Methylation‐associated silencing of miR‐9‐1 promotes nasopharyngeal carcinoma progression and glycolysis via HK2

• Published in: Cancer science Vol. 112; no. 10; pp. 4127 - 4138
• Main Authors: Xu, Qian‐Lan, Luo, Zan, Zhang, Bin, Qin, Guan‐Jie, Zhang, Ru‐Yun, Kong, Xiang‐Yun, Tang, Hua‐Ying, Jiang, Wei
• Format: Journal Article
• Language: English
• Published: Tokyo John Wiley & Sons, Inc 01.10.2021; John Wiley and Sons Inc
• Subjects: 3' Untranslated regions; Annealing; Binding sites; Cancer; Cell proliferation; DNA methylation; Ectopic expression; Fluorescence in situ hybridization; Gene expression; Glucose; Glycolysis; glycolysis metabolism; Hexokinase; HK2; Lactic acid; Metabolism; methylation; MicroRNAs; microRNA‐9‐1; miRNA; Nasopharyngeal carcinoma; Original; Tumor cell lines; Tumors; Western blotting; China
• ISSN: 1347-9032; 1349-7006
• DOI: 10.1111/cas.15103

Characteristically, cancer cells metabolize glucose through aerobic glycolysis, known as the Warburg effect. Accumulating evidence suggest that during cancer formation, microRNAs (miRNAs) could regulate such metabolic reprogramming. In the present study, miR‐9‐1 was identified as significantly hypermethylated in nasopharyngeal carcinoma (NPC) cell lines and clinical tissues. Ectopic expression of miR‐9‐1 inhibited NPC cell growth and glycolytic metabolism, including reduced glycolysis, by reducing lactate production, glucose uptake, cellular glucose‐6‐phosphate levels, and ATP generation in vitro and tumor proliferation in vivo. HK2 (encoding hexokinase 2) was identified as a direct target of miR‐9‐1 using luciferase reporter assays and Western blotting. In NPC cells, hypermethylation regulates miR‐9‐1 expression and inhibits HK2 translation by directly targeting its 3' untranslated region. MiR‐9‐1 overexpression markedly reduced HK2 protein levels. Restoration of HK2 expression attenuated the inhibitory effect of miR‐9‐1 on NPC cell proliferation and glycolysis. Fluorescence in situ hybridization results indicated that miR‐9‐1 expression was an independent prognostic factor in NPC. Our findings revealed the role of the miR‐9‐1/HK2 axis in the metabolic reprogramming of NPC, providing a potential therapeutic strategy for NPC. The miR‐9‐1 promoter is hypermethylated in nasopharyngeal carcinoma (NPC), thus decreasing its expression. Reduced miR‐9‐1 expression increases HK2 levels, thus increasing glycolysis. FISH score analysis showed that miR‐9‐1 is an independent prognostic factor in NPC.