CRAF Methylation by PRMT6 Regulates Aerobic Glycolysis-Driven Hepatocarcinogenesis via ERK-Dependent PKM2 Nuclear Relocalization and Activation
CRAF Methylation by PRMT6 Regulates Aerobic Glycolysis-Driven Hepatocarcinogenesis via ERK-Dependent PKM2 Nuclear Relocalization and Activation
复制标题
PRMT6介导的CRAF甲基化通过依赖于细胞外调节蛋白激酶（ERK）的丙酮酸激酶M2（PKM2）核重定位及激活，调控有氧糖酵解驱动的肝癌发生 。
DOI：
10.1002/hep.30923
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发表时间：
2020-01-24
期刊：
影响因子：
13.5
通讯作者：
Ma, Stephanie
中科院分区：
文献类型：
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作者：
Wong, Tin-Lok;Ng, Kai-Yu;Ma, Stephanie
背景和目的大多数肿瘤细胞使用有氧糖酵解（Warburg效应）来支持合成代谢生长，促进致瘤性和耐药。有趣的是，这种现象背后的分子机制还没有得到很好的理解。在这项工作中，我们在体外对患者来源的类器官和细胞培养以及体内正电子发射断层扫描-磁共振成像动物模型进行了功能获得和功能丧失的研究，我们发现蛋白精氨酸n-甲基转移酶6 （PRMT6）通过丙酮酸激酶M2异构体（PKM2）的核重定位调节人肝细胞癌（HCC）的有氧糖酵解，PKM2是Warburg效应的关键调节因子。方法和结果我们发现PRMT6在精氨酸100位点甲基化CRAF，干扰其RAS/RAF结合电位，从而改变细胞外信号调节激酶（ERK）介导的PKM2转运到细胞核。这种改变的PRMT6- erk - pkm2信号轴在内源性敲除PRMT6的HCC小鼠模型和HCC临床样本中得到进一步证实。我们还通过转录抑制因子1-沉默转录因子确定了PRMT6作为缺氧的靶标，将PRMT6与缺氧在驱动糖酵解事件中联系起来。最后，我们证明了使用2-脱氧葡萄糖（一种糖酵解抑制剂）在HCC中逆转PRMT6缺乏介导的致瘤性和索拉非尼耐药的治疗潜力。结论PRMT6-ERK-PKM2调控轴是肿瘤细胞Warburg效应的重要决定因素，并在致瘤性、索拉非尼耐药和糖代谢之间提供了机制联系。
Background and Aims Most tumor cells use aerobic glycolysis (the Warburg effect) to support anabolic growth and promote tumorigenicity and drug resistance. Intriguingly, the molecular mechanisms underlying this phenomenon are not well understood. In this work, using gain-of-function and loss-of-function in vitro studies in patient-derived organoid and cell cultures as well as in vivo positron emission tomography-magnetic resonance imaging animal models, we showed that protein arginine N-methyltransferase 6 (PRMT6) regulates aerobic glycolysis in human hepatocellular carcinoma (HCC) through nuclear relocalization of pyruvate kinase M2 isoform (PKM2), a key regulator of the Warburg effect. Approach and Results We found PRMT6 to methylate CRAF at arginine 100, interfering with its RAS/RAF binding potential, and therefore altering extracellular signal-regulated kinase (ERK)-mediated PKM2 translocation into the nucleus. This altered PRMT6-ERK-PKM2 signaling axis was further confirmed in both a HCC mouse model with endogenous knockout of PRMT6 as well as in HCC clinical samples. We also identified PRMT6 as a target of hypoxia through the transcriptional repressor element 1-silencing transcription factor, linking PRMT6 with hypoxia in driving glycolytic events. Finally, we showed as a proof of concept the therapeutic potential of using 2-deoxyglucose, a glycolysis inhibitor, to reverse tumorigenicity and sorafenib resistance mediated by PRMT6 deficiency in HCC. Conclusions Our findings indicate that the PRMT6-ERK-PKM2 regulatory axis is an important determinant of the Warburg effect in tumor cells, and provide a mechanistic link among tumorigenicity, sorafenib resistance, and glucose metabolism.