MTR4 drives liver tumorigenesis by promoting cancer metabolic switch through alternative splicing

Yu, Lili; Kim, Jinchul; Jiang, Lei; Feng, Bingbing; Ying, Yue; Ji, Kai-yuan; Tang, Qingshuang; Chen, Wancheng; Mai, Taoyi; Dou, Wenlong; Zhou, Jianlong; Xiang, Le-yang; He, Yang-fan; Yang, Dinghua; Li, Qingjiao; Fu, Xuemei; Xu, Yang
February 2020
Nature Communications;2/5/2020, Vol. 11 Issue 1, p1
Academic Journal
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 as GLUT1 and PKM2. 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. Aberrant alternative splicing has been shown to contribute to the tumorigenic processes. Here, the authors show that MTR4 is overexpressed in hepatocellular carcinoma and has a role in tumorigenesis through the modulation of the splicing of glycolytic genes PKM2 and GLUT1.


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