Arginine Methylation of SREBP1a via PRMT5 Promotes De Novo Lipogenesis and Tumor Growth
Arginine Methylation of SREBP1a via PRMT5 Promotes De Novo Lipogenesis and Tumor Growth
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SREBP1a 通过 PRMT5 的精氨酸甲基化促进从头脂肪生成和肿瘤生长。
DOI：
10.1158/0008-5472.can-15-1766
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发表时间：
2016-03-01
期刊：
影响因子：
11.2
通讯作者：
Huang, Gang
中科院分区：
文献类型：
--
作者：
Liu, Liu;Zhao, Xiaoping;Huang, Gang
固醇调节元件结合转录因子固醇调节元件结合蛋白（SREBP）和SREBF的失调激活癌细胞中的高水平的从头脂肪生成，这是驱动恶性生长的关键事件。在这项研究中，我们确定了一个重要的翻译后机制，SREBP 1a在癌细胞的代谢重编程过程中受到调节。质谱分析显示，蛋白质精氨酸甲基转移酶5（PRMT 5）作为SREBP 1a的结合伴侣，在R321上对称地将其二甲基化，从而促进转录活性。此外，PRMT 5诱导的甲基化阻止了GSK 3 β对S430上的SREBP 1a的磷酸化，导致其与Fbw 7（FBXW 7）解离并通过泛素-蛋白酶体途径逃避降解。因此，甲基化稳定的SREBP 1a增加了从头脂肪生成，并加速了体内和体外癌细胞的生长。在临床上，R321对称二甲基化状态与人肝细胞癌的恶性进展相关，它是预后不良的独立危险因素。通过展示PRMT 5诱导的SREBP 1a甲基化如何触发脂质生物合成的超活化，这是肿瘤发生中的一个关键事件，我们的研究结果表明了一种选择性攻击肿瘤代谢的新的通用策略。
Dysregulation of the sterol regulatory element-binding transcription factors sterol regulatory element-binding protein (SREBP) and SREBF activates de novo lipogenesis to high levels in cancer cells, a critical event in driving malignant growth. In this study, we identified an important posttranslational mechanism by which SREBP1a is regulated during metabolic reprogramming in cancer cells. Mass spectrometry revealed protein arginine methyltransferase 5 (PRMT5) as a binding partner of SREBP1a that symmetrically dimethylated it on R321, thereby promoting transcriptional activity. Furthermore, PRMT5-induced methylation prevented phosphorylation of SREBP1a on S430 by GSK3β, leading to its disassociation from Fbw7 (FBXW7) and its evasion from degradation through the ubiquitin-proteasome pathway. Consequently, methylation-stabilized SREBP1a increased de novo lipogenesis and accelerated the growth of cancer cells in vivo and in vitro. Clinically, R321 symmetric dimethylation status was associated with malignant progression of human hepatocellular carcinoma, where it served as an independent risk factor of poor prognosis. By showing how PRMT5-induced methylation of SREBP1a triggers hyperactivation of lipid biosynthesis, a key event in tumorigenesis, our findings suggest a new generalized strategy to selectively attack tumor metabolism.