MiR-448 promotes glycolytic metabolism of gastric cancer by downregulating KDM2B
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Xuehui Hong1,2,*, Yang Xu3,*, Xingfeng Qiu1,*, Yuekun Zhu4, Xing Feng5, Zhijie Ding1, Shifeng Zhang1, Lifeng Zhong1, Yifan Zhuang1, Chen Su1, Xinya Hong6, Jianchun Cai1,2
1Department of Gastrointestinal Surgery, Zhongshan Hospital of Xiamen University, Xiamen, Fujian, China
2Institute of Gastrointestinal Oncology, Medical College of Xiamen University, Xiamen, Fujian, China
3Department of General Surgery, The Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, China
4Department of General Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin, China
5Department of Radiation Oncology, Cancer Institute of New Jersey, Rutgers University, New Brunswick, New Jersey, USA
6Department of Medical Imaging and Ultrasound, Zhongshan Hospital of Xiamen University, Xiamen, Fujian, China
*These authors contributed equally to this work
Jianchun Cai, e-mail: [email protected]
Keywords: miR-448, glucose metabolism, gastric cancer, lysine (K)-specific demethylase 2B, mitochondria respiration
Received: December 13, 2015 Accepted: February 23, 2016 Published: March 10, 2016
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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