MiR-448 promotes glycolytic metabolism of gastric cancer by downregulating KDM2B.
MiR-448 promotes glycolytic metabolism of gastric cancer by downregulating KDM2B.
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DOI：
10.18632/oncotarget.8020
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发表时间：
2016-04-19
期刊：
影响因子：
--
通讯作者：
Cai J
中科院分区：
文献类型：
--
作者：
Hong X;Xu Y;Qiu X;Zhu Y;Feng X;Ding Z;Zhang S;Zhong L;Zhuang Y;Su C;Hong X;Cai J
MicroRNA在包括胃癌（GC）在内的各种人类癌症中至关重要。然而，GC发展的潜在机制仍然难以捉摸。在这项研究中，我们证明了miR-448在GC样品和细胞系中增加。miR-448的过表达通过刺激糖酵解促进GC细胞的增殖。从机制上讲，我们鉴定了KDM 2B，甲基化CpG的阅读器，作为miR-448的靶标，其抑制糖酵解并促进氧化磷酸化。miR-448的过表达降低了KDM 2B的mRNA和蛋白水平，而KDM 2B的再表达消除了miR-448介导的糖酵解活性。此外，我们发现Myc是KDM 2B的关键靶标，其控制GC中的代谢开关。重要的是，一组81例胃癌组织显示，miR-448水平与一组糖酵解基因密切相关，其中KDM 2B显示出最强的反相关系数。此外，miR-448水平升高与GC患者的不良临床结局显著相关。因此，我们确定了一种以前未被认识到的机制，通过该机制，miR-448协调表观遗传、转录和代谢网络以促进GC进展，这表明了针对癌症代谢途径的治疗干预的可能性。
MicroRNAs are critical in various human cancers, including gastric cancer (GC). However, the mechanism underlying the GC development remains elusive. In this study, we demonstrate that miR-448 is increased in GC samples and cell lines. Overexpression of miR-448 facilitated the proliferation of GC cells by stimulating glycolysis. Mechanistically, we identified KDM2B, a reader for methylated CpGs, as the target of miR-448 that represses glycolysis and promotes oxidative phosphorylation. Overexpression of miR-448 reduced both the mRNA and protein levels of KDM2B, whereas KDM2B re-expression abrogated the miR-448-mediated glycolytic activities. Furthermore, we discovered Myc as a key target of KDM2B that controls metabolic switch in GC. Importantly, a cohort of 81 GC tissues revealed that miR-448 level closely associated with a battery of glycolytic genes, in which KDM2B showed the strongest anti-correlation coefficient. In addition, enhanced miR-448 level was significantly associated with poor clinical outcomes of GC patients. Hence, we identified a previously unappreciated mechanism by which miR-448 orchestrate epigenetic, transcriptional and metabolic networks to promote GC progression, suggesting the possibility of therapeutic intervention against cancer metabolic pathways.
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