MTR4 drives liver tumorigenesis by promoting cancer metabolic switch through alternative splicing
MTR4 drives liver tumorigenesis by promoting cancer metabolic switch through alternative splicing
复制标题
MTR4通过选择性剪接促进癌症代谢转换来驱动肝脏肿瘤发生
DOI：
10.1038/s41467-020-14437-3
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发表时间：
2020-02-05
影响因子：
16.6
通讯作者：
Xu, Yang
中科院分区：
文献类型：
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作者：
Yu, Lili;Kim, Jinchul;Xu, Yang
从氧化磷酸化到糖酵解的代谢转换是肿瘤发生所必需的，以便为癌细胞提供生物合成的能量和底物。因此，阐明控制癌症代谢开关的机制是重要的。MTR 4是一种与核外泌体相关的RNA解旋酶，在RNA加工和监视中发挥关键作用。我们证明MTR 4在肝细胞癌（HCC）中经常过表达，并且是预测HCC患者预后不良的独立诊断标志物。MTR 4通过确保关键糖酵解基因如GLUT 1和PKM 2的前mRNA的正确选择性剪接来驱动癌症代谢。c-Myc与MTR 4基因的启动子结合，并且对于HCC细胞中MTR 4的表达是重要的，表明MTR 4是c-Myc在癌症代谢中的功能的介导物。这些发现揭示了MTR 4在癌症代谢开关中的重要作用，并将MTR 4作为治疗HCC的有希望的治疗靶点。
The metabolic switch from oxidative phosphorylation to glycolysis is required for tumorigenesis in order to provide cancer cells with energy and substrates of biosynthesis. Therefore, it is important to elucidate mechanisms controlling the cancer metabolic switch. MTR4 is a RNA helicase associated with a nuclear exosome that plays key roles in RNA processing and surveillance. We demonstrate that MTR4 is frequently overexpressed in hepatocellular carcinoma (HCC) and is an independent diagnostic marker predicting the poor prognosis of HCC patients. MTR4 drives cancer metabolism by ensuring correct alternative splicing of pre-mRNAs of critical glycolytic genes such asGLUT1andPKM2. c-Myc binds to the promoter of the MTR4 gene and is important for MTR4 expression in HCC cells, indicating that MTR4 is a mediator of the functions of c-Myc in cancer metabolism. These findings reveal important roles of MTR4 in the cancer metabolic switch and present MTR4 as a promising therapeutic target for treating HCC.