARM1 在许多不同的癌症类型中过表达，并且经常促进转录因子程序被篡夺为转化细胞状态的驱动因素，这一过程称为转录因子成瘾。靶向这些致癌转录因子途径很困难，但可以通过去除它们所依赖的关键共激活因子的活性来解决。CARM1 广泛表达，其 KO 在胚胎发育中比缺失精氨酸甲基转移酶蛋白精氨酸甲基转移酶 1 和蛋白精氨酸甲基转移酶 5 的危害更小，这表明针对 CARM1 的治疗性靶向可能具有良好的耐受性。在这里，我们将总结从小鼠研究中获得的 CARM1 的正常体内功能，扩展受 CARM1 调节的转录途径，并最终强调最近的研究，这些研究确定了 CARM1 在不同生物环境中的致癌特性。这篇综述旨在激发人们对开发针对 CARM1 的人类药物疗法的兴趣，因为目前尚无 CARM1 抑制剂可用于临床试验。
