m6A-dependent glycolysis enhances colorectal cancer progression
m6A-dependent glycolysis enhances colorectal cancer progression
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m6A 依赖性糖酵解促进结直肠癌进展
DOI：
10.1186/s12943-020-01190-w
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发表时间：
2020-04-03
期刊：
影响因子：
37.3
通讯作者：
Hong, Jie
中科院分区：
文献类型：
--
作者：
Shen, Chaoqin;Xuan, Baoqin;Hong, Jie
非遗传改变涉及结直肠癌发生的各个方面。rna的n6 -甲基腺苷（m6A）修饰是表观遗传调控的一个新层面。作为真核生物mRNA最丰富的化学修饰，m6A对mRNA的稳定性、剪接和翻译的调控至关重要。m6A调控基因的改变在多种人类疾病的发病机制中起着重要作用。然而，这种mRNA修饰是否参与结直肠癌（CRC）的葡萄糖代谢尚不清楚。方法采用转录组测序和液相色谱-串联质谱（LC-MS）分析m6A修饰与CRC中葡萄糖代谢的相关性。通过质谱代谢组学分析、体外和体内实验研究METTL3对结直肠癌糖酵解和肿瘤发生的影响。通过RNA merip测序、免疫沉淀和RNA稳定性分析，探讨METTL3在结直肠癌中的分子机制。结果徐州市中心医院结直肠癌患者METTL3与18f - fdg摄取有较强相关性。在多种CRC模型中，METTL3诱导的CRC肿瘤发生依赖于细胞糖酵解。在机制上，METTL3直接作用于hk2的5′/3′utr区和slc2a1 （GLUT1）的3′utr区，进一步稳定了这两个基因，激活了糖酵解途径。m6A介导的hk2和slc2a1 （GLUT1）稳定分别依赖于m6A读取器IGF2BP2或IGF2BP2/3。结论smettl3在结直肠癌中具有功能性和临床意义。METTL3通过m6A-IGF2BP2/3依赖机制稳定CRC中hk2和slc2a1 （GLUT1）的表达。靶向METTL3及其通路为结直肠癌高糖代谢患者提供了替代的合理治疗靶点。
BackgroundEpigenetic alterations are involved in various aspects of colorectal carcinogenesis.N6-methyladenosine (m6A) modifications of RNAs are emerging as a new layer of epigenetic regulation. As the most abundant chemical modification of eukaryotic mRNA, m6A is essential for the regulation of mRNA stability, splicing, and translation. Alterations of m6A regulatory genes play important roles in the pathogenesis of a variety of human diseases. However, whether this mRNA modification participates in the glucose metabolism of colorectal cancer (CRC) remains uncharacterized.MethodsTranscriptome-sequencing and liquid chromatography-tandem mass spectrometry (LC-MS) were performed to evaluate the correlation between m6A modifications and glucose metabolism in CRC. Mass spectrometric metabolomics analysis, in vitro and in vivo experiments were conducted to investigate the effects of METTL3 on CRC glycolysis and tumorigenesis. RNA MeRIP-sequencing, immunoprecipitation and RNA stability assay were used to explore the molecular mechanism of METTL3 in CRC.ResultsA strong correlation between METTL3 and18F-FDG uptake was observed in CRC patients from Xuzhou Central Hospital. METTL3 induced-CRC tumorigenesis depends on cell glycolysis in multiple CRC models. Mechanistically, METTL3 directly interacted with the 5′/3’UTR regions ofHK2, and the 3’UTR region ofSLC2A1(GLUT1), then further stabilized these two genes and activated the glycolysis pathway. M6A-mediatedHK2andSLC2A1(GLUT1) stabilization relied on the m6A reader IGF2BP2 or IGF2BP2/3, respectively.ConclusionsMETTL3 is a functional and clinical oncogene in CRC. METTL3 stabilizesHK2andSLC2A1(GLUT1) expression in CRC through an m6A-IGF2BP2/3- dependent mechanism. Targeting METTL3 and its pathway offer alternative rational therapeutic targets in CRC patients with high glucose metabolism.